AimsIn September 2012 the UK's Commission on Human Medicines (CHM) recommended changes in the management of paracetamol poisoning: use of a single ‘100 mg l−1’ nomogram treatment line, ceasing risk assessment, treating all staggered/uncertain ingestions and increasing the duration of the initial acetylcysteine (NAC) infusion from 15 to 60 min. We evaluated the effect of this on presentation, admission, treatment, adverse reactions and costs of paracetamol poisoning.MethodsData were prospectively collected from adult patients presenting to three large UK hospitals from 3 September 2011 to 3 September 2013 (year before and after change). Infusion duration effect on vomiting and anaphylactoid reactions was examined in one centre. A cost analysis from an NHS perspective was performed for 90 000 patients/annum with paracetamol overdose.ResultsThere were increases in the numbers presenting to hospital (before 1703, after 1854; increase 8.9% [95% CI 1.9, 16.2], P = 0.011); admitted (1060/1703 [62.2%] vs. 1285/1854 [69.3%]; increase 7.1% [4.0, 10.2], P < 0.001) and proportion treated (626/1703 [36.8%] vs. 926/1854 [50.0%]; increase: 13.2% [95% CI 10.0, 16.4], P < 0.001). Increasing initial NAC infusion did not change the proportion of treated patients developing adverse reactions (15 min 87/323 [26.9%], 60 min 145/514 [28.2%]; increase: 1.3% [95% CI –4.9, 7.5], P = 0.682). Across the UK the estimated cost impact is £8.3 million (6.4 million–10.2 million) annually, with a cost-per-life saved of £17.4 million (13.4 million–21.5 million).ConclusionsThe changes introduced by the CHM in September 2012 have increased the numbers of patients admitted to hospital and treated with acetylcysteine without reducing adverse reactions. A safety and cost-benefit review of the CHM guidance is warranted, including novel treatment protocols and biomarkers in the assessment of poisoning.

1 Vasorelaxation to b 2 -adrenoceptor stimulation occurs through both endothelium-dependent and endothelium-independent mechanisms, and the former is mediated through Ca 2 þ -independent activation of endothelial-type nitric oxide synthase (NOS-3). Since Ca 2 þ -independent NOS-3 activation may occur through its serine phosphorylation via protein kinase A (PKA) or Akt, we determined the PKA and Akt dependency of b 2 -adrenergic relaxation of rat aorta. 2 Rat aortic rings were pre-incubated with the PKA inhibitor H-89 (10 À7 M), the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (5 Â 10 À7 M), Akt inhibitor (10 À5 M), or vehicle, in the absence or presence of the NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME, 10 À4 M). Rings were then contracted with phenylephrine (10 À7 M), and concentration-relaxation responses determined to the b 2 -adrenoceptor agonist albuterol. 3 Rings exhibited a concentration-dependent relaxation to albuterol: pEC 50 6.970.2, E max 88.274.0%. L-NAME attenuated E max to 60.273.5% (Po0.001). 4 In the presence of L-NAME, wortmannin or Akt inhibitor did not influence albuterol responses, whereas H-89 reduced E max further, to 27.572.2% (Po0.001). 5 In the absence of L-NAME, E max to albuterol was reduced by H-89, wortmannin or Akt inhibitor, to 56.272.2, 56.071.6 and 55.471.8%, respectively (Po0.001 for each); the combinations H-89 plus wortmannin or H-89 plus Akt inhibitor reduced E max further still. 6 Western blotting of NOS-3 immunoprecipitates from rat aortas confirmed that albuterol increased serine phosphorylation of NOS-3, and this increase was attenuated by H-89 or Akt inhibitor. 7 Our results indicate that b 2 -adrenoceptor stimulation relaxes rat aorta through both NOdependent and independent mechanisms. The latter is predominantly PKA-mediated, whereas the former occurs through both PKA and PI3K/Akt activation.

Dr. Waring has a financial interest in and is world surgical monitor for Acufocus. No other author has a financial or proprietary interest in any material or method mentioned.

We demonstrated disturbed gastrointestinal motility in db/db mice with reduced areas of ICC and expression of SCF. Our results suggest the involvement of ICC in the gastroenteropathy of type 2 DM.