Supplementary MaterialsAdditional document 1: SPIRIT 2013 checklist: recommended items to address in a medical trial protocol and related documents. doses of PP100C01 are 2, 5, and 10?mol/kg. The primary outcome is the security and tolerability of PP100C01 when co-administered with a 12-h NAC regimen compared with NAC treatment only. Furthermore, the study will explore if PP100C01 offers potential efficacy for the treatment of paracetamol-induced liver injury by measurement of standard medical and exploratory biomarkers. Discussion The aim of the study is to test the security and tolerability of a SOD mimetic, PP100C01, in combination with a 12-h NAC routine in individuals 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 PP100C01 routine and may provide evidence of PP100C01 efficacy in the treatment of paracetamol-induced liver Rabbit Polyclonal to STAT1 (phospho-Tyr701) injury. Trial registration EudraCT, 2017C000246-21; ClinicalTrials.gov, “type”:”clinical-trial”,”attrs”:”text”:”NCT03177395″,”term_id”:”NCT03177395″NCT03177395. Registered on 6 June 2017. Electronic supplementary material The online version of this article (10.1186/s13063-018-3134-1) contains supplementary material, which is available to authorized users. strong class=”kwd-title” Keywords: Paracetamol, Acetylcysteine, Overdose, Hepatotoxicity, Calmangafodipir Background Paracetamol/acetaminophen (N-acetyl-p-aminophenol (APAP)) is the most common agent taken as an overdose in the UK. APAP is ingested by approximately 40% of patients admitted to hospital with self-harm. Annually, overdose directly leads to around SJN 2511 novel inhibtior 100,000 hospital attendances in the UK with around half of these patients being admitted to hospital for emergency antidote treatment [1]. APAP is responsible for the deaths of around 100C150 people per year in the UK [2]. 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. Experimental animal data demonstrate that APAP-induced toxicity occurs in two phases: an initial metabolic phase followed by an oxidative phase. In human patients, the metabolic phase is predominantly during the first 8?h (0C8?h) with the oxidative phase dominating thereafter ( ?8?h). During the metabolic phase, APAP metabolites are conjugated and excreted via the kidneys. In the oxidative phase the glutathione (GSH) stores are depleted and the reactive metabolite NAPQI binds to liver proteins with SJN 2511 novel inhibtior increased oxidative stress and, ultimately, loss of mitochondrial membrane potential and subsequent cell death [4]. Oxidative stress can directly trigger mitochondrial membrane permeability with pore opening and collapse of the mitochondrial membrane potential. The toxicity of reactive oxygen and reactive nitrogen species is potentiated by the fact that mitochondrial GSH levels are severely depleted during the APAP metabolism, which leaves these organelles highly vulnerable to injury. In humans, APAP-induced liver injury is usually asymptomatic in its SJN 2511 novel inhibtior early stages. Nausea, vomiting, and abdominal pain are common soon after overdose but SJN 2511 novel inhibtior are not specific for liver injury. As toxicity progresses, the patient may experience pain in the region of the liver. In severe poisoning, hepatic encephalopathy and acute kidney injury can occur and these features are used to identify patients that need liver transplantation to avoid death. Acetylcysteine (N-acetylcysteine (NAC)) was developed as an antidote for APAP poisoning in the 1970s and remains the mainstay for the prevention of APAP-induced hepatotoxicity. It is metabolised in the liver to the glutathione substrate cysteine. Glutathione is required for the detoxification of NAPQI to produce less toxic cysteine and mercapturic acid conjugates. POD patients in the UK receive an intravenous 21-h regimen of 150?mg/kg over 1?h, then 50?mg/kg over 4?h, then 100?mg/kg over 16?h (total dose 300?mg/kg) [5]. Although effective at preventing APAP-induced hepatotoxicity when used within 8?h of overdose, this regimen was largely empirical and not based on robust initial dose-ranging studies. The 21-h NAC regime is associated with the following challenges. i) Adverse drug reactions,.