A Gargantuan Acetaminophen Level in an Acidemic Patient Treated Solely With Intravenous N-Acetylcysteine

Zell-Kanter, Michele; Coleman, Patrick J.; Whiteley, Patrick; Leikin, Jerrold B.

doi:10.1097/mjt.0b013e3181ff7ac0

Cited by 21 publications

(12 citation statements)

References 14 publications

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“…33 Recent circumstantial evidence advocated for the clinical use of 4MP with APAP poisoning. 28,29 However, the benefit of such treatment is not well established.…”

Section: Discussionmentioning

confidence: 99%

“…A recent case report described a patient presenting with extremely high plasma APAP levels of 1,100 mg/L, who was initially treated with a single dose of Fomepizole (4-methylpyrazole, 4MP) followed by a standard NAC treatment regimen. 28 This led others to suggest that the co-treatment with 4MP was a likely reason for the survival of the patient. 29 Although 4MP is a competitive inhibitor of alcohol dehydrogenase, 30–32 and as such is clinically used as an antidote to methanol and ethylene glycol poisoning, 33 studies with human microsomes and HepG2 cells have demonstrated that 4MP can also inhibit CYP2E1 34,35 In addition, 4MP attenuated APAP-induced liver injury in rats 36,37 but appeared to be not more effective than NAC.…”

Section: Introductionmentioning

confidence: 99%

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4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes

et al. 2018

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Liver injury due to acetaminophen (APAP) overdose is the major cause of acute liver failure in the United States. While treatment with N-acetylcysteine is the current standard of care for APAP overdose, anecdotal evidence suggests that administration of 4-methylpyrazole (4MP) may be beneficial in the clinic. The objective of the current study was to examine the protective effect of 4MP and its mechanism of action. Male C57BL/6J mice were co-treated with 300 mg/kg of APAP and 50 mg/kg of 4MP. The severe liver injury induced by APAP at 6 h as indicated by elevated plasma alanine aminotransferase activities, centrilobular necrosis, and nuclear DNA fragmentation was almost completely eliminated by 4MP. In addition, 4MP largely prevented APAP-induced activation of c-Jun N-terminal kinase (JNK), mitochondrial translocation of phospho-JNK and Bax, and the release of mitochondrial intermembrane proteins. Importantly, 4MP inhibited the generation of APAP protein adducts and formation of APAP-glutathione (GSH) conjugates and attenuated the depletion of the hepatic GSH content. These findings are relevant to humans because 4MP also prevented APAP-induced cell death in primary human hepatocytes. In conclusion, early treatment with 4MP can completely prevent liver injury after APAP overdose by inhibiting cytochrome P450 and preventing generation of the reactive metabolite.

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“…33 Recent circumstantial evidence advocated for the clinical use of 4MP with APAP poisoning. 28,29 However, the benefit of such treatment is not well established.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes

et al. 2018

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“…It has been known for some time that 4MP can also reduce bioactivation of APAP (Thummel et al 1989) and protect against APAP hepatotoxicity in rats (Burk et al 1990;Brennan et al 1994). In 2013, a case report appeared describing a patient who had apparently consumed an extremely large dose of APAP, with a peak serum APAP concentration in a range which few people have been reported to survive (Zell-Kanter et al 2013). The authors treated the patient with NAC, along with a single dose of 4MP due to suspected alcohol co-ingestion, and the patient recovered.…”

Section: Novel Treatments For Apap Overdosementioning

confidence: 99%

The development and hepatotoxicity of acetaminophen: reviewing over a century of progress

McGill

Hinson

2020

Drug Metabolism Reviews

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Acetaminophen (APAP) was first synthesized in the 1800s, and came on the market approximately 65 years ago. Since then, it has become one of the most used drugs in the world. However, it is also a major cause of acute liver failure. Early investigations of the mechanisms of toxicity revealed that cytochrome P450 enzymes catalyze formation of a reactive metabolite in the liver that depletes glutathione and covalently binds to proteins. That work led to the introduction of N acetylcysteine (NAC) as an antidote for APAP overdose. Subsequent studies identified the reactive metabolite N-acetyl-p-benzoquinone imine, specific P450 enzymes involved, the mechanism of P450-mediated oxidation, and major adducted proteins. The mechanisms downstream of metabolism remain poorly understood but several events appear critical. These events include development of an initial oxidative stress, reactive nitrogen formation, altered calcium flux, JNK activation and mitochondrial translocation, inhibition of mitochondrial respiration, the mitochondrial permeability transition, and nuclear DNA fragmentation. Additional research is necessary to fill remaining gaps in our knowledge of the toxicity, such as the source of the initial oxidative stress, and to improve our understanding liver regeneration after APAP overdose. A better understanding of these mechanisms may lead to additional treatment options. Even though NAC is an excellent antidote, its effectiveness is limited to the first 16 hours following overdose.

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“…Although the elevated acetaminophen concentration surprised us, we were familiar with cases of massive acetaminophen overdoses presenting with coma and severe lactic acidosis in the absence of hepatic dysfunction [101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116]. Analysis of the previously reported cases revealed that hyperglycemia and hypothermia have also been described [103, 105-107, 111, 112, 116].…”

Section: Does An Isolated Massive Acetaminophen Overdose Explain the mentioning

confidence: 99%

Case Files from the University of California San Diego Health System Fellowship Coma and Severe Acidosis: Remember to Consider Acetaminophen

Villano

O'Connell

et al. 2015

J. Med. Toxicol.

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A 28-year-old man was brought to the Emergency Department (ED) for evaluation of a depressed level of consciousness that developed while in jail. Sixteen hours previously, he had been arrested on charges of murder. The patient's mental status was reported as normal at the time of arrest, and it had remained so during several hours of interrogation and during the booking process at jail. Following interrogation, the patient was placed into a cell with no other inmates. During the jail intake process, the patient had not reported any history of medical problems nor was he prescribed with any medications. Paramedics arrived to find him unresponsive, but maintaining airway reflexes and hemodynamically stable. They measured a blood glucose of 300 mg/dL and noted one episode of blood-tinged emesis during transport to the ED. No seizure activity was witnessed.On arrival to the ED, vital signs were: heart rate 132/min, blood pressure 129/74 mmHg, temperature 35.3°C (95.5°F), respiratory rate 24/min, and 100 % oxygen saturation on 15 l/ min of oxygen delivered by non-rebreather face mask.Physical examination was notable for a depressed level of consciousness. His eyes remained closed to pain, he withdrew all extremities equally to pain, and he was non-verbal. He had no signs of trauma, and his pupils were normal in size and reactive. Rapid sequence tracheal intubation was performed for airway protection. An electrocardiogram was normal except for sinus tachycardia at a rate of 111/min. An initial peripherally drawn arterial blood gas obtained immediately after intubation revealed: pH 6.97, pCO 2 40 mmHg, pO 2 215 mmHg. A computed tomography scan of the brain was normal. Initial blood chemistry panel was significant for a serum bicarbonate of 7 mEq/L, glucose of 362 mg/dL, and a normal potassium, blood urea nitrogen (BUN), creatinine, and calcium. The initial serum anion gap was 34 mEq/L. Measured serum osmolality was 320 mOsm/kg, yielding an osmol gap of 9 mOsm/kg (using formula of [2(Na)+BUN/2.8+glu-cose/18] for calculated serum osmolarity). Initial lactate was 156.5 mg/dL (normal reference range 4.5-19.8 mg/dL) and beta-hydroxybutyrate (βHB) 2.9 mg/dL (normal reference range 0.0-2.8 mg/dL). Initial liver panel included an aspartate aminotransferase (AST) of 64 U/L, alanine aminotransferase (ALT) of 27 U/L, and bilirubin of 0.4 mg/dL. Prothrombin time was 13.1 s (reference range 9.7-12.5), and lipase was normal at 25 U/L. Initial creatinine phosphokinase (CK) was slightly elevated at 373 U/L (0-175). Urinalysis was positive for small ketones and crystals were not present. Measurements of acetone and acetoacetate were not performed. Serum ethanol and salicylate levels were undetectable, and a urine drug of abuse panel by immunoassay was negative for amphetamines as a class, barbiturates as a class, benzodiazepines as a class, benzoylecgonine (cocaine metabolite), methadone, opiates as class, oxycodone, phencyclidine, and tetrahydrocannabinoids. Iron concentration was normal at 87 mcg/dL.Over the first hour of management,...

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A Gargantuan Acetaminophen Level in an Acidemic Patient Treated Solely With Intravenous N-Acetylcysteine

Cited by 21 publications

References 14 publications

4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes

4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes

The development and hepatotoxicity of acetaminophen: reviewing over a century of progress

Case Files from the University of California San Diego Health System Fellowship Coma and Severe Acidosis: Remember to Consider Acetaminophen

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