EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI) : Study protocol for a multicentre, observational trial

More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369

Reproductive toxicity of taurohyodeoxycolic acid.

The reproductive toxicity of taurohyodeoxycholic acid (3 alpha, 6 alpha-dihydroxy-5-beta-cholanoyl-2-amino-ethyl-sulfonic acid, THDCA, Io, Praxis, CAS 2958-04-5), a new synthetized biliary acid patented in Europe, Japan and the United States for prevention and therapy of gallstones and related symptoms, was assayed by performing segment I (fertility and general reproductive performance) and segment II (teratology) studies. In the first study THDCA was administered (100, 220 or 500 mg/kg by oral route) to male and female rats prior to and in the early stage of pregnancy. No adverse effects or dose-related abnormalities were observed in the reproductive performance of either sex; no death or evidence of teratogenicity in fetuses were also observed. In the second study THDCA was administered (100, 220 or 500 mg/kg by oral route) to rats and rabbits during the fetal organogenesis period. No maternal toxicity, teratogenicity or adverse effects on growth of embryos and fetuses and no reduction of the viability index were observed. From these studies the no-effect dose can be estimated at 500 mg/kg

Chronic toxicity of taurohyodeoxycolic acid in dogs.

Fifty-two-week oral toxicity and 24-week intramuscular toxicity of a new synthetized biliary acid, taurohyodeoxycholic acid (Io, Praxis, CAS 2958-04-5) were investigated in dogs. Taurohyodeoxycholic acid was orally administered at dose levels up to 500 mg/kg/d and i.m. administered at dose levels up to 200 mg/kg/d. No deviations from normality were observed in mortality, physical appearance and general behaviour of the treated animals. Food and water consumption and body weight gain of treated groups did not differ from those of control animals. No treatment-related changes were observed in hematology, serum biochemistry, urinalysis, organ weights and post-mortem macroscopic or histopathological examinations. No dose- or sex-related differences were observed. The no-effect dose level was estimated to be 500 mg/kg/d in the chronic oral toxicity study and 200 mg/kg/d in the intramuscular study

Bioequivalence study on two different sustained release morphine formulations

The purpose of this study, performed on cancer patients requiring treatment with morphine, was to assess the comparative bioavailability, effectiveness and tolerability of SR Morphine Sulphate (MSSR) with respect to a different sustained release formulation (MS Contin) in steady-state conditions. MSSR gelatinous, sustained release capsules have shown themselves to achieve good therapeutic results with only two daily administrations, whereas morphine syrup requires 4-6. To perform the bioequivalence test after repeated administrations, 12 hospitalized or out patients of both sexes, and more than 18 years old were selected. All were suffering from stable cancer pathologies with pain from neoplasms of such intensity as to require the use of strong opiates according to the criteria established by the World Health Organization. After a period of stabilization of the morphine syrup posology (seven days), the products were administered at random to each patient with a posology of 60 mg, twice a day, for a period of six days using a cross-over scheme. The treatments were performed after a wash-out of 2 days with morphine syrup. Samples of venous blood were taken at the first and sixth day at 0, 15, 30 minutes and 1, 2, 4, 6, 8 and 12 hours from the morning administration. The plasmatic levels of morphine were determined by means of HPLC. Pharmacokinetic parameters AUC, Tmax, and Cmax, were analyzed statistically by means of a Westlake test. The pharmacokinetic parameters were calculated and analysed statistically so far as concerns the curves relative to the first and last treatment

Assorbimento intranasale di preparazioni diverse di calcitonina spray.

In a cross-over study performed on 10 patients the intranasal absorption of calcitonin contained in three formulation spray was evaluated. One of them contained biliary acid (sodium taurocholate) as the absorption promoting factor while the other two drugs did not. The dosage of calcitonin in blood was effected by means of radioimmunoassay using salmon calcitonin marked with I126 in competition to the one present in the sample for a limited quantity of specific antibodies for salmon calcitonin. The minimum measurable quantity of calcitonin is 10 pg and the response is linear including values between 20% and 80%. It is observed that the plasmatic concentration of calcitonin dosed in different times after administration of the drug containing sodium taurocholate are always significantly higher (Student "t" test for unpaired data, p less than 0.005) than the measurements after administration of the other two drugs. They are about 8 times higher at the first half an hour, about 6 times after an hour and again double at the second hour. The AUC calculated for sodium taurocholate containing drug (1629 pg/ml/h) results significantly higher in relation to the other two drugs (1133 and 926 pg/ml/h) indicating a better bio-availability of calcitonin contained in that spray. The relative bioavailability between calcitonin spray with sodium taurocholate and the other two drugs in reference resulted to 144% and 176%. The presence of a transmucosal absorption promoting factor at the level of a nasal mucosa, represented in this case by sodium taurocholate, enhances significantly the absorption and the bioavailability of calcitonin present in the formulation spray