Gastrointestinal Toxicity of Nonsteroidal Antiinflammatory Drugs

Section of Gastroenterology, Boston University School of Medicine and Boston Medical Center, MA 02118-2393, USA.
New England Journal of Medicine (Impact Factor: 55.87). 07/1999; 340(24):1888-99. DOI: 10.1056/NEJM199906173402407
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    • "Among patients using NSAIDs, it is estimated that about 16,500 deaths occur every year in the United States. This figure is considerably greater than the number of deaths from multiple myeloma, asthma, cervical cancer, or Hodgkin's disease [7]. Unfortunately, many physicians and most patients are unaware of the magnitude of the problem. "
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    ABSTRACT: Aspirin is chemopreventive; however, side effects preclude its long-term use. NOSH-aspirin (NBS-1120), a novel hybrid that releases nitric oxide and hydrogen sulfide, was designed to be a safer alternative. Here we compare the gastrointestinal safety, anti-inflammatory, analgesic, anti-pyretic, anti-platelet, and chemopreventive properties of aspirin and NBS-1120 administered orally to rats at equimolar doses. Gastrointestinal safety: 6h post-administration, the number and size of hemorrhagic lesions in stomachs were counted; tissue samples were frozen for PGE2, SOD, and MDA determination. Anti-inflammatory: 1h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 5h. Anti-pyretic: fever was induced by LPS (ip) an hour before administration of the test drugs, core body temperature was measured hourly for 5h. Analgesic: time-dependent analgesic effects were evaluated by carrageenan-induced hyperalgesia. Antiplatelet: anti-aggregatory effects were studied on collagen-induced platelet aggregation of human platelet-rich plasma. Chemoprevention: Nude mice were gavaged daily for 25 days with vehicle, aspirin or NBS-1120. After one week, each mouse was inoculated subcutaneously in the right flank with HT-29 human colon cancer cells. Both agents reduced PGE2 levels in stomach tissue; however, NBS-1120 did not cause any stomach ulcers, whereas aspirin caused significant bleeding. Lipid peroxidation induced by aspirin was higher than that exerted by NBS-1120. SOD activity was significantly inhibited by aspirin but increased by NBS-1120. Both agents showed similar anti-inflammatory, analgesic, anti-pyretic, and anti-platelet activities. Aspirin increased plasma TNFα more than NBS-1120-treated animals. NBS-1120 was better than aspirin as a chemopreventive agent; it dose-dependently inhibited tumor growth and tumor mass.
    Biochemical pharmacology 09/2015; 98(4). DOI:10.1016/j.bcp.2015.09.014 · 5.01 Impact Factor
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    • "Mild symptoms such as nausea, diarrhea, abdominal pain, loss of appetite can be demonstrated. More serious symptoms include severe damage to the upper gastrointestinal tract manifested by bleeding, ulceration, erosions and perforations (often leading to death) [5]. The lower part of the gastrointestinal tract may also be subject to such damage. "
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    ABSTRACT: Background The previous study indicated the enhancement of the anti-inflammatory effect of ketoprofen by acute and sub chronic administration of zinc hydroaspartate. Methods The present study examined anti-inflammatory, anti-ulcerogenic and analgesic activity induced by chronic (14 days) administration of ZHA (30 mg/kg, po), with a combination of a single administration of ketoprofen, in rats. Moreover, the zinc concentration in serum and stomach mucosa was also determined. Results Chronic ZHA po administration exhibits anti-inflammatory activity and enhanced the effect induced by ketoprofen. Likewise, ZHA administration demonstrated anti-ulcerogenic activity. While ZHA alone did not exhibit analgesic action, it enhanced the effect of ketoprofen. Conclusions The present study demonstrated for the first time that chronic treatment with zinc salt exhibits anti-inflammatory activity. Besides, anti-ulcerogenic activity and the enhancing properties of zinc to ketoprofen induced anti-inflammatory and analgesic activity were also shown.
    Pharmacological reports: PR 10/2014; 66(5). DOI:10.1016/j.pharep.2014.05.007 · 1.93 Impact Factor
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    • "Traditional non-steroidal anti-inflammatory drugs (NSAIDs) which inhibit both COX subtypes are still the most commonly used medications for inflammation and pain (Salgin-Goksen et al., 2007). However, it is well known that NSAIDs have several serious side effects such as gastric ulceration, renal injury and cardiotoxicity (Allison et al., 1992; Wolfe et al., 1999). To limit the risk of GI damage induced by NSAIDs, highly selective COX-2 inhibitors (coxibs) have been developed where they exhibited equivalent anti-inflammatory/analgesic activities to those of non-selective COX inhibitors but with least GI toxicity (Micklewright et al., 2003). "
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    ABSTRACT: A novel set of 4-substituted-1-phenyl-pyrazolo[3,4-d]pyrimidine and 5-substituted-1-phenyl-pyrazolo[3,4-d]pyrimidin-4-one derivatives were synthesized and evaluated as potential anti-inflammatory agents. The newly prepared compounds were assessed through the examination of their in vitro inhibition of four targets; cyclooxygenases subtypes (COX-1 and COX-2), inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NF-κB). Compounds 8a, 10c and 13c were the most potent and selective ligands against COX-2 with inhibition percentages of 79.6, 78.7 and 78.9% at a concentration of 2 μM respectively, while compound 13c significantly inhibited both COX subtypes. On the other hand, fourteen compounds showed high iNOS inhibitory activities with IC50 values in the range of 0.22-8.5 μM where the urea derivative 11 was the most active compound with IC50 value of 0.22 μM. Most of the tested compounds were found to be devoid of inhibitory activity against NF-kB. Moreover, almost all compounds were not cytotoxic, (up to 25μg/ml), against a panel of normal and cancer cell lines. The in silico docking results were in agreement with the in vitro inhibitory activities against COXs and iNOS enzymes. The results of in vivo anti-inflammatory and antinociceptive studies were consistent with that of in vitro studies which confirmed that compounds 8a, 10c and 13c have significant anti-inflammatory and analgesic activities comparable to that of the control, ketorolac. Taken together, dual inhibition of COXs and iNOS with novel pyrazolopyrimidine derivatives is a valid strategy for the development of anti-inflammatory/analgesic agents with the probability of fewer side effects.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 06/2014; 62. DOI:10.1016/j.ejps.2014.05.025 · 3.35 Impact Factor
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