naproxen-n-butyl-nitrate and Pain

NO-naproxen, consisting of the NSAID naproxen linked to a nitric oxide (NO) moiety, is under development by AstraZeneca plc, under license from NicOx SA, for the potential treatment of acute/chronic pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Humans; Naproxen; Nitric Oxide; Nitric Oxide Donors; Pain; Structure-Activity Relationship

To assess the responsiveness of the Intermittent and Constant Osteoarthritis Pain (ICOAP) measure, Hip Disability and Osteoarthritis Outcome Score Physical Function Short Form (HOOS-PS), and the Knee Disability and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-PS) in a pharmacological trial.. Data were obtained from a randomized double-blind trial comparing naproxcinod with naproxen and ibuprofen in individuals with hip or knee osteoarthritis (OA) (NCT00662896). Participants completed the ICOAP, HOOS-PS/KOOS-PS, and Western Ontario and McMaster Universities OA Index (WOMAC) Likert version 3.0 before and 13 weeks after treatment. In hip and knee OA participants separately, the mean pre-post treatment change in scores, effect size (ES) and standardized response mean (SRM) were determined for each measure by treatment arm, and for all arms combined.. Of 349 trial participants, 156 with knee OA and 48 with hip OA completed all measures at both time-points and were included (mean age 61 years; two-thirds female). Although there was both within treatment and between treatment variability in response, among knee OA participants, ICOAP intermittent, constant, and total scores and KOOS-PS scores showed, on average, moderate effects, with ESs ranging from 0.46 to 0.54 and SRMs from 0.49 to 0.56. Similar changes were seen for the WOMAC pain and function subscales (0.58 and 0.58, respectively). In those with hip OA, no significant improvement in symptoms was seen for any measure.. Responsiveness to pharmaceutical intervention was demonstrated for ICOAP and KOOS-PS among participants with knee OA. Absence of treatment response precluded assessment of responsiveness in hip OA.

Topics: Aged; Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Disability Evaluation; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Ibuprofen; Male; Middle Aged; Naproxen; Nitric Oxide Donors; Osteoarthritis, Hip; Osteoarthritis, Knee; Pain; Pain Measurement; Severity of Illness Index; Treatment Outcome

Comparison of naproxcinod (375 and 750 mg), placebo (up to 13 weeks), and naproxen 500 mg (all bid) for treatment of osteoarthritis (OA) signs and symptoms.. A 53-week, randomized, double-blind, parallel-group study. One thousand twenty patients with primary knee OA were randomized to naproxcinod 750 mg, naproxcinod 375 mg, naproxen 500 mg, or placebo (all bid). Coprimary efficacy endpoints were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC™) pain and function subscales and patient overall rating of disease status. An analysis of covariance model tested superiority for both naproxcinod doses over placebo at week 13, and noninferiority of naproxcinod 750 mg bid versus naproxen at weeks 13 and 26.. Least-square mean changes from baseline were greater for both naproxcinod doses compared with placebo at week 13 for WOMAC pain (-31.3 [standard error 1.67], -28.1 [1.64], and -20.4 [1.62] mm with naproxcinod 750 mg bid [P < 0.0001], 375 mg bid [P = 0.0008], and placebo, respectively), WOMAC function (-27.8 [1.60], -23.8 [1.58], and -14.9 [1.56] mm, respectively, P < 0.0001), and patient overall rating of disease status (1.00 [0.061], 0.81 [0.060], and 0.49 [0.059], respectively, P < 0.0001). Naproxcinod 750 mg bid was noninferior to naproxen at weeks 13 and 26. Naproxcinod was well tolerated, with no notable differences in orthostatic blood pressure response between treatments.. Naproxcinod 750 mg bid and 375 mg bid demonstrated superior efficacy over placebo for treatment of OA and were well tolerated over 1 year. Naproxcinod 750 mg bid was noninferior to naproxen 500 mg bid.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Double-Blind Method; Female; Humans; Male; Middle Aged; Naproxen; Nitric Oxide Donors; Osteoarthritis, Knee; Pain; Pain Measurement; Prospective Studies; Treatment Outcome

To evaluate the efficacy and safety of the cyclooxygenase-inhibiting nitric-oxide donator, naproxcinod, compared with naproxen and placebo in patients with osteoarthritis (OA) of the knee.. 918 eligible patients were randomly assigned to double-blind treatment with either naproxcinod 375 mg, naproxcinod 750 mg, naproxen 500 mg or placebo, twice daily for 13 weeks. The primary objective was to show superiority of naproxcinod compared to placebo. Main efficacy criteria were assessment of pain and physical function using the Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC) and patients' overall rating of disease status (Likert scale). The main secondary objectives were to show that naproxcinod was non-inferior to naproxen 500 mg and to evaluate overall safety.. Both doses of naproxcinod were statistically and clinically superior to placebo in relieving signs and symptoms of OA of the knee after 13 weeks of treatment, as demonstrated by all three co-primary endpoints (P< or =0.0003). The evaluation of the other secondary efficacy measures was consistent with the primary endpoint results. Naproxcinod 750 mg was non-inferior to equimolar doses of naproxen 500 mg in the Intent-to-Treat (ITT) population. 24.5% of patients discontinued prematurely, with a higher incidence in the placebo group (18.6%) than the active groups (4.3-7.1%) discontinuing due to lack of efficacy. Both doses of naproxcinod were well-tolerated, with most adverse events being mild or moderate. Compared to placebo, naproxcinod 750 mg and 375 mg showed a similar blood pressure (BP) profile in contrast to naproxen which increased BP.. These results demonstrated the clinical efficacy and safety of naproxcinod in the management of the signs and symptoms of OA. Naproxcinod was well-tolerated, with BP effects similar to placebo and different from naproxen. Clinical Trials.gov identifier: NCT00542555.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Heart Rate; Humans; Male; Middle Aged; Naproxen; Nitric Oxide Donors; Osteoarthritis, Knee; Pain; Pain Measurement; Prospective Studies; Severity of Illness Index

Naproxcinod, a cyclooxygenase-inhibiting nitric oxide donator antiinflammatory drug, was evaluated in this phase 2, double-blind, randomized, parallel group study to determine its optimal dose in patients with osteoarthritis (OA).. In total 543 patients with OA of the hip or knee were randomized to receive naproxcinod 750 mg once daily (qd), 750 mg twice daily (bid), 1125 mg bid, rofecoxib 25 mg qd, or placebo for 6 weeks. The primary efficacy variable was the within-patient change from baseline to the average of Weeks 4 and 6 in WOMAC pain subscale score. Treatment-group differences were compared using ANCOVA with factors for treatment and country, and baseline pain subscale score as a covariate. Safety endpoints included vital signs and adverse events. Treatment-group differences in mean change from baseline to Week 6 in systolic blood pressure (SBP) were compared using an ANCOVA with treatment and country as fixed factors and baseline SBP as covariate.. All active treatments showed statistically significant reductions in WOMAC pain score compared to placebo (p

Topics: Aged; Antirheumatic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Naproxen; Nitric Oxide Donors; Osteoarthritis, Hip; Osteoarthritis, Knee; Pain; Pain Measurement; Severity of Illness Index; Treatment Outcome

1. Anti-inflammatory non steroidal drugs releasing NO (NO-NSAIDs) are a new class of anti-inflammatory drugs to which has been added an NO-releasing moiety. These compounds have been shown to retain the anti-inflammatory, analgesic and antipyretic activity of the parent compound but to be devoid of gastrointestinal (GI) toxicity. 2. Freund's adjuvant (FA) arthritis was induced in rats by a single intraplantar injection into the right hindpaw of 100 microl of mycobacterium butirricum (6 mg ml(-1)). The effect of equimolar doses of naproxen (1, 3 and 10 mg kg(-1)) and NO-naproxen (1.5, 4.5 and 16 mg kg(-1)) was evaluated using two dosage regimen protocols: (i) preventive, starting oral administration of the drugs at the time of induction of arthritis and for the following 21 days (day 1 - 21); (ii) therapeutic, starting oral administration of the drugs 7 days after adjuvant injection and for the following 14 days (day 7 - 21). 3. Hindpaw swelling (days 3, 7, 11, 14, 17, 21) and nociception (days 15 and 21) were measured. On day 22 rats were sacrificed, draining lymph nodes were removed and T cells isolated. In vitro proliferation of T cells following stimulation with concanavalin A (0.5 - 5 microg ml(-1)) was measured using a tritiated thymidine incorporation assay. IL-2 receptor expression on T cells was measured by FACS analysis. 4. Naproxen and NO-naproxen showed similar activity in reducing oedema formation in the non-injected (controlateral) hindpaw. Both drugs showed anti-nociceptive effect. NO-naproxen was anti-nociceptive at a dose of 4.5 mg kg(-1) while naproxen showed the same extent of inhibition only at a dose of 10 mg kg(-1). 5. T cells were isolated and characterized by FACS analysis. Stimulation of isolated T cells with concanavallin A in vitro caused a significant increase in thymidine uptake. NO-naproxen at a dose of 4.5 mg kg(-1) inhibited T cell proliferation to the same extent as 10 mg kg(-1) of naproxen. 6. Inhibition of T cell proliferation was well correlated with reduced IL-2 receptor expression on T cells. In addition, NO-naproxen reduced both IL-1beta and TNFalpha plasma levels whilst naproxen reduced IL-1beta levels only. 7. In conclusion, both naproxen and NO-naproxen reduce inflammation and nociception associated with arthritis. In addition NO-naproxen interferes to a larger extent with cellular mechanism involved in T cell activation in rat adjuvant arthritis indicating that introduction of the NO moiety in the naproxen structu

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Dose-Response Relationship, Drug; Edema; Flow Cytometry; Hindlimb; Inflammation; Interleukin-1; Male; Naproxen; Nitric Oxide; Nociceptors; Pain; Pain Measurement; Rats; Rats, Inbred Lew; Receptors, Interleukin-2; T-Lymphocytes; Thymidine; Time Factors; Tumor Necrosis Factor-alpha