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Using animal model, we successfully confirmed that various CYP450 inhibitors co-administered with AAP, as single or combinations, could maintain normal hepatic function even with AAP doses of 2000 mg/kg, demonstrating a protective index (LD50) of more than 4X.

a biomarker representing NAPQI) (p < 0.005). The survival was 100% (24/24) in a majority of antidote-treated groups, whereas the survival rate was 17% (2/12) in AAP-only group and 50% (6/12) in the NAC-treated group.

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A Study to Evaluate the Pharmacokinetics of Acetaminophen and Its Toxic Metabolites With 2 Formulations (Panadol and ) in Healthy Volunteers


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AAPM 2018¦~·|ºK (SNP-810)
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Development of a Novel Acetaminophen Formulations Without Hepatotoxic Side Effect
Tung-Yuan Shih, PhD, tyshih@sinewpharma.com1; Wan-Ling Yang, Master1; Pei-Wei Huang, Master1; Cheng-Huei Hsiong, PhD1; (1) Sinew Pharma, Inc., Taipei, Taiwan

Acetaminophen (AAP) is the leading worldwide cause of drug-induced acute liver failure (ALF), and can cause death. In 2014, the USFDA announced that the manufacture of prescription drug combinations containing more than 325 mg AAP would be discontinued. Furthermore, health care professionals were instructed to stop dispensing prescription drug combinations containing more than 325 mg AAP. However, there are no hepatotoxicity-free acetaminophen products available worldwide. This study explored whether selected Cytochrome P450 (CYP450) inhibitor could reduce or eliminate AAP-induced hepatotoxicity. We used a suitable, safe, and commonly used compound as a candidate AAP antidote in our study. Using animal model, we successfully confirmed that various CYP450 inhibitors co-administered with AAP, as single or combinations, could maintain normal hepatic function even with AAP doses of 2000 mg/kg, demonstrating a protective index (LD50) of more than 4X. These CYP450 inhibitors (referred to as antidote, research code: SNP-810) reduced AAP-induced hepatotoxicity by lowering the levels of aspartate aminotransferase, alanine aminotransferase, histology activity index (HAI-score) and inhibition of NAPQI formation (as shown by AAP-Cys, a biomarker representing NAPQI) (p < 0.005). The survival was 100% (24/24) in a majority of antidote-treated groups, whereas the survival rate was 17% (2/12) in AAP-only group and 50% (6/12) in the NAC-treated group. Thus, selected inhibitor combination demonstrated a more profound hepato-protective effect than the current NAC treatment for AAP overdose. Our findings demonstrated hepatotoxicity-free AAP can also improve patient outcomes and supported the possibility that this novel formulation can protect against the cytotoxicity induced by AAP. References: 1) Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA. 2013 Feb 20;309(7):657-9. doi: 10.1001/jama.2013.272. 2) Altyar A, Kordi L, Skrepnek G. Clinical and economic characteristics of emergency department visits due to acetaminophen toxicity in the USA. BMJ Open. 2015 Sep 9;5(9):e007368. doi: 10.1136/bmjopen-2014-007368.
Funding: SiNew Pharma Inc.

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After a single and multiple oral dose of Panadol®(´¶®³¯k) or
SNP-810 had demonstrated that SNP-810 could significantly decrease the AAP toxic metabolite
(p < 0.005), up to 53%.
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