Side-effects and Toxicology of the Salicylates

Rainsford, K. D.

doi:10.1016/b978-0-407-00316-3.50012-3

Cited by 12 publications

(17 citation statements)

References 598 publications

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“…These data are also instructive in Wolfe et al (1999) and Laine (2001); modified and with additional information from Rainsford (1984;2004a, 2005b highlighting the fact that high dose paracetamol (hitherto regarded as a GI safe drug) when taken at doses of [2 g day -1 alone or in combination with NSAIDs is associated with relative risks [2 (alone) or [6 (combination with NSAIDs) of haemorrhage.…”

Section: Gastro-intestinal (Gi) Toxicitymentioning

confidence: 86%

“…The extent of the loss of blood maybe overestimated using the radiochromium technique as a consequence of biliary excretion of the radiolabelled chromium (Schneider et al 1984;Rainsford 2004a). The extent of the mucosal changes (lesions, ulcers) and blood loss from ibuprofen is low compared with other NSAIDs but is above that of placebo and paracetamol (Strom et al 1997;Rainsford 1999c).…”

Section: Gastro-intestinal (Gi) Toxicitymentioning

confidence: 97%

“…These reactions have been frequently reported with aspirin and the terms ''aspirin-associated asthma'' or ''aspirin-sensitive asthma'' (ASA) have been employed to describe the association of symptoms of asthma with aspirin (Arnaud 1995;Rainsford 2004a: de Weck et al 2006Quiralte et al 2007). In patients with ASA small doses of aspirin can lead to severe attacks.…”

Section: Hypersensitivity Reactions and Asthmamentioning

confidence: 98%

“…Like many conventional (or traditional) tNSAIDs, ibuprofen inhibits both the constitutive cyclo-oxygenase-1 (COX-1) which is responsible for production of prostanoids (PGs and thromboxane A 2 , TxA 2 ) that control a range of physiological or ''housekeeping'' functions (vascular, blood flow, gastric and renal functions), and the inducible COX-2 whose synthesis is increased leading to amplified production of PGE 2 in inflammation and pain (Cryer and Feldman 1998;Rainsford 1999bRainsford , 2004aWarner et al 1999;Vane and Botting 2001). COX-1 inhibition has been considered a factor underlying the possibility of NSAIDs to cause some adverse effects (GI ulcers, bleeding, renal abnormalities) although there are other biochemical and cellular actions of NSAIDs that contribute to their untoward effects (Rainsford 2004a;Bjarnason et al 2007). The ratio of inhibition of COX-1 to COX-2 has been considered to relate to likelihood of developing upper GI and possibly renal and other reactions by NSAIDs in relation to their anti-inflammatory activities (Cryer and Feldman 1998;Warner et al 1999;Vane and Botting 2001).…”

Section: Modes Of Action In Relation To Pharmacokineticsmentioning

confidence: 99%

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Ibuprofen: pharmacology, efficacy and safety

2009

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This assessment of the safety and benefits of ibuprofen can be summarized thus: (1) Ibuprofen at OTC doses has low possibilities of serious GI events, and little prospect of developing renal and associated CV events. Ibuprofen OTC does not represent a risk for developing liver injury especially the irreversible liver damage observed with paracetamol and the occasional liver reactions from aspirin. (2) The pharmacokinetic properties of ibuprofen, especially the short plasma half-life of elimination, lack of development of pathologically related metabolites (e.g. covalent modification of liver proteins by the quinine-imine metabolite of paracetamol or irreversible acetylation of biomolecules by aspirin) are support for the view that these pharmacokinetic and notably metabolic effects of ibuprofen favour its low toxic potential. (3) The multiple actions of ibuprofen in controlling inflammation combine with moderate inhibition of COX-1 and COX-2 and low residence time of the drug in the body may account for the low GI, CV and renal risks from ibuprofen, especially at OTC doses.

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Section: Gastro-intestinal (Gi) Toxicitymentioning

confidence: 86%

Section: Gastro-intestinal (Gi) Toxicitymentioning

confidence: 97%

Section: Hypersensitivity Reactions and Asthmamentioning

confidence: 98%

Section: Modes Of Action In Relation To Pharmacokineticsmentioning

confidence: 99%

See 2 more Smart Citations

Ibuprofen: pharmacology, efficacy and safety

2009

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“…chronic infl ammatory disease or increased acidity which are reliably reproduced in laboratory animals. Hence, this prompted us to investigate the gastric mucosal reactions to paracetamol in animals with infl ammatory stress conditions and in whom gastric acid secretion was stimulated with a cholinomimetic drug given hydrochloric acid, both conditions of which are known to exacerbate injury from NSAIDs and which are known to be important in development of NSAID injury (Rainsford and Brune, 1976;Rainsford, 2004). We have previously shown these stressors can markedly enhance the gastro-ulcerogenic effects of most non-steroidal anti-infl ammatory drugs (NSAIDs), even those with the reputation for being the mildest irritants (Rainsford, 1987(Rainsford, , 1989(Rainsford, , 1999.…”

Section: Resultsmentioning

confidence: 99%

Paracetamol [acetaminophen]-induced gastrotoxicity: revealed by induced hyperacidity in combination with acute or chronic inflammation

Rainsford

Whitehouse

2006

Inflammopharmacol

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Paracetamol is regarded as a relatively safe drug in the gastro-duodenal region of humans but recent epidemiological investigations have suggested that at high doses there may be an increased risk of ulcers and bleeding. To investigate the possibility that inflammatory conditions and gastric acidity may play a role in potentiating development of gastric mucosal injury from paracetamol in rats (as noted previously with various non-steroidal anti-inflammatory drugs) we studied the gastric irritant effects of paracetamol and some phenolic and non-phenolic analgesics and antipyretics in rats with adjuvant or collagen II induced arthritis or zymosan-induced paw inflammation and given 1.0 ml hydrochloric acid (HCl) 0.1 M and/or an i. p. injection of the cholinomimetic, acetyl-beta-methyl choline chloride 5.0 mg/kg. Gastric lesions were determined 2 h after oral administration of 100 or 250 mg/kg paracetamol or at therapeutically effective doses of the phenolic or non-phenolic analgesics/antipyretics. The results showed that gastric mucosal injury occurred with all these agents when given to animals that received all treatments so indicating there is an adverse synergy of these three factors, namely: (i) intrinsic disease; (ii) hyperacidity; and (iii) vagal stimulation for rapidly promoting gastric damage, both in the fundic as well as the antral mucosa, for producing gastric damage by paracetamol, as well as the other agents. Removing one of these three predisposing factors effectively blunts/abolishes expression of this paracetamol-induced gastrotoxicity in rats. These three factors, without paracetamol, did not cause significant acute gastropathy.

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A Novel NF‐κB Inhibitor, Edasalonexent (CAT‐1004), in Development as a Disease‐Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects

Donovan

Zimmer

Offman

et al. 2017

The Journal of Clinical Pharma

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In Duchenne muscular dystrophy (DMD), NF‐κB is activated in skeletal muscle from infancy regardless of the underlying dystrophin mutation and drives inflammation and muscle degeneration while inhibiting muscle regeneration. Edasalonexent (CAT‐1004) is a bifunctional orally administered small molecule that covalently links 2 compounds known to inhibit NF‐κB, salicylic acid and docosahexaenoic acid (DHA). Edasalonexent is designed to inhibit activated NF‐κB upon intracellular cleavage to these bioactive components. Preclinical data demonstrate disease‐modifying activity in DMD animal models. Three placebo‐controlled studies in adult subjects assessed the safety, pharmacokinetics, and pharmacodynamics of single or multiple edasalonexent doses up to 6000 mg. Seventy‐nine adult subjects received edasalonexent, and 25 received placebo. Pharmacokinetic results were consistent with the intracellular cleavage of edasalonexent to its active components. Food increased plasma exposures of edasalonexent and salicyluric acid, an intracellularly formed metabolite of salicylic acid. The NF‐κB pathway and proteosome gene expression profiles in peripheral mononuclear cells were significantly decreased (P = .02 and P = .002, respectively) after 2 weeks of edasalonexent treatment. NF‐κB activity was inhibited following a single dose of edasalonexent but not by equimolar doses of salicylic acid and DHA. Edasalonexent was well tolerated, and the most common adverse events were mild diarrhea and headache. In first‐in‐human studies, edasalonexent was safe, well tolerated, and inhibited activated NF‐κB pathways, suggesting potential therapeutic utility in DMD regardless of the causative dystrophin mutation, as well as other NF‐κB–mediated diseases.

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Side-effects and Toxicology of the Salicylates

Cited by 12 publications

References 598 publications

Ibuprofen: pharmacology, efficacy and safety

Ibuprofen: pharmacology, efficacy and safety

Paracetamol [acetaminophen]-induced gastrotoxicity: revealed by induced hyperacidity in combination with acute or chronic inflammation

A Novel NF‐κB Inhibitor, Edasalonexent (CAT‐1004), in Development as a Disease‐Modifying Treatment for Patients With Duchenne Muscular Dystrophy: Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics in Adult Subjects

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