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Concept: Paracetamol

166

We have previously described the development of genetic models to study the in vivo functions of the hepatic cytochrome P450 system, through the hepatic deletion of either cytochrome P450 oxidoreductase (POR; HRN line) or cytochrome b5 (Cyb5; HBN line). However, HRN mice still exhibit low levels of mono-oxygenase activity, in spite of the absence of detectable reductase protein. To investigate whether this is because cytochrome b5 and cytochrome b5 reductase can act as sole electron donors to the P450 system, we have crossed HRN with HBN mice to generate a line lacking hepatic expression of both electron donors (HBRN). HBRN mice exhibited exacerbation of the phenotypic characteristics of the HRN line - liver enlargement, hepatosteatosis and increased expression of certain cytochrome P450s. Also, drug metabolising activities in vitro were further reduced relative to the HRN model, in some cases to undetectable levels. Pharmacokinetic studies in vivo demonstrated that midazolam half-life, Cmax and area under the concentration-time curve (AUC) were increased, and clearance was decreased, to a greater extent in the HBRN line than in either the HBN or HRN model. Microsomal incubations using NADPH concentrations below the apparent Km of cytochrome b5 reductase, but well above that for POR, led to the virtual elimination of 7-benzyloxyquinoline turnover in HRN samples. These data provide strong evidence that cytochrome b5/cytochrome b5 reductase can act as a sole electron donors to the cytochrome P450 system in vitro and in vivo.

Concepts: Cytochrome P450, Paracetamol, CYP3A4, P450-containing systems, Cytochrome P450 reductase

165

Mefenamic acid, (MFA), a carboxylic acid-containing nonsteroidal anti-inflammatory drug (NSAID) is metabolized into the chemically-reactive, MFA-1-O-acyl-glucuronide (MFA-1-O-G), MFA-acyl-adenylate (MFA-AMP), and the MFA-S-acyl-CoA (MFA-CoA), all of which are electrophilic and capable of acylating nucleophilic sites on biomolecules. In this study, we investigate the non-enzymatic ability of each MFA acyl-linked metabolite to transacylate amino and thiol functional groups on the acceptor biomolecules glycine (Gly), taurine (Tau), glutathione (GSH), and N-acetylcysteine (NAC). In vitro incubations with each of the MFA acyl-linked metabolites (1 μM) in buffer under physiological conditions with Gly, Tau, GSH, or NAC (10 mM) revealed that MFA-CoA was 11.5- and 19.5-fold more reactive than MFA-AMP towards the acylation of cysteine-sulfhydryl groups of GSH and NAC, respectively. However, MFA-AMP was more reactive towards both Gly and Tau, 17.5-fold more reactive towards the N-acyl-amidation of taurine than its corresponding CoA thioester, while MFA-CoA displayed little reactivity towards glycine. Additionally, MFA-GSH was 5.6- and 108-fold more reactive towards NAC than MFA-CoA and MFA-AMP, respectively. In comparison to MFA-AMP and MFA-CoA, MFA-1-O-G was not significantly reactive towards all four bionucleophiles. MFA-AMP, MFA-CoA, MFA-1-O-G, MFA-GSH, and MFA-Tau were also detected in rat in vitro hepatocyte MFA (100 μM) incubations while MFA-Gly was not. These results demonstrate that MFA-AMP selectively reacts nonenzymatically with the amino functional groups of glycine and lysine, MFA-CoA selectively reacts nonenzymatically with the thiol functional groups of GSH and NAC, and MFA-GSH reacts nonenzymatically with the thiol functional group of GSH, all of which may potentially elicit an idiosyncratic toxicity in vivo.

Concepts: Amino acid, Amine, Functional group, Disulfide bond, Non-steroidal anti-inflammatory drug, Paracetamol, Ibuprofen, Carboxylic acid

152

To compare Institut Georges Lopez (IGL-1) and Celsior preservation solutions for hepatic endothelium relaxation and liver cold ischemia reperfusion injury (IRI).

Concepts: Inflammation, Blood vessel, Liver, Ischemia, Reperfusion injury, Ischemic cascade, Paracetamol, Nitric oxide

96

Background Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking. Methods In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial. Results Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events. Conclusions Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319 .).

Concepts: Asthma, Median, Interquartile range, Paracetamol, Aspirin, Normal distribution, Inhaler, Nebulizer

82

To prevent pain inhibiting their performance, many athletes ingest over-the-counter (OTC) analgesics before competing. We aimed at defining the use of analgesics and the relation between OTC analgesic use/dose and adverse events (AEs) during and after the race, a relation that has not been investigated to date.

Concepts: Epidemiology, Clinical trial, Opioid, Pain, Paracetamol, Ibuprofen, Codeine

75

Fragranced consumer products-such as air fresheners, cleaning supplies, and personal care products- pervade society. This study investigated the occurrence and types of adverse effects associated with exposure to fragranced products in Australia, and opportunities for prevention. Data were collected in June 2016 using an on-line survey with a representative national sample (n = 1098). Overall, 33% of Australians report health problems, such as migraine headaches and asthma attacks, when exposed to fragranced products. Of these health effects, more than half (17.1%) could be considered disabling under the Australian Disability Discrimination Act. Additionally, 7.7% of Australians have lost workdays or a job due to illness from fragranced product exposure in the workplace, 16.4% reported health problems when exposed to air fresheners or deodorizers, 15.3% from being in a room after it was cleaned with scented products, and 16.7% would enter but then leave a business as quickly as possible due to fragranced products. About twice as many respondents would prefer that workplaces, health care facilities and professionals, hotels, and airplanes were fragrance-free rather than fragranced. While 73.7% were not aware that fragranced products, even ones called green and organic, emitted hazardous air pollutants, 56.3% would not continue to use a product if they knew it did. This is the first study in Australia to assess the extent of adverse effects associated with exposure to common fragranced products. It provides compelling evidence for the importance and value of reducing fragranced product exposure in order to reduce and prevent adverse health effects and costs.

Concepts: Health care, Illness, Paracetamol, Australia, Disability, Hygiene, Disability Discrimination Act 1995

67

Among pregnant women ibuprofen is one of the most frequently used pharmaceutical compounds with up to 28% reporting use. Regardless of this, it remains unknown whether ibuprofen could act as an endocrine disruptor as reported for fellow analgesics paracetamol and aspirin. To investigate this, we exposed human fetal testes (7-17 gestational weeks (GW)) to ibuprofen using ex vivo culture and xenograft systems. Ibuprofen suppressed testosterone and Leydig cell hormone INSL3 during culture of 8-9 GW fetal testes with concomitant reduction in expression of the steroidogenic enzymes CYP11A1, CYP17A1 and HSD17B3, and of INSL3. Testosterone was not suppressed in testes from fetuses younger than 8 GW, older than 10-12 GW, or in second trimester xenografted testes (14-17 GW). Ex vivo, ibuprofen also affected Sertoli cell by suppressing AMH production and mRNA expression of AMH, SOX9, DHH, and COL2A1. While PGE2 production was suppressed by ibuprofen, PGD2 production was not. Germ cell transcripts POU5F1, TFAP2C, LIN28A, ALPP and KIT were also reduced by ibuprofen. We conclude that, at concentrations relevant to human exposure and within a particular narrow ‘early window’ of sensitivity within first trimester, ibuprofen causes direct endocrine disturbances in the human fetal testis and alteration of the germ cell biology.

Concepts: Pregnancy, Embryo, Fetus, Testosterone, Paracetamol, Sertoli cell, Puberty, Leydig cell

62

Paracetamol overdose is common but patient stratification is suboptimal. We investigated the usefulness of new biomarkers that have either enhanced liver specificity (microRNA-122 [miR-122]) or provide mechanistic insights (keratin-18 [K18], high mobility group box-1 [HMGB1], and glutamate dehydrogenase [GLDH]). The use of these biomarkers could help stratify patients for their risk of liver injury at hospital presentation.

Concepts: Cohort study, Patient, Hospital, Physician, Paracetamol, Paracetamol toxicity, Stratification

62

Background Colchicine is effective for the treatment of recurrent pericarditis. However, conclusive data are lacking regarding the use of colchicine during a first attack of acute pericarditis and in the prevention of recurrent symptoms. Methods In a multicenter, double-blind trial, eligible adults with acute pericarditis were randomly assigned to receive either colchicine (at a dose of 0.5 mg twice daily for 3 months for patients weighing >70 kg or 0.5 mg once daily for patients weighing ≤70 kg) or placebo in addition to conventional antiinflammatory therapy with aspirin or ibuprofen. The primary study outcome was incessant or recurrent pericarditis. Results A total of 240 patients were enrolled, and 120 were randomly assigned to each of the two study groups. The primary outcome occurred in 20 patients (16.7%) in the colchicine group and 45 patients (37.5%) in the placebo group (relative risk reduction in the colchicine group, 0.56; 95% confidence interval, 0.30 to 0.72; number needed to treat, 4; P<0.001). Colchicine reduced the rate of symptom persistence at 72 hours (19.2% vs. 40.0%, P=0.001), the number of recurrences per patient (0.21 vs. 0.52, P=0.001), and the hospitalization rate (5.0% vs. 14.2%, P=0.02). Colchicine also improved the remission rate at 1 week (85.0% vs. 58.3%, P<0.001). Overall adverse effects and rates of study-drug discontinuation were similar in the two study groups. No serious adverse events were observed. Conclusions In patients with acute pericarditis, colchicine, when added to conventional antiinflammatory therapy, significantly reduced the rate of incessant or recurrent pericarditis. (Funded by former Azienda Sanitaria Locale 3 of Turin [now Azienda Sanitaria Locale 2] and Acarpia; ICAP ClinicalTrials.gov number, NCT00128453 .).

Concepts: Therapeutic effect, Pharmacology, Clinical trial, Medical terms, Randomized controlled trial, Paracetamol, Clinical research, Acute pericarditis

56

Codeine has been prescribed to pediatric patients for many decades as both an analgesic and an antitussive agent. Codeine is a prodrug with little inherent pharmacologic activity and must be metabolized in the liver into morphine, which is responsible for codeine’s analgesic effects. However, there is substantial genetic variability in the activity of the responsible hepatic enzyme, CYP2D6, and, as a consequence, individual patient response to codeine varies from no effect to high sensitivity. Drug surveillance has documented the occurrence of unanticipated respiratory depression and death after receiving codeine in children, many of whom have been shown to be ultrarapid metabolizers. Patients with documented or suspected obstructive sleep apnea appear to be at particular risk because of opioid sensitivity, compounding the danger among rapid metabolizers in this group. Recently, various organizations and regulatory bodies, including the World Health Organization, the US Food and Drug Administration, and the European Medicines Agency, have promulgated stern warnings regarding the occurrence of adverse effects of codeine in children. These and other groups have or are considering a declaration of a contraindication for the use of codeine for children as either an analgesic or an antitussive. Additional clinical research must extend the understanding of the risks and benefits of both opioid and nonopioid alternatives for orally administered, effective agents for acute and chronic pain.

Concepts: Pharmacology, Opioid, Paracetamol, Morphine, Heroin, Sleep apnea, Hydrocodone, Codeine