A unifying hypothesis for the mechanism of NSAID related gastrointestinal toxicity.

Mahmud, T.; Scott, David; Bjarnason, Ingvar

doi:10.1136/ard.55.4.211

Cited by 73 publications

(47 citation statements)

References 24 publications

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“…4 However, the sequence of events resulting from COX inhibition does not completely explain the overall GI toxicity of NSAIDs. 5,6 In fact, it is described that the NSAIDs can cause GI damage through a variety of different mechanisms, 7 including the damage of the gastric mucosa by a direct local effect. 3 In this regard, a hypothesis has been proposed that the NSAIDs compromise the integrity of the gastric mucosa by chemical association with the phospholipids, decreasing the hydrophobic properties of surface mucosal cells predominantly constituted by phosphatidylcholines.…”

Section: ' Introductionmentioning

confidence: 99%

Synchrotron SAXS and WAXS Study of the Interactions of NSAIDs with Lipid Membranes

et al. 2011

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Cell membranes often constitute the first biological structure encountered by drugs, and binding or interactions of drugs with lipid components of the membrane may explain part of their mechanism of activity or their side effects. The present study provides evidence of alterations in the structural properties of phospholipid bilayers at acidic conditions that can be correlated with the mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) and with their local action effect on the gastrointestinal tract lipids, aiming a molecular biophysical approach to the interaction of these drugs with lipid membranes. In this context, the structural modifications of the 1,2-dipalmitoyl-sn-glycero-3-phosphocholine bilayers at pH 5.0, induced by increasing concentrations of five NSAIDs (piroxicam, meloxicam, tolmetin, indomethacin, and nimesulide), were studied by small-angle and wide-angle X-ray scattering. Results obtained highlight the effect of each NSAID in modulating the membrane structure properties. All the NSAIDs promoted distinct biophysical effects by perturbing the membrane arrangement to different degrees that are intimately related to their different physicochemical properties as well as with the initial organization of the lipids, depending if they are in the gel (Lβˈ) or in the liquid-crystalline phase (Lα).

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Section: ' Introductionmentioning

confidence: 99%

Synchrotron SAXS and WAXS Study of the Interactions of NSAIDs with Lipid Membranes

et al. 2011

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“…It is these radicals that are then responsible for the toxic eVects of paracetamol as they induce severe oxidative damage in the major organ systems. DeWciencies in the CYP450 system in Gyps may also explain the toxicity we observe for ketoprofen and diclofenac, as this would allow the accumulation of the primary drugs, which are known to induce free radical cellular damage via the inhibition of the COX pathway or via other mechanisms (Mahmud et al 1996;Galati et al 2002).…”

Section: Discussionmentioning

confidence: 99%

The toxicokinetics of ketoprofen in Gyps coprotheres: toxicity due to zero-order metabolism

Naidoo

Venter

Wolter³

et al. 2010

Arch Toxicol

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In a safety study, Cape GriVon vultures (Gyps coprotheres) were dosed with ketoprofen at single doses of »1 mg/kg (n = 5) and 5 mg/kg (n = 11). No toxicity was reported in the 1 mg/kg group, with the AUC inf , V z and Cl being 10.42 g/ml h, 0.37 l/kg and 0.10 l/h kg, respectively. Toxicity occurred in the 5 mg/kg group, with 7 of the 11 birds dying. Clinical signs of toxicity included depression, loss of appetite and apparent coma. Animals died within 48 h of dosing. The AUC inf , V z and Cl in the birds that survived were 52.26 g/ml h, 0.45 l/kg and 0.10 l/h kg, respectively. The AUC inf , V z and Cl in the birds those died were 207.90 g/ml h, 0.26 l/kg and 0.02 l/h kg, respectively. Based on the increase in the AUC inf and C max in the birds that died, we surmise that toxicity resulted from saturation of the metabolic process. While the exact metabolic pathway remains unknown in these vultures, we believe that toxicity may be due to pharmacogenomic diVerences in the cytochrome P450 pathway.

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“…However, this improvement was associated with an increase in major bleeding events [absolute risk increase, 0.6-2.1%; relative risk increase, -54.5-37.0%] over variable periods from 8 days to 12 months. The mechanism of how aspirin may result in digestive diseases, particularly peptic ulcers, can be summarized by the following two points: i) Aspirin directly stimulates the phospholipid layer of gastric mucosa, which damages the hydrophobic protection barrier of the stomach (17), in addition to the increased release of cytotoxic substances (such as leukotrienes), which may also damage the gastric mucosa; ii) aspirin inhibits cyclooxygenase (COX)-1 and COX-2 in gastric mucosa (18). It is well-known that prostaglandin (PG) synthesis requires COX in gastric mucosa, and PGs can increase the blood flow of gastric mucosa and promote the synthesis of the mucus-HCO 3 barrier (19).…”

Section: Discussionmentioning

confidence: 99%

Clinical outcomes of various continued antiplatelet therapies in patients who were administered DAPT following the implantation of drug-eluting stents and developed gastrointestinal hemorrhage

Guo

Wei

2016

Experimental and Therapeutic Medicine

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Abstract. Although an increasing number of patients accept dual antiplatelet therapy (DAPT) following implantation of drug-eluting stents (DES) for coronary heart disease (CHD), the proportion of patients with DAPT who subsequently develop gastrointestinal hemorrhage continues to increase. To ensure the clinical outcomes from DES, it is important to formulate a novel continued antiplatelet therapy for patients who were administered DAPT and subsequently develop gastrointestinal hemorrhage following DES implantation. The present study aimed to evaluate the effects of continued aspirin, clopidogrel or DAPT use on the incidence of clinical adverse events and gastrointestinal rebleeding in patients who received DAPT and subsequently developed gastrointestinal hemorrhage following implantation of DES for CHD. Between 2004 and 2010, 108 consecutive patients receiving DAPT developed gastrointestinal hemorrhage following DES implantation for CHD at Liuzhou General Hospital (Liuzhou, Guangxi). These patients were divided into three groups according to the novel antiplatelet therapy. The occurrence of major adverse cardiac events (MACE), including cardiac death, non-fatal myocardial infarction, heart failure or target vessel revascularization, net adverse clinical events (NACE), including major bleeding, stroke or MACE, and gastrointestinal rebleeding during clinical follow-up following the initial procedure were compared among these three groups. The results of this analysis demonstrated that the occurrence rate of MACE, NECE and gastrointestinal rebleeding was not significantly different among these groups (P>0.05). Furthermore, survival analysis was performed and although the survival curves of MACE and NECE were not significantly different among these groups, gastrointestinal rebleeding was demonstrated to be significantly different among the three groups (P<0.05), and continued aspirin or clopidogrel use was superior to continued DAPT. In conclusion, the results of the present study indicated that there were no significant differences in the clinical effectiveness and safety of continuing antiplatelet monotherapy or DAPT in patients who are administered DAPT and experience gastrointestinal hemorrhage following DES implantation. As for the prevention of recurrent bleeding, antiplatelet monotherapy was demonstrated to be superior to DAPT. Moreover, the treatment of patients who are administered DAPT and experience gastrointestinal hemorrhage following DES implantation must involve an evaluation of the risk of complications, including stent thrombosis, continuous bleeding and recurrent hemorrhage.

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A unifying hypothesis for the mechanism of NSAID related gastrointestinal toxicity.

Cited by 73 publications

References 24 publications

Synchrotron SAXS and WAXS Study of the Interactions of NSAIDs with Lipid Membranes

Synchrotron SAXS and WAXS Study of the Interactions of NSAIDs with Lipid Membranes

The toxicokinetics of ketoprofen in Gyps coprotheres: toxicity due to zero-order metabolism

Clinical outcomes of various continued antiplatelet therapies in patients who were administered DAPT following the implantation of drug-eluting stents and developed gastrointestinal hemorrhage

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