• 1.

    Collins LG, Tyler DE. Experimentally induced phenylbutazone toxicosis in ponies: description of the syndrome and its prevention with synthetic prostaglandin E2. Am J Vet Res 1985; 46:16051615.

    • Search Google Scholar
    • Export Citation
  • 2.

    Wallace JL. Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years. Gastroenterology 1997; 112:10001016.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    McCarthy D. Nonsteroidal anti-inflammatory drug-related gastrointestinal toxicity: definitions and epidemiology. Am J Med 1998; 105(suppl 5A):3S9S.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Jones CJ, Streppa HK, Harmon BG, et al. In vivo effects of meloxicam and aspirin on blood, gastric mucosal, and synovial fluid prostanoid synthesis in dogs. Am J Vet Res 2002; 63:15271531.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Peura DA. Prevention of nonsteroidal anti-inflammatory drug-associated gastrointestinal symptoms and ulcer complications. Am J Med 2004; 117(suppl 5A):63S71S.

    • Search Google Scholar
    • Export Citation
  • 6.

    Vonderhaar MA, Salisbury SK. Gastroduodenal ulceration associated with flunixin meglumine administration in three dogs. J Am Vet Med Assoc 1993; 203:9295.

    • Search Google Scholar
    • Export Citation
  • 7.

    Lascelles BD, Blikslager AT, Fox SM, et al. Gastrointestinal tract perforation in dogs treated with selective cyclooxygenase-2 inhibitor: 29 cases (2002–2003). J Am Vet Med Assoc 2005; 227:11121117.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Gassner G, Stephan I, Schutt-Mast I. Observations on the side effects after application of non-steroidal anti-inflammatory agents in dogs. Tierarztl Prax Ausg K Klientiere Heimtiere 1998; 26:119123.

    • Search Google Scholar
    • Export Citation
  • 9.

    Wooten JG, Blikslager AT, Ryan KA, et al. Cyclooxygenase expression and prostanoid production in pyloric and duodenal mucosae in dogs after administration of nonsteriodal anti-inflammatory drugs. Am J Vet Res 2008; 69:457464.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Forsyth SF, Guilford WJ, Haslett SJ, et al. Endoscopy of the gastroduodenal mucosa after carprofen, meloxicam and ketoprofen administration in dogs. J Small Anim Pract 1998; 39:421424.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Villegas I, La Casa C, de la Lastra CA, et al. Mucosal damage induced by preferential COX-1 and COX-2 inhibitors: role of prostaglandins and inflammatory response. Life Sci 2004; 74:873884.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    MacDonald TM, Morant SV, Goldstein JL, et al. Channelling bias and the incidence of gastrointestinal haemorrhage in users of meloxicam, coxibs, and older, non-specific non-steroidal anti-inflammatory drugs. Gut 2003; 52:12651270.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Blikslager AT. Treatment of gastrointestinal ischemic injury. Vet Clin North Am Equine Pract 2003; 19:715727.

  • 14.

    Fox SM, Johnston SA. Use of carprofen for the treatment of pain and inflammation in dogs. J Am Vet Med Assoc 1997; 210:14931498.

  • 15.

    Kay-Mugford P, Benn SJ, LaMarre J, et al. In vitro effects of non-steroidal anti-inflammatory drugs on cyclooxygenase activity in dogs. Am J Vet Res 2000; 61:802810.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Ricketts AP, Lundy KM, Seibel SB. Evaluation of selective inhibition of canine cyclooxygenase 1 and 2 by carprofen and other nonsteroidal anti-inflammatory drugs. Am J Vet Res 1998; 59:14411446.

    • Search Google Scholar
    • Export Citation
  • 17.

    Rubio F, Seawall S, Pocelinko R, et al. Metabolism of carprofen, a nonsteroid anti-inflammatory agent, in rats, dogs, and humans. J Pharm Sci 1980; 69:12451253.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Plumb DC. Plumb's veterinary drug handbook. 6th ed. Somerset, NJ: Wiley-Blackwell Publishing, 2008; 137, 574575.

  • 19.

    Vane JR, Botting RM. Anti-inflammatory drugs and their mechanism of action. Inflamm Res 1998; 47(suppl 2):S78S87.

  • 20.

    Khattab MM, Gad MZ, Abdallah D. Protective role of nitric oxide in indomethacin-induced gastric ulceration by a mechanism independent of gastric acid secretion. Pharmacol Res 2001; 43:463467.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Suzuki T, Yoshida N, Nakabe N, et al. Prophylactic effect of rebamipide on aspirin-induced gastric lesions and disruption of tight junctional protein zonula occludens-1 distribution. J Pharmacol Sci 2008; 106:469477.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Borda IT. The spectrum of adverse gastrointestinal effects associated with non-steroidal anti-inflammatory drugs. In: Borda IT, Koff RS, eds. NSAIDs: a profile of adverse effects. Philadelphia: Hanley and Belfus, 1992;1580.

    • Search Google Scholar
    • Export Citation
  • 23.

    Somasundaram S, Sigthorsson G, Simpson RJ, et al. Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat. Aliment Pharmacol Ther 2000; 14:639650.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    McCafferty DM, Granger DN, Wallace JL. Indomethacin-induced gastric injury and leukocyte adherence in arthritic versus healthy rats. Gastroenterology 1995; 109:11731180.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Peskar BM. Role of leukotriene C4 in mucosal damage caused by necrotizing agents and indomethacin in the rat stomach. Gastroenterology 1991; 100:619626.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Martel-Pelletier J, Lajeunesse D, Reboul P, et al. Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs. Ann Rheum Dis 2003; 62:501509.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Clark TP, Chieffo C, Huhn JC, et al. The steady-state pharmacokinetics and bioequivalence of carprofen administered orally and subcutaneously in dogs. J Vet Pharmacol Ther 2003; 26:187192.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Deavers S, Huggins RA, Smith EL. Absolute and relative organ weights of the growing Beagle. Growth 1972; 36:195208.

  • 29.

    Busch U, Schmid J, Heinzel G, et al. Pharmacokinetics of meloxicam in animals and the relevance to humans. Drug Metab Dispos 1998; 26:576584.

    • Search Google Scholar
    • Export Citation
  • 30.

    Stewart J. Approximate integration. In: Calculus early transcen-dentals. 3rd ed. Belmont, Calif: Thomson Brooks Cole Publishing, 1995;457465.

    • Search Google Scholar
    • Export Citation
  • 31.

    Nedergaard S, Larsen EH, Ussing HH. Sodium recirculation and isotonic transport in toad small intestine. J Membr Biol 1999; 168:241251.

  • 32.

    Li H, Sheppard DN, Hug MJ. Transepithelial electrical measurements with the Ussing chamber. J Cyst Fibros 2004; 3(suppl 2):123126.

  • 33.

    Mlodzik-Danielewicz N, Tyrakowski T. Effects of amiloride and bumetanide on hyperpolarization after movement across the distal colon epithelium. Pharmacol Rep 2005; 57:489497.

    • Search Google Scholar
    • Export Citation
  • 34.

    Rechkemmer G, Frizzell RA, Halm DR. Active potassium transport across guinea-pig distal colon: action of secretagogues. J Physiol 1996; 493:485502.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Tai YH, Flick J, Levine SA, et al. Regulation of tight junction resistance in T84 monolayers by elevation in intracellular Ca2+: a protein kinase C effect. J Membr Biol 1996; 149:7179.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Davenport HW. Salicylate damage to the gastric mucosal barrier. N Engl J Med 1967; 276:13071312.

  • 37.

    Polentarutti BI, Peterson AL, Sjoberg AK, et al. Evaluation of viability of excised rat intestinal segments in the Ussing chamber: investigation of morphology, electrical parameters, and permeability characteristics. Pharm Res 1999; 16:446454.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Briere CA, Hosgood G, Morgan TW, et al. Effects of carprofen on the integrity and barrier function of canine colonic mucosa. Am J Vet Res 2008; 69:174181.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Yamada T, Deitch E, Specian RD, et al. Mechanisms of acute and chronic intestinal inflammation induced by indomethacin. Inflammation 1993; 17:641662.

  • 40.

    Reuter BK, Davies NM, Wallace JL. Nonsteroidal anti-inflammatory drug enteropathy in rats: role of permeability, bacteria, and enterohepatic circulation. Gastroenterology 1997; 112:109117.

    • Crossref
    • Search Google Scholar
    • Export Citation

Advertisement

In vitro effect of carprofen and meloxicam on the conductance and permeability to mannitol and the histologic appearance of the gastric mucosa of dogs

View More View Less
  • 1 Departments of Veterinary Clinical Sciences
  • | 2 Departments of Veterinary Clinical Sciences
  • | 3 Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.
  • | 4 Departments of Veterinary Clinical Sciences
  • | 5 Departments of Veterinary Clinical Sciences

Abstract

Objective—To evaluate the effects of carprofen and meloxicam on conductance and permeability to mannitol and on the histologic appearance of sections of canine gastric mucosa.

Sample—Gastric mucosa from 6 mature mixed-breed dogs.

Procedures—Sections of gastric mucosa were mounted in Ussing chambers, and carprofen (40 or 400μg/mL [CAR40 and CAR400, respectively]), meloxicam (8 or 80μg/mL [MEL8 and MEL80, respectively]), or no drug (controls) was added to the bathing solution. For all sections, conductance was calculated every 15 minutes for 240 minutes and flux of mannitol was calculated for 3 consecutive 1-hour periods; histologic examination was performed after the experiment. The area under the conductance-time curve for each chamber was calculated. Values of conductance × time, flux of mannitol, and the frequency distribution of histologic findings were analyzed for treatment effects.

Results—For CAR400- and MEL80-treated sections, conductance X time was significantly higher than that for control and MEL8-treated sections. The effect of CAR40 treatment was not different from that of any other treatment. Over the three 1-hour periods, mannitol flux increased significantly in MEL80-, CAR40-, and CAR400-treated sections but not in MEL8- treated or control sections. Major histologic changes including epithelial cell sloughing were limited to the CAR400-treated sections.

Conclusions and Clinical Relevance—In the gastric mucosa of dogs, carprofen and meloxicam increased in vitro conductance and permeability to mannitol. At a concentration of 400 μg/mL, carprofen caused sloughing of epithelial cells. Carprofen and meloxicam appear to compromise gastric mucosal integrity and barrier function in dogs.

Abstract

Objective—To evaluate the effects of carprofen and meloxicam on conductance and permeability to mannitol and on the histologic appearance of sections of canine gastric mucosa.

Sample—Gastric mucosa from 6 mature mixed-breed dogs.

Procedures—Sections of gastric mucosa were mounted in Ussing chambers, and carprofen (40 or 400μg/mL [CAR40 and CAR400, respectively]), meloxicam (8 or 80μg/mL [MEL8 and MEL80, respectively]), or no drug (controls) was added to the bathing solution. For all sections, conductance was calculated every 15 minutes for 240 minutes and flux of mannitol was calculated for 3 consecutive 1-hour periods; histologic examination was performed after the experiment. The area under the conductance-time curve for each chamber was calculated. Values of conductance × time, flux of mannitol, and the frequency distribution of histologic findings were analyzed for treatment effects.

Results—For CAR400- and MEL80-treated sections, conductance X time was significantly higher than that for control and MEL8-treated sections. The effect of CAR40 treatment was not different from that of any other treatment. Over the three 1-hour periods, mannitol flux increased significantly in MEL80-, CAR40-, and CAR400-treated sections but not in MEL8- treated or control sections. Major histologic changes including epithelial cell sloughing were limited to the CAR400-treated sections.

Conclusions and Clinical Relevance—In the gastric mucosa of dogs, carprofen and meloxicam increased in vitro conductance and permeability to mannitol. At a concentration of 400 μg/mL, carprofen caused sloughing of epithelial cells. Carprofen and meloxicam appear to compromise gastric mucosal integrity and barrier function in dogs.

Contributor Notes

Address correspondence to Dr. Hicks (mh@petemergency.com.au).

Dr. Hicks' present address is Pet Emergency and Specialist Centre, 1103 Dandenong Rd, Malvern East, VIC 3145, Australia.

Supported by the Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University.

The authors thank Catherine Koch and Dr. Kevin Kleinow for technical assistance.