Acetaminophen-induced fulminant hepatic failure in Dogs

Ortega, Luís; García, J. Iglesias; García, Antonio Torres; Silecchia, Gianfranço; Arenas, Juan; Suárez, África Peral; Azcoitia, M. Moreno; Esponera, Julián Sanz; González, Enrique Moreno; Cantero, José L.

doi:10.1002/hep.1840050425

Cited by 20 publications

(13 citation statements)

References 10 publications

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“…A large animal model of fulminant hepatic failure suitable for the development and evaluation of potential therapeutic modalities for this condition has yet to be described. During the last 10 yr, acetaminophen toxicity (16)(17)(18) and surgically produced ischemic necrosis (4-10) have been the most widely utilized models of acute hepatic failure. Galactosamine intoxication, a model developed principally in rats (29-32), has not been studied extensively in large animals because of the considerable expense of the drug.…”

Section: Discussionmentioning

confidence: 99%

“…The reported results of various experimental models (11)(12)(13)(14)(15)(16)(17)(18) have been compared with the results reported by Prescott et al (19) of a series of 30 patients with paracetamol overdose. In humans, the plasma acetaminophen level obtained 12 h after ingestion has been shown to be the best predictor of hepatic injury due to the drug (19).…”

Section: Discussionmentioning

confidence: 99%

“…None of the previous studies that have evaluated acetaminophen toxicity in large animals (11)(12)(13)(14)(15)(16)(17)(18)(19) have considered this observation. In the present report, a procedure has been developed that maintains plasma concentrations of acetaminophen for up to 20 h at a high enough concentration to create a reproducible form of severe hepatic injury that is not complicated by the appearance of methemoglobinemia.…”

Section: Discussionmentioning

confidence: 99%

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A Dog Model for Acetaminophen-Induced Fulminant Hepatic Failure

et al. 1989

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The development of a large animal model of fulminant hepatic failure produced with acetaminophen that should be useful in the development and evaluation of potential medical therapies for the important clinical problem of fulminant hepatic failure is described. Acetaminophen in dimethyl sulfoxide (600 mg/ml) given as three subcutaneous injections, with the first dose (750 mg/kg body wt) being given at noon, the second dose (200 mg/kg body wt) being given 9 h later, and the third dose (200 mg/kg body wt) being given 24 h after the initial dose consistently produces fulminant hepatic failure in dogs. The dimethyl sulfoxide vehicle, injected intramuscularly, does not influence either animal survival or hepatic function in control-treated dogs. No deaths occur within the first 36 h. By 72 h after initial drug administration, the mortality is 90%. Histopathological and biochemical investigations demonstrate a high degree of hepatocellular necrosis in nonsurviving animals without appreciable damage to the kidneys, lungs, or heart. The drug schedule and preparation outlined avoids the administration of large volumes of vehicle and results in prolonged high levels of acetaminophen in the blood sufficient to induce severe hepatic injury. Ranitidine (120 mg/kg body wt i.m.) given 30 min before each acetaminophen dose significantly reduces the mortality and hepatic necrosis produced using this model. This model satisfies all criteria established by Miller et al. for the production of a suitable large animal model of fulminant acute hepatic failure. A major deterrent to the development of new therapies for the important clinical problem of fulminant hepatic failure is the lack of a safe, reliable, and inexpensive large animal model to use in such studies (1-3). Currently, the two most frequently used large animal models of fulminant hepatic failure are produced either as a result of ischemic hepatic injury or acetaminophen-induced hepatotoxicity. Ischemic hepatic necrosis necessitates surgical intervention, requires considerable technical expertise, involves great expense, and is associated with a high degree of model-to-model variability (4-10). The second model capitalizes on the well-known hepatotoxicity of acetaminophen (11-15) and has been studied widely. Unfortunately, it has never been standardized or been shown to be reproducible, producing inconsistent toxicity from animal to animal and between experiments (16-18). Potentially, there are three important reasons for this lack of reproducible results with the acetaminophen model. First, no attention has been given to the determination of acetaminophen blood levels in the animals being studied despite the fact that it is known that high blood levels of the drug are required to produce hepatic necrosis. Second, the duration of elevated levels of the drug necessary to produce consistent panlobular necrosis has not been determined.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Dog Model for Acetaminophen-Induced Fulminant Hepatic Failure

et al. 1989

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“…This review discusses two of the more widely used hepatotoxins, galactosamine [29][30][31][32][33][34][35][36] and acetaminophen. [37][38][39][40][41][42][43][44] Over the past 30 years, acetaminophen overdose has become the most common cause of FHF in the United Kingdom. 2…”

Section: Chemical Modelsmentioning

confidence: 99%

“…Even so, models of acetaminopheninduced liver failure have been successfully developed in dogs. 42,59 This would suggest that methemoglobinemia does not pose an insurmountable obstacle to the development of an acetaminophen-induced porcine model.…”

Section: Acetaminophen Modelsmentioning

confidence: 99%

Animal models of fulminant hepatic failure: A critical evaluation

et al. 2000

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Few conditions in medicine are more dramatic or more devastating than acute liver failure. Our understanding and treatment of this condition have been limited by the lack of satisfactory animal models. The most widely used models consist of surgical anhepatic and devascularization procedures and hepatotoxins, such as galactosamine and acetaminophen. Potential disadvantages with surgical models are their inability to recreate the inflammatory milieu that exists in acute liver failure and their reliance on surgical expertise. Models using hepatotoxins are free of such constraints. Galactosamine-induced hepatotoxicity is more predictable than acetaminophen, but its cost and lack of a human equivalent clinical syndrome has restricted its use. Acetaminophen-based models offer the greatest potential but have proven the most difficult to develop because of difficulties with reproducibility and refractory anemia. Although progress has been made, research must continue in this area to establish an animal model with minimal disadvantages that would accurately reflect the clinical syndrome seen in humans.

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Paracetamol

and¹,

Chapman²

2000

Handbook of Poisoning in Dogs and Cats

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Acetaminophen-induced fulminant hepatic failure in Dogs

Cited by 20 publications

References 10 publications

A Dog Model for Acetaminophen-Induced Fulminant Hepatic Failure

A Dog Model for Acetaminophen-Induced Fulminant Hepatic Failure

Animal models of fulminant hepatic failure: A critical evaluation

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