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AIMS: Metformin may have clinical benefits in dialysis patients; however, its safety in this population is unknown. This systematic review evaluated the safety of metformin in dialysis patients. METHODS: MEDLINE, Embase, CENTRAL, PsycINFO and the Cochrane Library were searched for randomised controlled trials and observational studies evaluating metformin use in dialysis patients. Three authors reviewed the studies and extracted data. The primary outcomes were mortality, occurrence of lactic acidosis and myocardial infarction (MI) in patients taking metformin during dialysis treatment for ≥12 months (long term). Risk of bias was assessed using Risk Of Bias In Nonrandomised Studies of Interventions (ROBINS-1). Overall quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Fifteen observational studies were eligible; 7 were prospective observational studies and 8 were case reports/case series. No randomised controlled trials were identified. The 7 prospective observational studies (n = 194) reported on cautious metformin use in patients undergoing maintenance dialysis. Only 3 provided long-term follow-up data. In 2 long-term studies of metformin therapy (≤1000 mg/d) in patients undergoing peritoneal dialysis (PD), 1 reported 6 deaths (6/83; 7%) due to major cardiovascular events (3 MI) and the other reported no deaths (0/35). One long-term study of metformin therapy (250 mg to 500 mg thrice weekly) in patients undergoing haemodialysis reported 4 deaths (4/61; 7%) due to major cardiovascular events (2 MI). These findings provide very low-quality evidence as they come from small observational studies. CONCLUSION: The evidence regarding the safety of metformin in people undergoing dialysis is inconclusive. Appropriately designed randomised controlled trials are needed to resolve this uncertainty.

The heme peroxidase enzyme myeloperoxidase (MPO) is released by activated neutrophils and monocytes, where it uses hydrogen peroxide (H2O2) to catalyze the production of the potent oxidants hypochlorous acid (HOCl), hypobromous acid (HOBr) and hypothiocyanous acid (HOSCN) from halide and pseudohalide (SCN-) ions. These oxidants have been implicated as key mediators of tissue damage in many human inflammatory diseases including atherosclerosis, asthma, rheumatoid arthritis, cystic fibrosis and some cancers. It is shown here that acetaminophen (paracetamol), a phenol-based drug with analgesic and antipyretic actions, is an efficient inhibitor of HOCl and HOBr generation by isolated MPO-H2O2-halide systems. With physiological halide concentrations, acetaminophen concentrations required for 50% inhibition of oxidant formation (IC50) were 77±6μM (100mMCl-) and 92±2μM (100mMCl- plus 100μMBr-), as measured by trapping of oxidants with taurine. The IC50 for inhibition of HOCl generation by human neutrophils was ca. 100μM. These values are lower than the maximal therapeutic plasma concentrations of acetaminophen (≤150μM) resulting from typical dosing regimes. Acetaminophen did not diminish superoxide generation by neutrophils, as measured by lucigenin-dependent chemiluminescence. Inhibition of HOCl production was associated with the generation of fluorescent acetaminophen oxidation products, consistent with acetaminophen acting as a competitive substrate of MPO. Inhibition by acetaminophen was maintained in the presence of heparan sulfate and extracellular matrix, materials implicated in the sequestration of MPO at sites of inflammation in vivo. Overall, these data indicate that acetaminophen may be an important modulator of MPO activity in vivo. © 2009 Elsevier Inc.

Longitudinal anthropometric and socioeconomic assessment was made of 127 families of children admitted to the British American Hospital in Lima, Peru, with malnutrition in 1961 to 1971. In 1972, those recruited during 1961 to 1966 had higher incomes and were more likely to have running water and electricity than those recruited later, who were more likely to be using candles or kerosene and to buy water in cylinders, at a unit cost 16.7 times higher. Mean mid parental heights were equal, but the children from families with water and electricity services were taller for their age. Expenditures for illumination were similar, whether for electricity or for candles or kerosene, but the cost of water by volume was very much higher in families without running water. When expenditure was expressed as percentage of income or as the amount of working time to pay for water, the differences were even greater: 2.6% to 2.7% vs 0.4% to 0.7% and 423 to 445 vs 71 to 129 minutes/month.

Acetaminophen (APAP) is a widely used drug in our environment with few adverse effects. Because of this, several patients affected by APAP hepatotoxicity unknown that the APAP dose-intake was excessive. This damage is mainly produced via one of APAP metabolites: N-acetyl-para-benzo-quinone imine (NAPQI), which is very toxic. The drug’s ingested doses as well as the length of time from APAP ingestion to N-acetylcysteine (NAC) therapy are the most essential determining factors in both the development and severity of APAP hepatotoxicity. However, there are other factors related, including alcohol intake, herbs and medications, age and genetic factors, nutritional status, and chronic liver disease. The ingestion of a toxic dose of APAP causes different clinical manifestations that depend fundamentally on the time elapsed since the intake. The diagnosis process depends on the intake (acute single overdose of after repeated overdoses). The Rumack-Matthew nomogram is acceptable after an acute single overdose, being the “possible hepatic toxicity” point 200 µg/mL at 4 hours and 25 µg/mL at 16 hours). This normogram is no applicable in after repeated overdoses. NAC is the antidote for APAP intoxication, and could be administered orally or intravenous. Finally, a multidisciplinary approach with the support of Psychiatry, Intensive Care Unit as well as Gastroenterology and Digestive Department will be necessary, especially in the case of attempted autolysis and severe liver failure., {"references":["Bunchorntavakul C, Reddy KR. Acetaminophen-related Hepatotoxicity. Clin Liver Dis 2013;17:587-607. doi:10.1016/j.cld.2013.07.005.","Herndon CM, Dankenbring DM. Patient perception and knowledge of acetaminophen in a large family medicine service. J Pain Palliat Care Pharmacother 2014;28:109-16. doi:10.3109/15360288.2014.908993.","Graham GG, Scott KF. Mechanism of action of paracetamol. 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In the preceding "Insight" piece, Gray and Graham (GG Finkel, 1990]. Recommendations made in ignorance of uncertainty are vulnerable to four common pitfalls: (1) they do not allow for the weighing of the probabilities and the consequences of error; (2) they do not permit a reliable comparison of the costs and benefits of a portfolio of decisions, so that priorities can be established; (3) they fail to communicate to decision makers and the public the range of control options that would be compatible with different assessments of the true state-of-nature; and (4) they preclude the opportunity for identifying research initiatives that might reduce uncertainty and thereby reduce the probability or the impact of being caught by surprise. In selecting for analysis EPA's estimate of the annual excess death toll from carcinogenic air pollutants, G&G reveal the flaws in a particularly important "risk number" that EPA presents in a particularly clumsy fashion. As they indicate, it is easy for the reader of Cancer Risk from Outdoor Exposure to Air Toxics to infer that the interval 1734-2597 is meant to subsume the total

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