naproxcinod, a new cyclooxygenase-inhibiting nitric oxide donator (cinod)

Drug Evaluation

10.1517/14712590902926071 © 2009 Informa UK Ltd ISSN 1471-2598 649All rights reserved: reproduction in whole or in part not permitted

Naproxcinod,anewcyclooxygenase-inhibitingnitricoxidedonator(CINOD)Piet GeusensUniversity Hasselt, Biomedical Research Institute, Belgium

Background: COX-inhibiting nitric oxide donators (CINODs) are a new class of drugs that combine the actions of the parent COX inhibitor with nitric oxide (NO), with the aim of reducing potential toxicity of the parent drug, while maintaining its analgesic and anti-inflammatory effects. AZD3582 (Naproxcinod®) is the first in the class of CINODs. Objective/methods: To review the effects of NO donation, CINODS in general and naproxen in osteoarthritis (OA), based on literature in PubMed. Results: In preclinical and human studies, this drug produced similar analgesic and anti-inflammatory effects to its parent naproxen, with improved gastrointestinal safety in OA patients. The results of recent clinical trials, which were designed to study effects on blood pressure, are expected shortly, after peer-review. Conclusions: As naproxen is considered the safest COX inhibitor choice from a cardiovascular perspective, AZD3582 has the potential to become a new drug treatment in patients with OA, in whom pain and function are not controlled by the use of analgesics.

Keywords: CINODs, cycloogenase-inhibiting nitric oxide donators, Naproxcinod, osteoarthritis

Expert Opin. Biol. Ther. (2009) 9(5):649-657

1. Introduction

Osteoarthritis (OA) is one of most common joint diseases worldwide and is characterised by joint pain, stiffness, impairment of physical function and significant economic burden on both patients and the health-care systems [1].

Several guidelines on the management of OA are available [2-9]. The most recent guidelines are available from the Osteoarthritis Society International (OARSI) on hip and knee OA, the European League Against Rheumatism (EULAR) on hand, hip and knee OA and the National Institute for Health and Clinical Excellence (NICE) on all OA [3,6-9]. They recommend that a combination of pharmacological and non-pharmacological modalities is the most effective strategy to manage the pain and disability associated with OA. They recommend acetamino-phen as first-line pharmacological therapy. In the event of inadequate response, a switch to NSAIDs is advocated at the lowest effective dose and, in patients with increased gastrointestinal risk, the addition of proton pump inhibitors (PPI) or misoprostol followed by monitoring of the patient. The American Heart Association (AHA) recently issued a different statement that included a stepped care approach, starting with nonpharmacological approach, followed by acetaminophen, full doses of aspirin or short term narcotics and, in non-responders, a switch to non-selective NSAIDs, and only to COX-2-selective NSAIDs in the event of failure of this approach [10]. However, this statement resulted in several concerns and controversies, including the need to take into consideration the gastrointestinal (GI) tolerance [11].

NSAIDs are widely used by patients with acute or chronic pain due to OA [5,12,13]. Non-selective NSAIDs inhibit COX-1 and COX-2 and increase the relative risk of perforation, clinically manifest ulcer and bleeding (PUBs) and perforation,

1. Introduction

2. COX-inhibiting nitric oxide

donators (CINODs)

3. NO-Naproxen AZD3582

(Naproxcinod®)

4. Conclusions and expert opinion

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650 ExpertOpin.Biol.Ther.(2009) 9(5)

obstruction, bleeding (POBs) by 2.7 – 5.4 [14-16]. OA and RA patients were found to be 2.5 – 5.5 times more hospitalized for nonselective NSAID-related GI events than the general population [17] and 5 – 10% of PUB’s are fatal [18].

COX-2-selective inhibitors have been developed based on the finding that the COXs that are constitutively involved in the physiology of the GI mucosa (COX-1) are different from the ones that are inducible by inflammation (COX-2) [19-21]. Therefore, selective inhibition of COX-2 could dissociate anti-inflammatory activity from GI side effects. In this way, COX-2-selective inhibitors should reduce clinically manifest ulcers and ulcer complications compared with non-selective NSAIDs, meanwhile exerting similar effects on acute pain and chronic pain in patients with OA or rheumatoid arthritis (RA).

During the course of randomised clinical studies and postmarketing surveys, it became clear that selective COX-2 inhibitors could be associated with an increased incidence of cardiovascular (CV) thrombotic events, including stroke and particularly myocardial infarction (MI), as demonstrated in the Vioxx GI Outcomes Research (VIGOR) study, in which the risk of myocardial infarction was higher in RA-patients treated with rofecoxib than in naproxen users [22]. At that time, it was debated whether this difference in CV risk was the result of a protective effect of naproxen on the incidence of myocardial infarction (MI) [22], or a consequence (side-effect) of the use of COX2 inhibitors. However, in studies developed to observe whether the use of COX-2 inhibitors protected against the occurrence of colonic polyps, it has become clear that rofecoxib, as compared with placebo, doubles the risk of thrombotic events, mainly MI and ischemic CV events [23,24]. Also for other COX-2 inhibitors, celecoxib and valdecoxib, an elevated cardiovascular risk has been shown [25,26].

Although the exact mechanism of this association is still unclear, the balance between prostacyclin (PGI2) and thromboxane A2 (TXA2) is presumably shifted to an increased risk for thrombo-embolic events [21]. It has been suggested that COX-2 is upregulated in vascular segments under conditions of increased vascular shear stress, and that the reduction of endovascular production of prostacyclin by the use of COX-2 inhibitors induces an elevated risk of vascular thrombotic events [27].

Several clinical trials have been performed to study both the GI and CV safety of COX2 (Tables 1 – 3), including VIGOR (rofecoxib versus naproxen) [22], Celecoxib Long-term Arthritis Safety Study (CLASS; celecoxib versus diclofenac and ibuprofen) [28], Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL; etoricoxib versus diclofenac in a pooled analysis) [29,30], and Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET; lumiracoxib versus ibuprofen and naproxen) [31,32].

These studies differed between each other in many aspects. Differences included indications for treatment (OA and/or RA), number of patients included (between 8059 and 37,701), the comparator non-selective NSAIDs (naproxen, diclofenac

or ibuprofen; none was placebo-controlled), duration of the study (6 – 36 months), exclusion or not because of history of GI risks/events, allowance of GI protection during the study, definitions of upper GI side effect endpoints, exclusion or not because of history of CV risks/events, use or not of low dose aspirin, and definitions of CV side effect endpoints.

In these studies, rofecoxib and etoricoxib decreased the risk of GI event endpoints (Table 1), but the size and significance of effects according to definitions of GI events differed between the drugs. Celecoxib did not decrease the primary GI endpoint (POBs) over the entire duration of the study, but significantly reduced the risk of GI events when symptomatic ulcers were included in the analysis [28].

In these studies, rofecoxib increased the risk of MI (hazard ratio(HR) 4.25, confidence interval (CI) 1.39 – 17.37) [22], which was the reason for withdrawal of rofecoxib (Vioxx®) from the market in September 2004. Low-dose celecoxib and etoricoxib did not affect the risk of pre-specified composite CV endpoints in the total group of patients and in specified subgroups (on low dose aspirin or not) as compared with their comparator non-selective NSAID(s) (Table 2) [28-30]. Lumira-coxib, another COX-2-selective NSAID, showed a similar incidence of CV side effects as compared with naproxen or ibuprofen, but is meanwhile withdrawn from the market because of potential hepatotoxicity [33].

Also, non-selective NSAIDs, such as ibuprofen [34], diclofenac [34], but probably not naproxen [34] and even paracetamol [35] have been associated with an increased risk of CV events compared with placebo in meta-analyses. Patients on celecoxib had fewer side effects on renal function and blood pressure than those on diclofenac (Table 3) [28]. Patients on etoricoxib had more oedema (at high dose) and more hypertension than those on diclofenac [29,30]. Patients on lumiracoxib had more renal side effects than those on naproxen and diclofenac [31,32]. The use of conventional non-selective NSAIDs is associated with oedema, congestive heart failure, cardiac arrhythmias and an increased risk of cardiovascular events [36-39].

In a recent review, [40] it was concluded that changes in CV risk are linked to inhibition of COX-2 inhibition and dose-driven, and have been documented for selective and non-selective COX inhibitors. One exception was naproxen, that at standard twice-daily doses provided sustained inhi-bition of platelet COX-1 [40]. In addition, a systematic review of observational studies indicated that naproxen was neutral in terms of CV safety [41,42] and therefore consid-ered the safest COX inhibitor choice from a cardiovascular perspective [41,42].

In this context, it was realised that the development and choice of new selective or non-selective NSAIDs had to be evaluated in the broad context of both GI and CV safety and protection [28-32]. I review the effect of NO donation, COX-inhibiting nitric oxide donators (CINODS) in general and the CINOD of naproxen in OA, based on relevant literature found in PubMed.

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Table1.GIendpointsinstudiesofselectiveCOX2inhibitors.

Drug(ref.) Study GIprotectionallowedinstudy

GIendpoints Hazardratio’s,relativerisks(RR)orincidence(%)ofupperGIriskendpoints(All)

Rofecoxib [22] VIGOR Yes Confirmed POBU 0.5 (0.3 – 0.6)

Complicated GI (POB) 0.4 (0.2 – 0.8)

Celecoxib [28] CLASS No POB RR: 0.53 (0.26 – 1.11)‡

Symptomatic U + POB RR: 0.59 (0.38 – 0.94)‡

Etoricoxib [29,30] MEDAL Yes Clinical POBU* All 0.69 (0.57 – 0.83)‡

No PPI 0.62 (0.45 – 0.83)‡

+ PPI 0.74 (0.58 – 0.95)§

Complicated GI (POB)* All 0.91 (0.67 – 1.24)

No PPI 1.03 (0.70 – 1.52)

+ PPI 0.72 (0.42 – 1.22)

Uncomplicated U* All 0.57 (0.45 – 0.74)§

No PPI 0.58 (0.41 – 0.81)‡

+ PPI 0.57 (0.39 – 0.83)§

Lumiracoxib [31,32] TARGET No Definite or probable complicated U (POB)

Versus ibuprofen + naproxen

0.34 (0.22 – 0.52)‡

Versus ibuprofen 0.29 (0.14 – 0.59)‡

Versus naproxen 0.37 (0.22 – 0.63)‡

*No treatment-by-subgroup interaction.‡Significant in subgroup of patients without aspirin.§Significant in subgroups of patients with and without aspirin.

B: Bleeding; CLASS: Celecoxib Long-term Arthritis Safety Study; GI: Gastrointestinal; MEDAL: Multinational Etoricoxib and Diclofenac Arthritis Long-term; O: Obstruction;

P: Perforation; PPI: Proton pump inhibitors; TARGET: Therapeutic Arthritis Research and Gastrointestinal Event Trial; U: Ulcer; VIGOR: Vioxx GI Outcomes Research.

2. COX-inhibitingnitricoxidedonators(CINODs)

CINODs are a new class of anti-inflammatory and analgesic drugs for the treatment of acute and chronic pain. CINODS have a multi-pathway mechanism combining the action of COX-1 and COX-2 inhibition and nitric oxide donation. The role of NO has recently be reviewed in detail, and readers are also referred to these publications for additional detailed references for preclinical studies [1,43-50].

2.1 PreclinicalstudieswithNOandCINODsNO has a complex mechanism of action and its role in the cellular metabolism of chondrocytes has a dual effect on the joint. NO has pro-inflammatory and catabolic potency, but has also been shown to play a protective role in the joint. These contrasting effects are considered to be concentration and/or time dependent [43,44].

NO cooperates with endogenous prostaglandins (PGs) in the maintenance of gastric mucosa integrity and microcircu-lation [51,52], by enhancing gastric mucus/alkaline secretion and inhibiting gastric acid secretion [51]. NO was also demonstrated

to be an important modulator of adhesive interactions between leucocytes and the vascular endothelium, as demonstrated in single-venule experiments using in vivo video microscopy [53]. These findings raised the possibility that NO could be GI protective in NSAID-induced gastric damage that is charac-terized by increased leukocyte adherence, reduced gastric blood flow and impaired mucosal repair [43]. Indeed, it has been shown that NSAID-induced acute gastric mucosal damage is a neutrophyl-dependent process, which was not found in immunodepleted rats and in rats treated with monoclonal antibodies directed against adhesion leukocyte or endothelial adhesion molecules [43].

In animal studies, CINODs produced substantially less GI damage than the parent NSAID, including acetaminophen, aspirin, ketoprofen and naproxen [43], despite markedly inhibiting gastric PG synthesis [43,54,55]. In rats, CINODS did not cause the decrease in GI mucosal blood flow following administration of the parent NSAID, did not interfere with the healing of pre-existing gastric ulcers, and resulted in some cases in accelerated experimental gastric ulcer healing [54,56-59].

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Table2.CardiovascularendpointsinstudiesofselectiveCOX2inhibitors.

Drug(ref.) Study Aspirinallowed CVendpoints Hazardratio’sorincidenceofCVendpoints

Rofecoxib [22] VIGOR No MI 4.25 (1.39 – 17.37)

CV death 0.2% versus 0.2%, NS‡

Celecoxib [28] CLASS Yes MI, stroke or angina 0.9% versus 1.0%, NS

Etoricoxib [29,30] MEDAL Stimulated Any thrombotic events* 0.95 (0.81 – 1.11)

Arterial thrombotic events* 0.96 (0.81 – 1.13)

APTC (all MI, stroke or vascular death)* 0.96 (0.79 – 1.16)

Lumiracoxib [31,32] TARGET Yes APTC (all MI, stroke or vascular death)

Versus ibuprofen + naproxen 1.14 (0.78 – 1.66)

Versus ibuprofen 0.76 (0.41 – 1.40)

Versus naproxen 1.46 (0.89 – 2.37)

Confirmed or probable MI (clinical and silent)

Versus ibuprofen + naproxen 1.31 (0.70 – 2.45)

Versus ibuprofen 0.66 (0.21 – 2.09)

Versus naproxen 1.77 (0.82 – 3.84)

*Per-protocol analysis, similar results after intention to treat analysis.‡Incidence.

APTC: Anti-Platelet Trialists’ Collaboration endpoint; CLASS: Celecoxib Long-term Arthritis Safety Study; CV: Cardiovascular; MEDAL: Multinational Etoricoxib and

Diclofenac Arthritis Long-term; MI: Myocardial infarction; NS: Not significant; TARGET: Therapeutic Arthritis Research and Gastrointestinal Event Trial;

VIGOR: Vioxx GI Outcomes Research.

Table3.IncidenceofothersideeffectsinstudiesofselectiveCOX2inhibitors.

Study(ref.) Drugs Sideeffects

Renal Oedema Bloodpressure Hypertension CHF

Creatinine+ Systolic Diastolic

VIGOR [22] Rofecoxib 1.2% Nr Nr Nr Nr Nr

Naproxen 0.9%

CLASS [28] Celecoxib 0.7%* 2.8% Nr Nr 1.7%* Nr

Diclofenac 1.2% 3.5% 2.3%

MEDAL [29,30] Etoricoxib 0.4 – 2.3% 0.8 – 1.9% (at 90 mg)§

Nr nr 2.2 – 2.5%§ 0.1 – 0.7%

Diclofenac 0.4 – 1.8% 0.4 – 0.8% 0.7 – 1.6% 0.1 – 0.3%

TARGET [31,32] Lumiracoxib 0.51%¶ Nr +0.4 mm‡ -0.1 mm‡ Nr 0.24%

Naproxen/Diclofenac

0.37% +2.1 mm +0.5 mm 0.34%

*p < 0.05 vs. control drug.‡p < 0.0001 vs. control drug.§p < 0.05 for discontinuations between treatment groups.¶Major renal events, NS.

CHF: Cardiac heart failure; CLASS: Celecoxib Long-term Arthritis Safety Study; MEDAL: Multinational Etoricoxib and Diclofenac Arthritis Long-term; Nr: Not reported;

TARGET: Therapeutic Arthritis Research and Gastrointestinal Event Trial; VIGOR: Vioxx GI Outcomes Research.

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Surprisingly, CINODs increased the anti-inflammatory and analgesic potency of these drugs [44]. NO exerts analgesic actions and reduces the release of pro-inflammatory media-tors from a number of cells (including IL-1 via inhibition of caspases) [44]. NO also reduces the expression of the inducible NO synthetase (which produces supraphysiological concen-trations of NO that can contribute to inflammation and tissue injury) [44].

NO is a key regulator of vascular function with effects on vascular tone, platelet function, and endothelial function [45]. The cardiovascular effects of NO as shown in animal studies include inhibition of vasopressure responses, blood pressure reduction in hypertensive rats and inhibition of platelet aggregation [45].

In animal studies, NO-releasing agents have been shown to protect against side effects of other drugs, such as bone protection with NO-glucocorticoids, liver protection with NO-acetaminophen and additional cardioprotective and antithrombotic effects with NO-aspirin [43,56].

3. NO-Naproxen(AZD3582(Naproxcinod®)

AZD3582 [24-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphtyl)propanote], Naproxcinod® is the first in the class of CINODs and has been evaluated in preclinical and clinical studies. It is metabolized to naproxen and has been shown to donate nitric oxide in vitro and in vivo [43].

3.1 PreclinicaldataAZD3582 is metabolized to naproxen and has been shown to donate NO in vitro [60] and in vivo [61]. It stimulated the expression of heme oxygenase-mRNA in endothelial cells in vitro, a crucial mediator of antioxidant and tissue-protective actions [62].

In preclinical studies, AZD3582 has been shown to be analgesic and anti-inflammatory [63]. It had improved histological GI safety over naproxen in rats [64], despite suppression of whole blood thromboxane synthesis to a degree similar to that of naproxen [65].

AZD3582 dose-dependently displayed a noticeable and significant anti-ischemic effect in reperfused ischemic rabbit hearts [61] and did not exhibit the hypertensive effects of naproxen [66-68].

3.2 StudiesinhumansIn a proof of concept study in 31 healthy volunteers with GI tolerance as primary endpoint, AZD3582 (750 mg twice daily for 12 days) caused fewer gastric erosions in both the stomach and the duodenum (mean of 4.1 erosions) than naproxen (mean of 11.5 erosions, p < 0.0001), while 0.2 erosions were found with placebo [69]. AZD3582 caused less of an adverse effect in intestinal permeability than naproxen, and was similar to placebo.

In a randomized, double-blind study in 970 patients with hip or knee OA and with GI tolerance as primary endpoint,

the incidence of endoscopic gastroduodenal ulcers (diameter ≥ 3 mm) with AZD3582 (750 mg twice daily) was 9.7% and with naproxen (500 mg twice daily) 13.7% (p = 0.07, not significant), versus 0.0% on placebo [70]. The incidence of Lanza scores > 2 was higher with naproxen (43.7%) than with AZD3582 (32.2%) (p < 0.001). Compared with baseline, significantly fewer ulcers and erosions developed in stomach (+2.2 versus +4.1 on naproxen) and stomach/duodenum combined (+3.1 versus +5.5), and fewer erosions developed in stomach (+1.4 versus +2.9), duodenum (+0.2 versus +0.5), and both combined (+1.6 versus 3.4) with AZD3582 than with naproxen. Gastrointestinal symp-tom rating scale (GSRS) reflux and abdominal pain subscale scores were lower for AZD3582 than for naproxen but there was no difference for indigestion, constipation and diarrhea. AZD3582 was as effective as naproxen at improving Western Ontario and McMaster Universities (WOMAC) scores. Both agents were well tolerated, with no significant effects on blood pressure. Thus, at doses with similar efficacy in relieving osteoarthritis symptoms, the primary end point of six-week endoscopic gastroduodenal ulcer incidence was not met and was not significantly different between AZD3582 and naproxen. Most secondary endoscopic gastrointestinal end points favored AZD3582.

To define the efficacy, safety and tolerability of AZD3582 compared with those of rofecoxib, naproxen, and placebo, and to define the dosage of AZD3582 (125, 375 or 750 mg twice a day) that is non-inferior to rofecoxib, the effect of AZD3582 was studied in 672 patients with knee OA in a randomized double-blind study [71]. Patients who experienced increased pain on withdrawal of analgesia were randomized to receive AZD3582 (125, 375 or 750 mg twice a day), rofecoxib (25 mg once a day), naproxen (500 mg twice a day), or placebo for 6 weeks. Efficacy, tolerability and safety were monitored throughout the study. The primary variable was the change in WOMAC Osteoarthritis Index pain subscale from baseline to the mean of weeks 4 and 6, comparing AZD3582 with placebo for superiority and with rofecoxib for non-inferiority using a predefined margin of 10 mm. For the primary variable (efficacy), AZD3582 375 mg and 750 mg were superior to placebo (least squares mean differ-ence [95% confidence interval] -12 mm [-18,-6], p < 0.001 and -13 mm [-19,-7], p < 0.001, respectively), which were reported to be similar to naproxen (no data available) and to rofecoxib (-10 mm [-16,-4], p < 0.01), and were non-inferior to rofecoxib (-2 mm [-8,4], p < 0.001 and -3 mm [-9,3], p < 0.001, respectively). AZD3582 125 mg was not significantly different from placebo for the primary variable.

Meanwhile, a Phase III program has been designed and executed to request regulatory approval for naproxcinod in the US and in Europe. Superiority comparisons versus placebo on three co-primary endpoints (WOMAC™ pain subscale, WOMAC function subscale and subject’s overall rating of disease status) in two well designed, well controlled trials conform to FDA guidance for demonstrating the efficacy of

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654 ExpertOpin.Biol.Ther.(2009) 9(5)

new drugs for the treatment of the signs and symptoms of osteoarthritis. Non-inferiority comparisons to existing products are required by the European Medicines Agency (EMEA) for demonstrating the efficacy of new drugs. Another important issue is the evaluation of naproxcinod’s blood pres-sure profile, in comparison with traditional NSAIDs and COX 2 inhibitors.

These results of the Phase III studies have been submitted to the authorities [72], but were not yet available at the time of submission of this review. Additional information can be found on the website of the FDA and EMEA.

The first clinical trial is a 13-week, double-blind, placebo and naproxen-controlled trial in 918 patients with osteoarthritis of the knee. Eligible patients were randomized to one of four treatment groups: 375 mg naproxcinod twice daily, 750 mg naproxcinod twice daily, 500 mg naproxen twice daily or placebo twice daily.

The second study recruited 1020 patients with osteoarthritis of the knee and is a 53 week, double-blind trial, in which patients were randomized to one of the following treatment groups: 375 mg naproxcinod twice daily (52 weeks), 750 mg naproxcinod twice daily (52 weeks), 500 mg naproxen twice daily (52 weeks) and placebo twice daily during the first 13 weeks. After 13 weeks, the placebo-treated patients were randomized to either 375 mg naproxcinod twice daily or 750 mg naproxcinod twice daily for the remainder of the trial (39 weeks).

The third study is a 13-week, double-blind, placebo- and naproxen-controlled trial in 810 patients with OA of the hip. Eligible patients had a diagnosis of primary osteoar-thritis of the hip of at least three months in duration and were randomized on a 2:2:1 basis to receive respectively: 750 mg naproxcinod twice daily, placebo twice daily or 500 mg naproxen twice daily.

In addition to demonstrating the efficacy of naproxcinod, the Phase III program was designed to show that it has no detrimental effect on blood pressure, in contrast to naproxen. Both hypertensive and non-hypertensive patients were enrolled in the three Phase III trials, although patients with uncontrolled hypertension have been excluded. Patients’ blood pressure is measured during each of the Phase III trials

by using controlled Office Blood Pressure Measurements (OBPMs) during each visit to the treatment centers. In the planning of the Phase III program, the pooling of OBPM data from more than one study in order to obtain the necessary statistical power to correctly assess the effects of naproxcinod on blood pressure, compared with naproxen, is foreseen. A pre-specified analysis of the pooled blood pressure data from the three Phase III studies will be conducted following the completion of the third Phase III trial. Preliminary results, available in the documents of the EMEA, suggest favorable results in terms of efficiency, safety and blood pressure for Naproxcinod compared with naproxen and placebo, but the interpretation of these results await detailed peer-reviewed data which were not available at the time of submission of this manuscript.

4. Conclusionsandexpertopinion

In the complex clinical context of efficiency and safety (GI, CV, renal, hepatic and hematologic) of selective and non-selective COX inhibitors, prescription and use should be based on the broad array of risk and safety profiles of both the drug and the patient. CINODs are a new class of drugs that combine the actions of the parent COX inhibitor with NO, with the aim of reducing potential toxicity of the parent drug, while maintaining its analgesic and anti-inflammatory effects. AZD3582 (Naproxcinod®) is the first in the class of CINODs. In preclinical and human studies, this drug pro-duced similar analgesic and anti-inflammatory effects to the parent naproxen, with partial improved GI safety in human OA. As naproxen is considered the safest COX inhibitor choice from a cardiovascular perspective (Table 4) [41,42,73], AZD3582 has the potential to become a new drug treat-ment in patients with OA, in whom pain and function are not controlled by the use of analgesics.

Declarationofinterest

The author states no conflict of interest and has received no payment in preparation of this manuscript.

Table4.ProposedindicationsfortheuseofselectiveCOX2andnon-selectiveNSAIDsaccordingtoGIandCVrisk[73].

CVrisk GIrisk*

Low Moderate High

Low NSAID NSAID + PPI/misoprostol or COX2 inhibitor COX2 inhibitor + PPI

High‡ NSAID§ + PPI or misoprostol NSAID§ + PPI or misoprostol Avoid NSAIDs or COX2 inhibitor

*Gastrointestinal risk is arbitrarily defined as low (no risk factors), moderate (presence of one or two risk factors), or high (more than two risk factors, previous ulcer

complications, or concomitant use of corticosteroids or anticoagulants). All patients with a history of ulcers who require NSAIDs should be tested for Helicobacterpylori

and if infection is present, eradication therapy should be given.‡High cardiovascular risk is arbitrarily defined as the requirement for low-dose aspirin for primary cardiovascular event prevention (calculated 10-year cardiovascular

risk > 10%) or secondary prevention of serious cardiovascular events. Ibuprofen should be avoided with aspirin.§Naproxen is the preferred NSAID in patients with a high cardiovascular risk.

PPI: Proton pump inhibitors.

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AffiliationPiet Geusens MD PhDUniversity Hasselt, University Hospital, The Netherlands & Biomedical Research Institute, Subdivision of Rheumatology, Department of Internal Medicine, Maastricht, Belgium Tel: +32 43 3875026; Fax: +32 89 304186; E-mail: piet.geusens@scarlet.be