Blood Pressure Effects of Naproxcinod in Hypertensive Patients

Townsend, Raymond R.; Bittar, Neville; Rosen, Jeffrey B.; Smith, William C.; Ramsay, A. Melvin; Chrysant, Steven G.; Weiss, Robert; Pivodic, Aldina; Duquesroix, Brigitte; Djian, Jacques

doi:10.1111/j.1751-7176.2010.00419.x

Cited by 11 publications

(6 citation statements)

References 34 publications

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“…Contrastingly, naproxcinod completed phase III clinical trials. Taken together, the results showed its efficacy in treating knee and hip osteoarthritis without increasing the systolic blood pressure of normo or hypertensive patients . Although some pilot trials also indicated that naproxcinod exhibited better GI tolerability, this NO‐releasing derivative of naproxen failed to significantly reduce the primary endpoint of 6 weeks endoscopic gastroduodenal ulcer incidence in a double blind study in patients with hip or knee osteoarthritis .…”

Section: Association Of Nsaids With Protective Mediatorsmentioning

confidence: 94%

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Pereira-Leite

Nunes

Jamal

et al. 2016

Medicinal Research Reviews

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The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long-term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX-2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine-associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti-inflammatory therapy.

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Section: Association Of Nsaids With Protective Mediatorsmentioning

confidence: 94%

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Pereira-Leite

Nunes

Jamal

et al. 2016

Medicinal Research Reviews

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“…In these studies gastrointestinal side effects and hypertension, commonly seen with NSAIDs, were kept to a minimum through the release of nitric oxide [130, 131]. …”

Section: Scientific Rationale and Competitive Environmentmentioning

confidence: 99%

Emerging drugs for Duchenne muscular dystrophy

Malik

Rodino‐Klapac

Mendell

2012

Expert Opinion on Emerging Drugs

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Introduction Duchenne muscular dystrophy (DMD) is the most common, severe childhood form of muscular dystrophy. Treatment is limited to glucocorticoids that have the benefit of prolonging ambulation by approximately 2 years and preventing scoliosis. Finding a more satisfactory treatment should focus on maintaining long-term efficacy with a minimal side effect profile. Areas covered Authors discuss different therapeutic strategies that have been used in pre-clinical and clinical settings. Expert opinion Multiple treatment approaches have emerged. Most attractive are molecular-based therapies that can express the missing dystrophin protein (exon skipping or mutation suppression) or a surrogate gene product (utrophin). Other approaches include increasing the strength of muscles (myostatin inhibitors), reducing muscle fibrosis, and decreasing oxidative stress. Additional targets include inhibiting NF-κB to reduce inflammation, or promoting skeletal muscle blood flow and muscle contractility using phosphodiesterase inhibitors or nitric oxide (NO) donors. The potential for each of these treatment strategies to enter clinical trials is a central theme of discussion. The review emphasizes that the goal of treatment should be to find a product at least as good as glucocorticoids with a lower side effect profile or with a significant glucocorticoid sparing effect.

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“…The addition of the NO-donating moiety was aimed at reducing common adverse effects of chronic NSAID use, such as gastrointestinal damage and increased blood pressure. Indeed, naproxcinod was shown in several clinical trials to be effective in relieving the signs and symptoms of OA compared to placebo [ 27 , 34 – 36 ], but with a lower incidence of hypertension compared to NSAIDs [ 37 , 38 ]. Moreover, it has been demonstrated that the effects of naproxcinod ascribed to NO such as the control of blood pressure (BP) persist over time [ 38 ] up to 13 weeks, suggesting that the compound does not lead to development of nitrate tolerance with the chronic use.…”

Section: Discussionmentioning

confidence: 99%

Naproxcinod shows significant advantages over naproxen in the mdx model of Duchenne Muscular Dystrophy

Miglietta

Palma

Sciorati

et al. 2015

Orphanet J Rare Dis

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BackgroundIn dystrophin-deficient muscles of Duchenne Muscular Dystrophy (DMD) patients and the mdx mouse model, nitric oxide (NO) signalling is impaired. Previous studies have shown that NO-donating drugs are beneficial in dystrophic mouse models. Recently, a long-term treatment (9 months) of mdx mice with naproxcinod, an NO-donating naproxen, has shown a significant improvement of the dystrophic phenotype with beneficial effects present throughout the disease progression. It remains however to be clearly dissected out which specific effects are due to the NO component compared with the anti-inflammatory activity associated with naproxen. Understanding the contribution of NO vs the anti-inflammatory effect is important, in view of the potential therapeutic perspective, and this is the final aim of this study.MethodsFive-week-old mdx mice received either naproxcinod (30 mg/kg) or the equimolar dose of naproxen (20 mg/kg) in the diet for 6 months. Control mdx mice were used as reference. Treatments (or vehicle for control groups) were administered daily in the diet. For the first 3 months the study was performed in sedentary animals, then all mice were subjected to exercise until the sixth month. Skeletal muscle force was assessed by measuring whole body tension in sedentary animals as well as in exercised mice and resistance to fatigue was measured after 3 months of running exercise. At the end of 6 months of treatment, animals were sacrificed for histological analysis and measurement of naproxen levels in blood and skeletal muscle.ResultsNaproxcinod significantly ameliorated skeletal muscle force and resistance to fatigue in sedentary as well as in exercised mice, reduced inflammatory infiltrates and fibrosis deposition in both cardiac and diaphragm muscles. Conversely, the equimolar dose of naproxen showed no effects on fibrosis and improved muscle function only in sedentary mice, while the beneficial effects in exercised mice were lost demonstrating a limited and short-term effect.ConclusionIn conclusion, this study shows that NO donation may have an important role, in addition to anti-inflammatory activity, in slowing down the progression of the disease in the mdx mouse model therefore positioning naproxcinod as a promising candidate for treatment of DMD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0311-0) contains supplementary material, which is available to authorized users.

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Blood Pressure Effects of Naproxcinod in Hypertensive Patients

Cited by 11 publications

References 34 publications

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Emerging drugs for Duchenne muscular dystrophy

Naproxcinod shows significant advantages over naproxen in the mdx model of Duchenne Muscular Dystrophy

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