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These consensus guidelines provide recommendations for the safe handling of monoclonal antibodies. Definitive recommendations are given for the minimum safe handling requirements to protect healthcare personnel. The seven recommendations cover: (i) appropriate determinants for evaluating occupational exposure risk; (ii) occupational risk level compared with other hazardous and non-hazardous drugs; (iii) stratification of risk based on healthcare personnel factors; (iv) waste products; (v) interventions and safeguards; (vi) operational and clinical factors and (vii) handling recommendations. The seventh recommendation includes a risk assessment model and flow chart for institutions to consider and evaluate clinical and operational factors unique to individual healthcare services. These guidelines specifically evaluated monoclonal antibodies used in the Australian cancer clinical practice setting; however, the principles may be applicable to monoclonal antibodies used in non-cancer settings. The guidelines are only applicable to parenterally administered agents. [ABSTRACT FROM AUTHOR]

Cox, S. R., Liao, S., Payne-Johnson, M., Zielinski, R. J., Stegemann, M. R. Population pharmacokinetics of mavacoxib in osteoarthritic dogs. J. vet. Pharmacol. Therap. , 1-11. Mavacoxib (Trocoxil™) is an oral long-acting COX-2 inhibitor approved for the treatment of osteoarthritis in dogs. Two field trials were conducted in client-owned dogs suffering from osteoarthritis, with dosages of 4 mg/kg body weight (BW) (Study 1) or 2 mg/kg BW (Study 2). Mavacoxib plasma concentrations were determined from trough blood samples and from blood samples collected at 4-10 months after the last dose. A one-compartment linear model was fitted to the concentration data (1317 concentration records from 286 patients), and parameters for oral clearance ( Cl/ F), apparent volume of distribution (V/ F) and their between-subject variabilities (BSV) were estimated. Covariates were included in the model based on the outcomes of stepwise regression procedures. In the final model, the typical value of Cl/ F was a function of BW, age and breed. German shepherds and Labrador retrievers were found to have 31% higher values of Cl/ F than patients from different breeds with similar ages and BWs. The typical value of V/ F was found to be dependent only on BW. The two field studies appeared to differ similarly with respect to Cl/ F and V/ F. The explanation for this difference is not known, but the difference was accounted for in the final model as a 23.9% lower bioavailability in Study 2. Mavacoxib exhibited relatively broad BSV in Cl/ F and V/ F, with coefficients of variation of 47% and 19%, respectively. The typical value for mavacoxib's terminal elimination plasma half-life ( t) was 44 days, but a minority of patients (approximately 5%) had empirical Bayes estimates of t exceeding 80 days. Simulations with the model indicated that the majority of patients treated with mavacoxib 2 mg/kg will maintain trough plasma mavacoxib concentrations associated with efficacy. Results of the population pharmacokinetic analysis helped to reduce the dose from 4 to 2 mg/kg and thus increased the therapeutic index for this molecule. [ABSTRACT FROM AUTHOR]

Phosphogypsum (PG) is a by-product of the chemical reaction called the “wet process” whereby sulphuric acid reacts with phosphate rock (PR) to produce phosphoric acid, needed for fertilizer production. Through the wet process, some impurities naturally present in the PR become incorporated in PG, including U decay-series radionuclides, are the main important concern which could have an effect on the surrounding environment and prevent its safe utilization. In order to determine the distribution and bioavailability of radionuclides to the surrounding environment, we used a sequential leaching of PG samples from Aqaba and Eshidiya fertilizer industry. The results showed that the percentages of 226Ra and 210Pb in PG are over those in the corresponding phosphate rocks (PG/PR), where 85% of the 226Ra and 85% of the 210Pb fractionate to PG. The sequential extraction results exhibited that most of 226Ra and 210Pb are bound in the residual phase (non-CaSO4) fraction ranging from 45–65% and 55%–75%, respectively, whereas only 10%–15% and 10%–20% respectively of these radionuclides are distributed in the most labile fraction. The results obtained from this study showed that radionuclides are not incorporated with gypsum itself and may not form a threat to the surrounding environment. [ABSTRACT FROM AUTHOR]

Rationale: Cigarette smoke (CS) exposure is an important risk factor for chronic obstructive pulmonary disease; however, not all smokers develop disease, suggesting that other factors influence disease development.Objectives: We sought to determine whether neuropilin-1 (Nrp1), an integral component of receptor complexes mediating alveolar septation and vascular development, was involved in maintenance of normal alveolar structure, and/or altered susceptibility to the effects of CS.Methods: Transgenic mice were generated to achieve inducible lung-specific deletion of epithelial Nrp1. We determined whether conditional Nrp1 deletion altered airspace size, then compared the effects of chronic CS or filtered air exposure on airspace size, inflammation, and the balance between cell death and proliferation in conditionally Nrp1-deficient adult mice and littermate controls. Finally, we evaluated the effects of Nrp1 silencing on cell death after acute exposure of A549 cells to cigarette smoke extract or short chain ceramides.Measurements and Main Results: Genetic deletion of epithelial Nrp1 in either postnatal or adult lungs resulted in a small increase in airspace size. More notably, both airspace enlargement and apoptosis of type I and type II alveolar epithelial cells were significantly enhanced following chronic CS exposure in conditionally Nrp1-deficient adult mice. Silencing of Nrp1 in A549 cells did not alter cell survival after vehicle treatment but significantly augmented apoptosis after exposure to cigarette smoke extract or ceramide.Conclusions: These data support a role for epithelial Nrp1 in the maintenance of normal alveolar structure and suggest that dysregulation of Nrp1 expression may promote epithelial cell death in response to CS exposure, thereby enhancing emphysema development. [ABSTRACT FROM AUTHOR]

The objectives of this study were to determine pharmacokinetics of intravenous (i.v.) ceftiofur in foals, to compare ultra-high performance liquid chromatography tandem mass spectometry (UPLC-MS/MS) and microbiologic assay for the measurement of ceftiofur concentrations, and to determine the minimum inhibitory concentration ( MIC) of ceftiofur against common equine bacterial pathogens. In a cross-over design, ceftiofur sodium was administered i.v. to six foals (1–2 days-of-age and 4–5 weeks-of-age) at dosages of 5 and 10 mg/kg. Subsequently, five doses of ceftiofur were administered i.v. to six additional foals between 1 and 5 days of age at a dose of 5 mg/kg q 12 h. Concentrations of desfuroylceftiofur acetamide (DCA), the acetamide derivative of ceftiofur and desfuroylceftiofur-related metabolites were measured in plasma, synovial fluid, urine, and CSF by use of UPLC-MS/MS. A microbiologic assay was used to measure ceftiofur activity for a subset of plasma samples. Following i.v. administration of ceftiofur at a dose of 5 mg/kg to 1–2 day-old foals, DCA had a t½ of 7.8 ± 0.1 h, a body clearance of 74.4 ± 8.4 mL/h/kg, and an apparent volume of distribution of 0.83 ± 0.09 L/kg. After multiple i.v. doses at 5 mg/kg, DCA concentrations in CSF were significantly lower than concurrent plasma concentrations. Ceftiofur activity using a microbiologic assay significantly underestimated plasma concentrations of DCA. The MIC of ceftiofur required to inhibit growth of 90% of isolates of Escherichia coli, Pasteurella spp, Klebsiella spp, and β-hemolytic streptococci was <0.5 μg/mL. Intravenous administration of ceftiofur sodium at the rate of 5 mg/kg every 12 h would provide sufficient coverage for the treatment of susceptible bacterial isolates. [ABSTRACT FROM AUTHOR]

Leaching of freshly erupted air-fall ash, unaffected by rain, from the May 18, 1980, eruption of Mount St. Helens volcano, Washington, shows that Ca, Na, Mg, SO, and Cl are the predominant chemical species released on first exposure of the ash to water. Extremely high correlation of Ca with SO and Na with Cl in water leachates suggests the presence of CaSO and NaCl salts on the ash. The amount of water soluble material on ash increases with distance from source and with the weight fraction of small (less than 63 micrometers) ash particles of high-surface area. This suggests that surface reactions such as adsorption are responsible for concentrating the soluble material. CaSO, NaCl, and other salts are probably formed as microscopic crystals in the high-temperature core of the eruption column and are then adsorbed by silicate ash particles. The environmentally important elements Zn, Cu, Cd, F. Pb, and Ba are released by a water leach in concentrations which could pose short-term hazards to some forms of aquatic life. However, calculated concentrations are based on a water-to-ash ratio of 4:1 or less, which is probably an underestimation of the regionally operative ratio. A subsequent leach of ash by warm alkaline solution shows dramatic increases, in the amount of dissolved SiO, U, and V, which are probably caused by increased dissolution of the glassy component of ash. Glass dissolution by alkaline ground water is a mechanism for providing these three elements to sedimentary traps where they may coaccumulate as uraniferous silica or U-V minerals. Leaching characteristics of ash from Mount St. Helens are comparable to characteristics of ash of similar composition from volcanoes in Guatemala. Ashes from each locality show similar ions predominating for a given leachate and similar fractions of a particular element in the ash removed on contact with the leach solution. [ABSTRACT FROM AUTHOR]