Estimation of acute flurbiprofen and ketoprofen toxicity in rat gastric mucosa at therapy-relevant doses

Holzer, Peter; Jocič, Milana; Cabré, Francesc; Mauleón, David

doi:10.1007/pl00000241

Cited by 13 publications

(8 citation statements)

References 34 publications

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“…Indeed, a recent study by our group showed that another CINOD, the NO-donating flurbiprofen HCT 1026, was effective in slowing muscle dystrophy and that, at least in animal models, it was superior to the glucocorticoid prednisolone [18]. However, flurbiprofen produces severe gastrointestinal damage which makes it unsuitable for long-term treatment, especially in paediatric patients [46]. Therefore, we have focused on NCX 320 because it is based on ibuprofen, whose profile of safety and tolerability is well established and consequently is accepted for paediatric use [47].…”

Section: Discussionmentioning

confidence: 99%

A dual acting compound releasing nitric oxide (NO) and ibuprofen, NCX 320, shows significant therapeutic effects in a mouse model of muscular dystrophy

Sciorati¹,

Miglietta

Buono

et al. 2011

Pharmacological Research

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Section: Discussionmentioning

confidence: 99%

A dual acting compound releasing nitric oxide (NO) and ibuprofen, NCX 320, shows significant therapeutic effects in a mouse model of muscular dystrophy

Sciorati¹,

Miglietta

Buono

et al. 2011

Pharmacological Research

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“…Interestingly, R-flurbiprofen does not inhibit cyclooxygenase activity [4] and has been considered as the non-functional constituent of marketed flurbiprofen-racemate. However, R-flurbiprofen reduces inflammation [5] via inhibition of the transcription factor NF-κB [5] and is essentially free of the side effects typical to classical NSAIDs, such as gastrointestinal or renal toxicity [6]. Because of the anti-inflammatory efficacy and essential lack of toxicity R-flurbiprofen has been evaluated as a potential remedy in Alzheimer's disease with some success in clinical trials [7].…”

Section: Introductionmentioning

confidence: 99%

R-Flurbiprofen Reduces Neuropathic Pain in Rodents by Restoring Endogenous Cannabinoids

et al. 2010

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BackgroundR-flurbiprofen, one of the enantiomers of flurbiprofen racemate, is inactive with respect to cyclooxygenase inhibition, but shows analgesic properties without relevant toxicity. Its mode of action is still unclear.Methodology/Principal FindingsWe show that R-flurbiprofen reduces glutamate release in the dorsal horn of the spinal cord evoked by sciatic nerve injury and thereby alleviates pain in sciatic nerve injury models of neuropathic pain in rats and mice. This is mediated by restoring the balance of endocannabinoids (eCB), which is disturbed following peripheral nerve injury in the DRGs, spinal cord and forebrain. The imbalance results from transcriptional adaptations of fatty acid amide hydrolase (FAAH) and NAPE-phospholipase D, i.e. the major enzymes involved in anandamide metabolism and synthesis, respectively. R-flurbiprofen inhibits FAAH activity and normalizes NAPE-PLD expression. As a consequence, R-Flurbiprofen improves endogenous cannabinoid mediated effects, indicated by the reduction of glutamate release, increased activity of the anti-inflammatory transcription factor PPARγ and attenuation of microglia activation. Antinociceptive effects are lost by combined inhibition of CB1 and CB2 receptors and partially abolished in CB1 receptor deficient mice. R-flurbiprofen does however not cause changes of core body temperature which is a typical indicator of central effects of cannabinoid-1 receptor agonists.ConclusionOur results suggest that R-flurbiprofen improves the endogenous mechanisms to regain stability after axonal injury and to fend off chronic neuropathic pain by modulating the endocannabinoid system and thus constitutes an attractive, novel therapeutic agent in the treatment of chronic, intractable pain.

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“…The profens are racemates, and their ability to block arachidonic acid oxygenation is associated with the (S)-enantiomers. However, (R)-flurbiprofen is analgesic in humans with modest enantioconversion in vivo and has a better gastrointestinal safety profile than the (S)-enantiomer (L€ otsch et al 1995;Holzer et al 2001). Bishay et al (2010) found that systemically administered (R)-flurbiprofen alleviated mechanical hyperalgesia, cold allodynia and cold hyperalgesia in the spared nerve injury model of neuropathic pain accompanied by a normalisation of AEA levels in the dorsal root ganglia, dorsal horn and forebrain.…”

Section: Oxygenating Enzymes (Cox-2)mentioning

confidence: 97%

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

Fowler

2015

Handbook of Experimental Pharmacology

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The endocannabinoids anandamide and 2-arachidonoylglycerol are metabolised by both hydrolytic enzymes (primarily fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL)) and oxygenating enzymes (e.g. cyclooxygenase-2, COX-2). In the present article, the in vivo data for compounds inhibiting endocannabinoid metabolism have been reviewed, focussing on inflammation and pain. Potential reasons for the failure of an FAAH inhibitor in a clinical trial in patients with osteoarthritic pain are discussed. It is concluded that there is a continued potential for compounds inhibiting endocannabinoid metabolism in terms of drug development, but that it is wise not to be unrealistic in terms of expectations of success.

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Estimation of acute flurbiprofen and ketoprofen toxicity in rat gastric mucosa at therapy-relevant doses

Cited by 13 publications

References 34 publications

A dual acting compound releasing nitric oxide (NO) and ibuprofen, NCX 320, shows significant therapeutic effects in a mouse model of muscular dystrophy

A dual acting compound releasing nitric oxide (NO) and ibuprofen, NCX 320, shows significant therapeutic effects in a mouse model of muscular dystrophy

R-Flurbiprofen Reduces Neuropathic Pain in Rodents by Restoring Endogenous Cannabinoids

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

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