Abstract
BackgroundParacetamol (acetaminophen) overdose (POD) is the commonest cause of acute liver failure in Europe and North America. Current treatment involves the use of the antidote N-acetylcysteine (NAC) in patients deemed at risk of liver damage. This regimen was introduced in the 1970s and has remained largely unchanged even though the initial NAC infusion is frequently associated with adverse reactions, in particular nausea, vomiting, and anaphylactoid reactions. NAC has reduced efficacy for preventing liver injury in those patients who present later after overdose. We designed a randomised study investigating the safety and tolerability of a superoxide dismutase (SOD) mimetic, calmangafodipir (PP100–01), co-treatment with a 12-h NAC regimen compared with NAC treatment alone in patients with POD.Methods/designWe have designed an open-label, randomised, exploratory, rising dose design, NAC-controlled, phase 1 safety and tolerability study in patients treated with NAC for POD. A total of 24 patients will be assigned into one of three dosing cohorts of eight patients (n = 6 for PP100–01 and NAC; n = 2 for NAC alone). The doses of PP100–01 are 2, 5, and 10 μmol/kg. The primary outcome is the safety and tolerability of PP100–01 when co-administered with a 12-h NAC regimen compared with NAC treatment alone. Furthermore, the study will explore if PP100–01 has potential efficacy for the treatment of paracetamol-induced liver injury by measurement of conventional clinical and exploratory biomarkers.DiscussionThe aim of the study is to test the safety and tolerability of a SOD mimetic, PP100–01, in combination with a 12-h NAC regimen in patients presenting within 24 h of POD. This study will provide valuable data regarding the incidence of adverse events caused by the 12-h NAC plus PP100–01 regimen and may provide evidence of PP100–01 efficacy in the treatment of paracetamol-induced liver injury.Trial registrationEudraCT, 2017–000246-21; ClinicalTrials.gov, NCT03177395. Registered on 6 June 2017.
Highlights
IntroductionParacetamol (acetaminophen) overdose (POD) is the commonest cause of acute liver failure in Europe and North America
Paracetamol overdose (POD) is the commonest cause of acute liver failure in Europe and North America
Hospitalisation due to APAP overdose accounted for approximately 80,000 bed days in the UK in 2005–2006
Summary
Paracetamol (acetaminophen) overdose (POD) is the commonest cause of acute liver failure in Europe and North America. Current treatment involves the use of the antidote N-acetylcysteine (NAC) in patients deemed at risk of liver damage. This regimen was introduced in the 1970s and has remained largely unchanged even though the initial NAC infusion is frequently associated with adverse reactions, in particular nausea, vomiting, and anaphylactoid reactions. In the USA, APAP overdose accounts for more than 56,000 hospital attendances and around 450 deaths due to acute liver failure each year [3]. In paracetamol overdose (POD), the normal APAP detoxification pathways (sulphation and glucuronidation) are overwhelmed, leading to the formation of the reactive intermediate metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which binds covalently to liver proteins resulting in cell death. Oxidative stress can directly trigger mitochondrial membrane permeability with pore opening and collapse of the mitochondrial membrane potential
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
