Population pharmacokinetics and pharmacokinetic/pharmacodynamic evaluation of marbofloxacin against Coagulase-negative staphylococci, Staphylococcus aureus and Mycoplasma agalactiae pathogens in goats

Marbofloxacin is a broad-spectrum fluoroquinolone, and an extra-label use has been reported in horse, sheep and goat. However, extrapolation of dosage regimens from cattle to horse and small ruminants could lead to incorrect dosing due to pharmacokinetic differences among species, increasing the risk of antimicrobial resistance or toxicity. Pharmacokinetic properties of marbofloxacin, including PK/PD analysis, have been studied by intravenous, intramuscular and subcutaneous administration in lactating and non-lactating goats. A population pharmacokinetic model of marbofloxacin in goats was built using 10 pharmacokinetic studies after intravenous, intramuscular, and subcutaneous administration at a dose of 2, 5 and 10 mg/kg. Serum or plasma and milk concentration-time profiles were simultaneously fitted with a non-linear mixed effect model with Monolix software. Level of milk production (lactating and non-lactating) and health status (healthy and un-healthy) were retained as covariates on volume of distribution and clearance. Marbofloxacin concentrations were well described in plasma/serum and milk by the population model. Simulated dose regimens of marbofloxacin administered at 2, 5 and 10 mg/kg by intramuscular route for five days were evaluated (n = 5000 per group). Steady-state fAUCs for each dose regimen were obtained. Probability of target attainment of fAUC/MIC ratios were determined and PK/PDco values (highest MIC for which 90% of individuals can achieve a prior numerical value of the fAUC/MIC index) were established using Monte Carlo simulations (n = 50,000). MIC values for wild type isolates of Staphylococcus aureus, coagulase negative staphylococci, and Mycoplasma agalactiae were determined and tentative epidemiological cutoff (TECOFF) were obtained at 1.0, 0.5 and 0.5 mg/L, respectively. The PK/PDco for the dose regimen of 2 mg/kg/24 h and 5 mg/kg/24 h (0.125 and 0.25 mg/L) were lower than TECOFF (0.5 and 1 mg/L). The dosage regimen of 10 mg/kg/24 h was adequate for intermediate MIC values of 0.125–0.50 mg/L and could be effective for a population with a target fAUC/MIC ratio ˂ 48 for Coagulase negative staphylococci and Mycoplasma agalactiae, but not for Staphylococcus aureus. Results obtained in thi

VetCAST method for determination of the pharmacokineticpharmacodynamic cut-off values of a long-acting formulation of florfenicol to support clinical breakpoints for florfenicol Antimicrobial Susceptibility Testing in cattle

The PK/PD cut-off (PK/PDCO ) value of florfenicol for calf pathogens was determined for long acting formulations (MSD Nuflor® and a bioequivalent generic product). PK/PDCO is one of the three MICs considered by VetCAST, a sub-committee of the European Committee on Susceptibility Testing, to establish a Clinical Breakpoint for interpreting Antimicrobial Susceptibility Testing. A population model was built by pooling three pharmacokinetic data sets, obtained from 50 richly sampled calves, receiving one of two formulations (the pioneer product and a generic formulation). A virtual population of 5000 florfenicol disposition curves was generated by Monte Carlo Simulations over the 96 h of the assumed duration of action of the formulations. From this population, the maximum predicted MIC, for which 90% of calves can achieve some a priori selected critical value for two PK/PD indices, AUC/MIC and T>MIC, was established. Numerical values were established for two bacterial species of the bovine respiratory disease complex, Pasteurella multocida and Mannheimia haemolytica. It was concluded that the PK/PDCO of florfenicol for both AUC/MIC and T>MIC was 1 mg/L

Constraint-Preconditioned Krylov Solvers for Regularized Saddle-Point Systems

We consider the iterative solution of regularized saddle-point systems. When the leading block is symmetric and positive semi-definite on an appropriate subspace, Dollar, Gould, Schilders, and Wathen (2006) describe how to apply the conjugate gradient (CG) method coupled with a constraint preconditioner, a choice that has proved to be effective in optimization applications. We investigate the design of constraint-preconditioned variants of other Krylov methods for regularized systems by focusing on the underlying basis-generation process. We build upon principles laid out by Gould, Orban, and Rees (2014) to provide general guidelines that allow us to specialize any Krylov method to regularized saddle-point systems. In particular, we obtain constraint-preconditioned variants of Lanczos and Arnoldi-based methods, including the Lanczos version of CG, MINRES, SYMMLQ, GMRES(m) and DQGMRES. We also provide MATLAB implementations in hopes that they are useful as a basis for the development of more sophisticated software. Finally, we illustrate the numerical behavior of constraint-preconditioned Krylov solvers using symmetric and nonsymmetric systems arising from constrained optimization.Comment: Accepted for publication in the SIAM Journal on Scientific Computin

Multiple Linear Regression: Identify Potential Health Care Stocks for Investments Using Out-of-Sample Predictions

College‐level statistics courses emphasize the use of the coefficient of determination, R‐squared, in evaluating a linear regression model: higher R‐squared is better. This often gives students an impression that higher R‐squared implies better predictability since textbooks tend to use sample data to support the theory and students rarely have an opportunity to work on real data. In this paper, health care stocks are used as predictors and the result demonstrates that high R‐squared does not necessarily mean high predictability and that multiple linear regression can be used in the study of data behavior. In particular, by learning the pattern of the near and far out‐of‐sample‐prediction errors for different time periods throughout a dataset, the near out‐of‐sample prediction errors can be used to control the prediction errors and identify a subset of predictors that can well reflect the trend of S&P 500

Synthesis and Electrochemical Analysis of PdCO/MWCNT and PdCo/GO Towards Formic Acid Fuel Cells

With more and more technological advances being made, a growing global population, and greater push towards greener energy brings a great need for alternative sources of energy. In order to keep up with ever increasing demands for energy, direct formic acid fuel cells (DFAFCs) show great promise. However, the need for a cost effective, robust and efficient anodic catalyst towards DFAFCs is still imminent. Therefore, this study aims to investigate the efficiency, conductivity, and stability of palladium and cobalt binary nanocomposites on multiwalled carbon nanotubes (MWCNTs). Three nanocomposites were synthesized with varying amounts of cobalt and a fixed amount of palladium on MWCNTs using a simple one pot synthesis utilizing sodium borohydride as a reducing agent. This allowed the palladium and cobalt nanoparticles to disperse along the carbon nanotube surface to provide greater catalytic surface area. The morphology was characterized by scanning electron microscopy (SEM) imaging technique showing the binary nanocomposites were dispersed along the carbon nanotube surface. Cyclic voltammetry (CV) was then employed for the electrochemical characterization of formic acid oxidation (FAO) using the nanocomposites in a 0.50 M formic acid with 0.10 M sulfuric acid electrolyte. A glassy carbon electrode was modified with a fixed amount of the nanocomposites to enable correct comparisons of the effect of various amounts of cobalt. So far, the nanocomposites are demonstrating the direct 2 formic acid oxidation pathway. This along with all other electrochemical data will be compared to a standard commercially available 20% palladium on carbon Pearlman catalyst

Effect of neutron alignments on the structure of Tl 197

The excited states of 197Tl have been studied via 19 Au(4He, 4n)197 Tl reaction at a beam energy of 50 MeV from the K-130 cyclotron at the Variable Energy Cyclotron Centre (VECC). The γ rays were detected using the VECC array for Nuclear Spectroscopy (VENUS) with six Compton-suppressed clover HPGe detectors. An improved level scheme of 197 Tl has been proposed from this work, which has been extended to 5.1 MeV of excitation energy and 39/2 ℏ of spin from the placement of 28 new γ-ray transitions. Band crossings in the known one- and three-quasiparticle (qp) bands have been identified for the first time in this work. Two new bands, based on 3-qp and 5-qp configurations, have been observed for the first time in this nucleus; both of which are identified as the magnetic rotational (MR) in nature. The excitation energies of these bands are similar to that of the doubly degenerate bands observed for the similar 3-qp and 5-qp configurations in 195 Tl. These indicate a transition from an aplanar geometry of the neutron, proton, and the core angular momentum vectors to a planar one for neutron number N≥116 in Tl isotopes. The total Routhian surface calculations suggest a change in shape from oblate for the 1-qp configuration to a near-spherical one for the 3- and 5-qp configurations. This is consistent with the observed MR nature of the bands with multi-qp configuration. The MR bands are well reproduced by a model calculations in the frame work of the shears mechanism with the principal axis cranking.One of the authors (H.P.) is grateful for the support from the Ramanujan Fellowship Research Grant under SERB-DST Grant No. SB/S2/RJN-031/2016

Anodic Alumina Membranes: From Electrochemical Growth to Use as Template for Fabrication of Nanostructured Electrodes

The great success of anodic alumina membranes is due to their morphological features coupled to both thermal and chemical stability. The electrochemical fabrication allows accurate control of the porous structure: in fact, the membrane morphological characteristics (pore length, pore diameter and cell density) can be controlled by adjusting the anodizing parameters (bath, temperature, voltage and time). This article deals with both the fabrication and use of anodic alumina membranes. In particular, we will show the specific role of the addition of aluminum ions to phosphoric acid-based anodizing solution in modifying the morphology of anodic alumina membranes. Anodic alumina membranes were obtained at −1◦ C in aqueous solutions of 0.4 M H3 PO4 added with different amounts of Al(OH)3 . For sake of completeness, the formation of PAA in pure 0.4 M H3 PO4 in otherwise identical conditions was also investigated. We found that the presence of Al(OH)3 in solution highly affects the morphology of the porous layer. In particular, at high Al(OH)3 concentration (close to saturation) more compact porous layers were formed with narrow pores separated by thick oxide. The increase in the electric charge from 20 to 160 C cm−2 also contributes to modifying the morphology of porous oxide. The obtained anodic alumina membranes were used as a template to fabricate a regular array of PdCo alloy nanowires that is a valid alternative to Pt for hydrogen evolution reaction. The PdCo alloy was obtained by electrodeposition and we found that the composition of the nanowires depends on the concentration of two metals in the deposition solution

A Comparative Study of a 1/4-Scale Gulfstream G550 Aircraft Nose Gear Model

A series of fluid dynamic and aeroacoustic wind tunnel experiments are performed at the University of Florida Aeroacoustic Flow Facility and the NASA-Langley Basic Aerodynamic Research Tunnel Facility on a high-fidelity -scale model of Gulfstream G550 aircraft nose gear. The primary objectives of this study are to obtain a comprehensive aeroacoustic dataset for a nose landing gear and to provide a clearer understanding of landing gear contributions to overall airframe noise of commercial aircraft during landing configurations. Data measurement and analysis consist of mean and fluctuating model surface pressure, noise source localization maps using a large-aperture microphone directional array, and the determination of far field noise level spectra using a linear array of free field microphones. A total of 24 test runs are performed, consisting of four model assembly configurations, each of which is subjected to three test section speeds, in two different test section orientations. The different model assembly configurations vary in complexity from a fully-dressed to a partially-dressed geometry. The two model orientations provide flyover and sideline views from the perspective of a phased acoustic array for noise source localization via beamforming. Results show that the torque arm section of the model exhibits the highest rms pressures for all model configurations, which is also evidenced in the sideline view noise source maps for the partially-dressed model geometries. Analysis of acoustic spectra data from the linear array microphones shows a slight decrease in sound pressure levels at mid to high frequencies for the partially-dressed cavity open model configuration. In addition, far field sound pressure level spectra scale approximately with the 6th power of velocity and do not exhibit traditional Strouhal number scaling behavior

Paediatric medicines regulation in Europe: evolution in drug development

Tese de mestrado, Regulação e Avaliação do Medicamento e Produtos de Saúde, 2020, Universidade de Lisboa, Faculdade de Farmácia.O Regulamento Europeu sobre Medicamentos Pediátricos, adotado em 2007, teve como objetivo solucionar o problema da utilização de medicamentos não pediátricos nesta população. Este regulamento cria incentivos para o desenvolvimento de medicamentos em pediatria que, devido às suas características, têm um baixo interesse comercial na indústria farmacêutica e, portanto, estão ausentes no mercado sem alternativas terapêuticas. Desde 2007, houve um impacto positivo deste regulamento na disponibilidade de medicamentos para a população pediátrica, considerando os seus objetivos. O desenvolvimento de medicamentos pediátricos integrou-se no desenvolvimento geral do medicamento, através da consideração desta população num plano de investigação dedicado, considerando o potencial uso pediátrico desses medicamentos. Vários novos medicamentos foram autorizados, com indicações pediátricas e formas farmacêuticas adequadas para essas faixas etárias. O elevado número de planos de investigação pediátrica aprovados também indica que existem novos medicamentos em desenvolvimento e que as informações sobre a população pediátrica tiveram definitivamente um aumento significativo. Esta dissertação tem como objetivo descrever a evolução da implementação do regulamento europeu sobre medicamentos pediátricos e, consequentemente, o seu impacto no desenvolvimento de novos medicamentos para esta população. Especificamente, caracterizará os esforços criados para desenvolver novos ensaios clínicos e medicamentos indicados para população pediátrica, identificando as necessidades terapêuticas pediátricas bem como melhores práticas na gestão da utilização “off-label”. A utilização de medicamentos de uso pediátrico em "off-label", embora legítima, é uma preocupação séria e real. As consequências relacionadas com o tratamento de crianças com formulações e regimes terapêuticos inadequados que não foram adequadamente comprovados para esta faixa etária podem ser subterapêuticas - falhada eficácia terapêutica e progressão da doença - ou eventualmente toxicidade e podem levar a efeitos negativos e potencialmente graves no crescimento e desenvolvimento da criança.The European Regulation on Paediatric Medicines adopted in 2007 aimed at solving the problem of the use of non-paediatric medicines. This Regulation creates incentives for the development of medicines in paediatrics which, because of their characteristics, have a low commercial interest in the pharmaceutical industry and, therefore, are lacking in the market without therapeutic alternatives. Since 2007, there has been a positive impact of this Regulation on the availability of medicines to the paediatric population, considering its objectives. The development of paediatric drugs became integrated into the overall development of the drug, through the consideration of this population in a dedicated Research Plan, considering the potential paediatric use of these drugs. Several new medicines have been authorised, with paediatric indications and pharmaceutical forms suitable for these age groups. The high number of approved Paediatric Investigation Plans also indicates that there are other medicines under development, and information about the paediatric population has definitely had a significant increase. This dissertation aims to describe the evolution of the implementation of the European regulation on paediatric medicines and, consequently, its impact on the development of new medicines for this population. Specifically, it will characterize the efforts created to develop new clinical trials and drugs indicated for the paediatric population, identifying the paediatric therapeutic needs as well as best practices in managing “off-label” use. The use of unauthorised paediatric drugs, while legitimate, is a serious and real concern. The consequences related to the treatment of children with unsuitable formulations and therapeutic regimens that have not been adequately proven in a certain age group (off-label use) may be subtherapeutic - failure of therapy and continuation of the disease - or eventually toxicity and may lead to negative and potentially serious effects on the child's growth and development