Roles of COX inhibition in pathogenesis of NSAID-induced small intestinal damage

Takeuchi, Koji; Tanaka, Akiko; Kato, Shinichi; Amagase, Kikuko; Satoh, Hiroshi

doi:10.1016/j.cca.2009.12.026

Cited by 99 publications

(85 citation statements)

References 40 publications

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“…There is a study suggesting that bacterial flora may play a role on the pathogenesis of NSAIDs bowel injury. This study has demonstrated that antimicrobials attenuated NSAIDs induced enteropathy in rats [26]. From these observations, it may be possible that gastrointestinal bacteria counts may be lower in young cats than in adult cats.…”

Section: Discussionmentioning

confidence: 56%

Therapeutic and Adverse Effects of Flunixin-Meglumine in Adult and Young Cats

Takata

Hikasa

Satoh

2011

The Journal of Veterinary Medical Science

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ABSTRACT. In this study, we elucidated the difference in nonsteroidal anti-inflammatory drug sensitivities between young and adult cats on therapeutic and adverse effects. In the prevention of lipopolysaccharide (LPS)-induced hyperthermia using flunixin-meglumine, young (<3 months old) and adult (>12 months old) cats of both sexes were given LPS (0.3 g/kg, i.v.), and body temperature was measured 24 hr later. Flunixin (1 mg/kg, s.c.) was administered 30 min before the LPS injection. LPS-induced hyperthermia was almost completely inhibited by pre-treatment with flunixin in both adult and young cats. In addition, flunixin showed almost the same antipyretic effects in both young and adult cats. The animals were administered flunixin (1 mg/kg, s.c.) once a day for 3 days, and sacrificed 24 hr later to examine the gastrointestinal mucosal lesions. In adult cats, flunixin caused many severe lesions in the small intestine. In contrast, very few gastrointestinal lesions were produced by flunixin in young cats. In the pharmacokinetics of flunixin, plasma concentrations of flunixin were analysed using a high performance liquid chromatography. There were no significant differences in plasma concentration of flunixin between young and adult cats from 0.5 to 4 hr after the injection. These results demonstrated that NSAIDs could be used more safely in young than in adult cats from the points of gastrointestinal adverse effects. Furthermore, this difference in gastrointestinal lesions between adult and young cats was not related with the plasma concentration of flunixin.KEY WORDS: flunixin-megulumine, gastrointestinal effect, lipopolysaccharide, nonsteroidal anti-inflammatory drug, pharmacokinetics.J. Vet. Med. Sci. 73(12): 1591-1596, 2011 Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used analgesics in veterinary and human medicine. In most species, they are very effective in acute and chronic pains. For example, NSAIDs are often the first drugs used for treatment of pain caused by osteoarthritis in veterinary medicine [20]. In the analgesic study of cats, the effect of flunixin-meglumine (FNX) has been reported in 40 cats undergoing a variety of surgical procedures [9]. It is also well known that NSAIDs cause some adverse effects such as gastrointestinal side-effects in the veterinary medicine. In rats, many kind of NSAIDs have been reported to cause gastrointestinal lesions because of the inhibition of prostaglandins synthesis even new NSAIDs [1]. However, the data on the usage of NSAIDs in cats are less complete than in dogs and, to date, there are no published data about gastrointestinal side-effects in cats.Most NSAIDs are cleared from the body through hepatic metabolism comprising primarily glucuronidation followed by excretion of the resultant polar metabolites via bile and/ or urine. Flunixin is well absorbed from the gastrointestinal tract and undergoes enterohepatic circulation, resulting in a bioavailability of >100% in dogs and cats [16]. At least, two other active transport pathways are invol...

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Section: Discussionmentioning

confidence: 56%

Therapeutic and Adverse Effects of Flunixin-Meglumine in Adult and Young Cats

Takata

Hikasa

Satoh

2011

The Journal of Veterinary Medical Science

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“…Also, although COX-2 is expressed briefly in response to tissue injury (131), the use of COX-2 and prostaglandin inhibitors appears only to impart a modest effect over wound healing (131,244). Even though these types of inhibitors block inflammation, they exacerbate injury since they prevent wound healing especially in the intestine (354). Conversely, COX-2 inhibition reduces renal fibrosis (129,302), suggesting that PGE2 may contribute to fibrosis in the kidney.…”

Section: Cyclo-oxygenase-2mentioning

confidence: 99%

The wound healing, chronic fibrosis, and cancer progression triad

Rybinski

Franco‐Barraza

Cukierman

2014

Physiological Genomics

215

175

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For decades tumors have been recognized as “wounds that do not heal.” Besides the commonalities that tumors and wounded tissues share, the process of wound healing also portrays similar characteristics with chronic fibrosis. In this review, we suggest a tight interrelationship, which is governed as a concurrence of cellular and microenvironmental reactivity among wound healing, chronic fibrosis, and cancer development/progression (i.e., the WHFC triad). It is clear that the same cell types, as well as soluble and matrix elements that drive wound healing (including regeneration) via distinct signaling pathways, also fuel chronic fibrosis and tumor progression. Hence, here we review the relationship between fibrosis and cancer through the lens of wound healing.

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“…Meanwhile, neutrophils accumulate at the site of inflammation and cause production of superoxide radicals. NO reacts with the superoxide radicals, resulting in the formation of peroxynitrite, a very cytotoxic substance (23,24). This sequence of events eventually leads to the development of intestinal lesions.…”

Section: Mechanism Underlying Msg-induced Intestinal Protectionmentioning

confidence: 99%

New Therapeutic Strategy for Amino Acid Medicine: Prophylactic and Healing Promoting Effect of Monosodium Glutamate Against NSAID-Induced Enteropathy

et al. 2012

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Abstract.We reviewed the effect of monosodium glutamate (MSG) on the development and healing of nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal lesions in rats. Loxoprofen (60 mg/kg, p.o.) induced lesions in the small intestine within 24 h, accompanied by a decrease of Muc2 expression and an increase in enterobacterial invasion and inducible nitric oxide synthase (iNOS) expression. These lesions were prevented when MSG was given as a mixture of powdered food for 5 days before the loxoprofen treatment. This effect of MSG was accompanied by an increase in Muc2 expression / mucus secretion as well as the suppression of bacterial invasion and iNOS expression. These intestinal lesions healed spontaneously within 6 days, but the process was impaired by the repeated administration of low-dose loxoprofen (30 mg/kg) for 5 days after the ulceration, with the decrease of vascular endothelial derived growth factor (VEGF) expression and angiogenesis. The healing-impairing effect of loxoprofen was prevented by feeding 5% MSG for 5 days after the ulceration. These results suggest that MSG not only prevents loxoprofen-induced small intestinal damage but also promotes a healing of these lesions; the former is functionally associated with the increase in Muc2 expression / mucus secretion and the suppression of bacterial invasion and iNOS expression, while the latter is associated with the stimulation of VEGF expression/angiogenesis.

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Roles of COX inhibition in pathogenesis of NSAID-induced small intestinal damage

Cited by 99 publications

References 40 publications

Therapeutic and Adverse Effects of Flunixin-Meglumine in Adult and Young Cats

Therapeutic and Adverse Effects of Flunixin-Meglumine in Adult and Young Cats

The wound healing, chronic fibrosis, and cancer progression triad

New Therapeutic Strategy for Amino Acid Medicine: Prophylactic and Healing Promoting Effect of Monosodium Glutamate Against NSAID-Induced Enteropathy

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