A review of alternative intravenous acetylcysteine regimens for acetaminophen overdose

Burnham, Kevin; Yang, Tianrui; Smith, Haleigh; Knight, Steven D.

doi:10.1080/17512433.2021.1946392

Cited by 5 publications

(6 citation statements)

References 42 publications

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“…5 Nephrotoxicity and acute renal failure could occur even without hepatic damage. 6,7 The therapeutic strategies development on APAP-induced liver failure has been extensively studied, [8][9][10] however, few researches focused on APAPinduced nephrotoxicity. N-acetyl cysteine (NAC) is a clinically preferred antidote to APAP-induced hepatotoxicity, but it fails in preventing APAP-induced nephrotoxicity, and may even aggravate renal damage.…”

Section: Introductionmentioning

confidence: 99%

Tanshinone IIA prevents acetaminophen‐induced nephrotoxicity through the activation of the Nrf2‐Mrp2/4 pathway in mice

Zhang

Long

et al. 2022

Environmental Toxicology

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It's known that APAP overdose often leads to hepatotoxicity and nephrotoxicity. In the present study, we investigated the preventative effect of Tan IIA on APAP‐induced nephrotoxicity. Mice were orally administrated with Tan IIA (10 or 30 mg/kg/day) for 1 week and subsequently gavaged with 200 mg/kg of APAP. Tan IIA reduced APAP‐induced nephrotoxicity as evidenced by histopathological evaluation and serum creatinine levels. Tan IIA pretreatment promoted the efflux of the toxic intermediate metabolite N‐acetyl‐p‐benzoquinone imine (NAPQI), thus reduced its injury to mouse kidney. After Tan IIA pretreatment, a remarkable increase in mRNA and protein expression of Nrf2 and its target genes Mrp2 and Mrp4 was observed in Nrf2+/+ mice kidneys, however, no obvious change of Mrp2 and Mrp4 mRNA and protein expression was detected in Nrf2−/− mice kidneys. HK‐2 cells were used for exploring the roles of Tan IIA in the Nrf2‐MRPs pathway in vitro. Consistently, Tan IIA up‐regulated the Nrf2‐MRPs pathway and promoted the nuclear Nrf2 accumulation in HK‐2 cells. Collectively, our findings suggested that Tan IIA facilitated the clearance of toxic intermediate metabolite NAPQI from the kidney through upregulation of the Nrf2‐MRP2/4 pathway, thereby, performing preventive effects against APAP‐induced nephrotoxicity.

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Section: Introductionmentioning

confidence: 99%

Tanshinone IIA prevents acetaminophen‐induced nephrotoxicity through the activation of the Nrf2‐Mrp2/4 pathway in mice

Zhang

Long

et al. 2022

Environmental Toxicology

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“…Sterile inflammation is likely to occur when DAMPs are passively released from dying or damaged hepatocytes after APAP overdose followed by the binding of DAMPs to TLRs in Kupffer cells at the late stage of APAP-induced hepatotoxicity. NAC is the only FDA-approved antidote against APAP overdose but its limited efficacy is concerning in late-presenting patients who have already undergone oxidative stress in the liver during the earlier stage of pathogenesis [ 12 ]. Taken together, we propose a novel hypothesis that chemical inhibition of IKKβ activity in sterile inflammation could mitigate APAP-induced hepatotoxicity in mice, and might have a potential to complement NAC treatment as an antidote against APAP overdose.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…N -Acetyl cysteine (NAC) is the only FDA-approved antidote against APAP overdose [ 12 ]. As a mechanism, NAC replenishes cellular glutathione levels, thus enhancing the detoxification of NAPQI in the cytoplasm and scavenging ROS in the mitochondria to support energy metabolism [ 12 ]. Although NAC is highly effective when given at early time-points after APAP overdose, its limited efficacy is concerning in late-presenting patients who have already undergone oxidative stress in the liver in the earlier stage of pathogenesis [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Targeting IKKβ Activity to Limit Sterile Inflammation in Acetaminophen-Induced Hepatotoxicity in Mice

et al. 2023

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The kinase activity of inhibitory κB kinase β (IKKβ) acts as a signal transducer in the activating pathway of nuclear factor-κB (NF-κB), a master regulator of inflammation and cell death in the development of numerous hepatocellular injuries. However, the importance of IKKβ activity on acetaminophen (APAP)-induced hepatotoxicity remains to be defined. Here, a derivative of caffeic acid benzylamide (CABA) inhibited the kinase activity of IKKβ, as did IMD-0354 and sulfasalazine which show therapeutic efficacy against inflammatory diseases through a common mechanism: inhibiting IKKβ activity. To understand the importance of IKKβ activity in sterile inflammation during hepatotoxicity, C57BL/6 mice were treated with CABA, IMD-0354, or sulfasalazine after APAP overdose. These small-molecule inhibitors of IKKβ activity protected the APAP-challenged mice from necrotic injury around the centrilobular zone in the liver, and rescued the mice from hepatic damage-associated lethality. From a molecular perspective, IKKβ inhibitors directly interrupted sterile inflammation in the Kupffer cells of APAP-challenged mice, such as damage-associated molecular pattern (DAMP)-induced activation of NF-κB activity via IKKβ, and NF-κB-regulated expression of cytokines and chemokines. However, CABA did not affect the upstream pathogenic events, including oxidative stress with glutathione depletion in hepatocytes after APAP overdose. N-acetyl cysteine (NAC), the only FDA-approved antidote against APAP overdose, replenishes cellular levels of glutathione, but its limited efficacy is concerning in late-presenting patients who have already undergone oxidative stress in the liver. Taken together, we propose a novel hypothesis that chemical inhibition of IKKβ activity in sterile inflammation could mitigate APAP-induced hepatotoxicity in mice, and have the potential to complement NAC treatment in APAP overdoses.

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“…However, this drug could induce many adverse effects, for instance, allergy, anaphylaxis, angioedema, and bronchospasm [7]. Recently, there has been a great interest to discover novel agents that may have a potential effect in treating paracetamol-induced toxicity with less hazard [8].…”

Section: Introductionmentioning

confidence: 99%

Assessment the effects of lacteal forte® and vitamin B12 versus N-acetylcysteine in treatment of acetaminophen‐induced hepatorenal toxicity

Conference¹

2022

Egypt. J. Chem.

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Acetaminophen (APAP) is one of the most frequently used analgesics and antipyretics worldwide, however, an overdose of paracetamol is a leading cause of hepato-renal injury. N-acetylcysteine (NAC) has been used as a remedy for paracetamolinduced toxicity, however several adverse effects of long-term use of NAC have been reported. Therefore, we assessed the ameliorating effect of lacteol forte® and vitamin B12 alone or in combination against APAP-induced hepatorenal injury in rats and compare it with that of NAC. Fife groups of rats were given APAP (400 mg/kg BW, i.p.), while the control group was treated only with 0.9% saline. Treatment with NAC, lacteal forte®, and vitamin B12 was done 24hrs after APAP. Serum biochemical parameters related to liver and kidney injury, including, AST, ALT, HDL, urea, and creatinine were estimated in all groups, hepatic and renal lipid peroxidation, and antioxidant biomarker levels were also determined. The expression of the tumor necrosis factor (TNF-α), TNFR-1, COX-1 and COX-2 genes was investigated. Finally, sections of the liver and kidney of all rats were examined for any histopathological changes. Results: Compared to control rats, APAP induced acute hepatic and renal toxicity manifested by significant increases in serum biochemical parameters related to liver and kidney injuries. Also, APAP significantly increased hepatic, and renal lipid peroxidation and decreased antioxidant biomarker levels. APAP upregulated the expression of TNF-α and TNFR-1 genes, while it downregulated the expression of COX-1 and COX-2 genes. It also produced marked histopathological lesions of liver and kidney. The test treatment with lacteal forte and vitamin B12 combination had improved serum parameters and gene expression, enhanced endogenous antioxidant status, reduced lipid peroxidation, and histopathological lesions in a comparable fashion to that of NAC effects. Conclusions: Our data confirmed that treatment with vitamin B12 and lacteal forte® combination has exerted potent antioxidant and free radical-scavenging activities comparable to that NAC. Suggesting that combination of vitamin B1 and lacteal forte® may be considered a safer alternative to NAC in ameliorating APAP induced toxicities. More research will be required to estimate the level of toxic metabolite, NAPQI, to determine the actual mode of action of these medications in protecting against APAP toxicity.

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A review of alternative intravenous acetylcysteine regimens for acetaminophen overdose

Cited by 5 publications

References 42 publications

Tanshinone IIA prevents acetaminophen‐induced nephrotoxicity through the activation of the Nrf2‐Mrp2/4 pathway in mice

Tanshinone IIA prevents acetaminophen‐induced nephrotoxicity through the activation of the Nrf2‐Mrp2/4 pathway in mice

Targeting IKKβ Activity to Limit Sterile Inflammation in Acetaminophen-Induced Hepatotoxicity in Mice

Assessment the effects of lacteal forte® and vitamin B12 versus N-acetylcysteine in treatment of acetaminophen‐induced hepatorenal toxicity

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