Reducing Clinically Significant Gastrointestinal Toxicity Associated with Nonsteroidal Antiinflammatory Drugs

Jacobsen, Ryan B; Phillips, Beth Bryles

doi:10.1345/aph.1d621

Cited by 19 publications

(11 citation statements)

References 56 publications

(152 reference statements)

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“…As initially discussed by Wallace (173), there is ample evidence that selective inhibitors of COX-2 produce less gastric damage than standard NSAIDs when administered acutely to healthy animals. However, most patients taking standard NSAIDs do not develop clinically significant gastric injury, although a subset of patients is more susceptible to the gastric-damaging actions of these drugs (54). Moreover, the presence of both NOS isoforms in the vasculature raises the question of which is the predominant cause of the increased production of vasodilatory PGs that are critical to preserving renal blood flow during volume depletion and dehydration stress.…”

Section: Physiological Implications Of the Modulation Of The Cyclooxymentioning

confidence: 99%

Reciprocal regulation of the nitric oxide and cyclooxygenase pathway in pathophysiology: relevance and clinical implications

Salvemini

Kim

Mollace

2013

American Journal of Physiology-Regulatory, Integrative and Comp

129

100

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The nitric oxide (NO) and cyclooxygenase (COX) pathways share a number of similarities. Nitric oxide is the mediator generated from the NO synthase (NOS) pathway, and COX converts arachidonic acid to prostaglandins, prostacyclin, and thromboxane A(2). Two major forms of NOS and COX have been identified to date. The constitutive isoforms critically regulate several physiological states. The inducible isoforms are overexpressed during inflammation in a variety of cells, producing large amounts of NO and prostaglandins, which may underlie pathological processes. The cross-talk between the COX and NOS pathways was initially reported by Salvemini and colleagues in 1993, when they demonstrated in a series of in vitro and in vivo studies that NO activates the COX enzymes to produce increased amounts of prostaglandins. Those studies led to the concept that COX enzymes represent important endogenous "receptor" targets for amplifying or modulating the multifaceted roles of NO in physiology and pathology. Since then, numerous studies have furthered our mechanistic understanding of these interactions in pathophysiological settings and delineated potential clinical outcomes. In addition, emerging evidence suggests that the canonical nitroxidative species (NO, superoxide, and/or peroxynitrite) modulate biosynthesis of prostaglandins through non-COX-related pathways. This article provides a comprehensive state-of-the art overview in this area.

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Section: Physiological Implications Of the Modulation Of The Cyclooxymentioning

confidence: 99%

Reciprocal regulation of the nitric oxide and cyclooxygenase pathway in pathophysiology: relevance and clinical implications

Salvemini

Kim

Mollace

2013

American Journal of Physiology-Regulatory, Integrative and Comp

129

100

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“…Recent clinical trials have shown that the use of two of these inhibitors, celecoxib and rofecoxib, is associated with effective anti-inflammatory relief in osteoarthritis and rheumatoid arthritis as well as with a significantly lower incidence of ulcer complications [34][35][36].…”

Section: Reactive Oxygen Species and Gastric Ulcerationmentioning

confidence: 99%

Reactive Oxygen Species-Induced Gastric Ulceration: Protection By Melatonin

Bandyopadhyay¹,

Chattopadhyay

2006

CMC

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Gastric hyperacidity and ulceration of the stomach mucosa due to various factors are serious health problems of global concern. Although the mechanism of acid secretion from the parietal cells is now well understood, the processes involved in gastric ulceration are still not clear. Among the various causes of gastric ulceration, lesions caused by stress, alcohol consumption, Helicobacter pylori and due to use of non-steroidal anti-inflammatory drugs have been shown to be mediated largely through the generation of reactive oxygen species, especially the hydroxyl radical. A number of excellent drugs, developed over the decades, have proven useful in controlling hyperacidity and ulceration although their long-term use is reported to be associated with various side effects. Hence the investigations continue with an objective to find a compound possessing anti-secretory, anti-ulcer and antioxidant properties which will serve as a therapeutic agent to reduce gastric hyperacidity and ulcers. This article describes the role of reactive oxygen species in gastric ulceration, briefly presents a note on the currently available drugs controlling them, and focuses on the role of melatonin, a pineal secretory product, in protecting against gastric lesions. In experimental studies, melatonin has been shown to be effective in reducing mucosal breakdown and ulcer formation in a wide variety of situations. Additionally, the low toxicity of melatonin supports further investigation of this molecule as a promising gastro-protective agent. Finally, we include a commentary on how melatonin research with respect to gastric pathophysiology can move forward with a view to eventually using this indole as a therapeutic agent alone or in combination with the existing drugs to control gastric ulceration in humans in order to increase their efficacy and/or to reduce their side effects.

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“…Compared to NSAID plus PPI, co-therapy with misoprostol may be associated with a higher incidence of gastrointestinal symptoms (diarrhea, abdominal pain and flatulence), [14][15][16] while sucralfate, 17,18 and H 2 -receptor antagonists 17,[19][20][21][22][23] may be less efficacious. Although both a COX-2 selective inhibitor or a non-selective NSAID in conjunction with a PPI are considered effective strategies for reducing the risk of ulcer complications, 24,25 limited information is available regarding direct comparisons of risk-benefit and cost effectiveness of these two therapeutic op-tions. The decision about which protective strategy to choose remains controversial and requires consideration of the delicate balance between risks, benefits, and costs.…”

Section: Introductionmentioning

confidence: 93%

Celecoxib versus a Non-Selective NSAID Plus Proton-Pump Inhibitor

Chen¹,

Pucino²,

Resman-Targoff³

2006

J. Of Pain & Palliative Care Pharmacotherapy

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used worldwide. However, associated adverse gastrointestinal effects (NSAID gastropathy) such as bleeding, perforation and obstruction result in considerable morbidity, mortality, and expense. Although it is essential to employ gastroprotective strategies to minimize these complications in patients at risk, controversy remains on whether celecoxib alone or a non-selective NSAID in conjunction with a proton-pump inhibitor (PPI) is a superior choice. Recent concerns regarding potential cardiovascular toxicities associated with cox-2 selective inhibitors may favor non-selective NSAID/PPI co-therapy as the preferred choice. Concomitant use of low-dose aspirin with any NSAID increases the risk of gastrointestinal complications and diminishes the improved gastrointestinal safety profile of celecoxib; whereas use of ibuprofen plus PPI regimens may negate aspirin's antiplatelet benefits. Evidence shows that concurrent use of a non-selective NSAID (such as naproxen) plus a PPI is as effective in preventing NSAID gastropathy as celecoxib, and may be more cost-effective. Patients failing or intolerant to this therapy would be candidates for celecoxib at the lowest effective dose for the shortest duration of time. Potential benefits from using low-dose celecoxib with a PPI in patients previously experiencing bleeding ulcers while taking NSAIDs remains to be proven. An evidence-based debate is presented to assist clinicians with the difficult decision-making process of preventing NSAID gastropathy while minimizing other complications.

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Reducing Clinically Significant Gastrointestinal Toxicity Associated with Nonsteroidal Antiinflammatory Drugs

Abstract: COX-2 inhibitors and proton-pump inhibitors are effective and well-tolerated therapies to reduce clinically significant upper gastrointestinal adverse events associated with NSAIDs.

Cited by 19 publications

References 56 publications

Reciprocal regulation of the nitric oxide and cyclooxygenase pathway in pathophysiology: relevance and clinical implications

Reciprocal regulation of the nitric oxide and cyclooxygenase pathway in pathophysiology: relevance and clinical implications

Reactive Oxygen Species-Induced Gastric Ulceration: Protection By Melatonin

Celecoxib versus a Non-Selective NSAID Plus Proton-Pump Inhibitor

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