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This study is part of an ongoing effort to develop animal models that provide milk and sufficient infant (offspring) plasma samples to fully describe a drug's pharmacokinetics to quantitate the risk to the nursing infant. Ciprofloxacin was administered to six healthy Holstein cows as a constant rate intravenous infusion (flow rate was weight adjusted) to achieve a steady-state concentration of approximately 300 ng/mL for 7 days. Plasma and milk samples were collected from the cow at regular intervals over the course of the 7 days. The plasma and milk samples were analyzed for ciprofloxacin by high-performance liquid chromatography. The milk was fed to calves, and calf plasma samples were analyzed to study the lactational transfer of ciprofloxacin from dam to nursing neonate. Remarkably, concentrations of ciprofloxacin in milk were 45 times higher than plasma drug concentrations in the dam. Approximately 6% of the administered dose was transferred to the milk, resulting in an average oral dose of 0.5 mg/kg to the calves with every feeding. The drug did not accumulate in the calves, and plasma concentrations were between one-tenth and one-fifth the plasma concentrations of the dam. [ABSTRACT FROM AUTHOR]

Malreddy, P. R., Coetzee, J. F., KuKanich, B., Gehring, R. Pharmacokinetics and milk secretion of gabapentin and meloxicam co-administered orally in Holstein-Friesian cows. J. vet. Pharmacol. Therap. 36, 14-20. Management of neuropathic pain in dairy cattle could be achieved by combination therapy of gabapentin, a GABA analog and meloxicam, an nonsteroidal anti-inflammatory drug. This study was designed to determine specifically the depletion of these drugs into milk. Six animals received meloxicam at 1 mg/kg and gabapentin at 10 mg/kg, while another group ( n = 6) received meloxicam at 1 mg/kg and gabapentin at 20 mg/kg. Plasma and milk drug concentrations were determined over 7 days postadministration by HPLC/MS followed by noncompartmental pharmacokinetic analyses. The mean (±SD) plasma Cmax and Tmax for meloxicam (2.89 ± 0.48 μg/mL and 11.33 ± 4.12 h) were not much different from gabapentin at 10 mg/kg (2.87 ± 0.2 μg/mL and 8 ± 0 h). The mean (±SD) milk Cmax for meloxicam (0.41 ± 80.16 μg/mL) was comparable to gabapentin at 10 mg/kg (0.63 ± 0.13 μg/mL and 12 ± 6.69 h). The mean plasma and milk Cmax for gabapentin at 20 mg/kg P.O. were almost double the values at 10 mg/kg. The mean (±SD) milk to plasma ratio for meloxicam (0.14 ± 0.04) was lower than for gabapentin (0.23 ± 0.06). The results of this study suggest that milk from treated cows will have low drug residue concentration soon after plasma drug concentrations have fallen below effective levels. [ABSTRACT FROM AUTHOR]

Mosher, R. A., Coetzee, J. F., Cull, C. A., Gehring, R., KuKanich, B. Pharmacokinetics of oral meloxicam in ruminant and preruminant calves. J. vet. Pharmacol. Therap. 35, 373-381. The pharmacokinetics of oral meloxicam has been studied in ruminant, but not preruminant calves. Oral meloxicam was administered at 0.5 mg/kg to six ruminant calves via gavage (RG); to six preruminant calves via gavage (PRG); and to six preruminant calves via suckling in milk replacer (PRF). Plasma drug concentrations, determined over 120-h postadministration, were analyzed by compartmental and noncompartmental methods. The rate of drug absorption was faster ( P < 0.01) in PRF (0.237 ± 0.0478/h) than RG calves (0.0815 ± 0.0188/h), while absorption in PRG calves (0.153 ± 0.128/h) was not different from other groups. Cmax was lower ( P = 0.03) in PRF (1.27 ± 0.430 μg/mL) than in PRG calves (2.20 ± 0.467 μg/mL), while Cmax of RG calves (1.95 ± 0.955 μg/mL) was not different from other groups. V/ F was higher in PRF calves (365 ± 57 mL/kg) than either PRG (177 ± 63 mL/kg, P < 0.01) or RG (232 ± 83 mL/kg, P = 0.01) calves. These observations were likely due to differences in bioavailability, physiological maturity, and timing of the drug delivery into different compartments of the ruminant gastrointestinal tract. Results suggest that an adjustment in meloxicam dose may be necessary when administered with milk replacer. [ABSTRACT FROM AUTHOR]

Al-Bataineh, M. M., van der Merwe, D., Schultz, B. D., Gehring, R. Molecular and functional identification of organic anion transporter isoforms in cultured bovine mammary epithelial cells (BME-UV). J. vet. Pharmacol. Therap. 35, 209-215. Mammary epithelial cells express a diversity of membrane transporters including members of organic cation and organic anion (OAT) transporter subfamilies. Four mammal OAT isoforms have been identified: OAT-1, OAT-2, OAT-3, and OAT-4. The pharmacological significance of OAT isoforms has been emphasized because of their role in the movement of a wide variety of substrates across epithelial barriers. The present study identified (molecularly and functionally) bovine OAT isoforms in bovine mammary epithelial (BME-UV) cells. mRNA expression levels of all tested transporters in BME-UV cells were less than expression levels of the corresponding transporters in bovine kidney. Directionality in the flux of P-aminohippuric acid and acetylsalicylate, compounds known to interact with OAT-1 and OAT-2, respectively, across BME-UV monolayers was not observed at the concentrations used in this study. Directionality was, however, observed in the flux of estrone sulfate (EsS). Adding probenecid, penicillin G or nonradiolabeled EsS to the apical donor compartment significantly increased the apical-to-basolateral flux of EsS across the BME-UV monolayer. These results suggest that BME-UV cells express an organic anion transport system, making it a potentially useful model to study the role of this transport system in the mammary epithelial barrier. [ABSTRACT FROM AUTHOR]

Lainesse, C., Gehring, R., Pasloske, K., Smith, G., Soback, S., Wagner, S., Whittem, T. Challenges associated with the demonstration of bioequivalence of intramammary products in ruminants. J. vet. Pharmacol. Therap. 35 (Suppl. 1), 65-79. This article explores the numerous challenges encountered when the goal is to demonstrate bioequivalence (BE) between test and reference intramammary (IMM) products in ruminants. Numerous pathophysiological factors of mastitis and physicochemical properties of IMM formulations are implicated in the difficulties in confirming BE for this dosage form. Advantages and disadvantages of current BE study designs are discussed, and alternative perspectives are outlined. Ongoing and future research increasing our knowledge of the pharmacokinetics and pharmacodynamics of antimicrobial drugs delivered through this route is crucial to better understanding the implications of clinically significant formulation differences in the demonstration of BE and may also help in developing more effective IMM formulations for ruminants. [ABSTRACT FROM AUTHOR]

Gehring, R., Martinez, M. Assessing product bioequivalence for extended-release formulations and drugs with long half-lives. J. vet. Pharmacol. Therap. 35 (Suppl. 1), 3-9. When a drug product remains in the body for a duration of hours or days, estimating the extent of drug exposure is relatively straightforward. For immediate release (IR) dosage forms, the peak drug concentration ( Cmax) and time to peak concentrations ( Tmax) are typically adequate for comparing product rates of drug absorption. However, unique complexities need to be addressed when a drug remains in the system for a duration of months or years. Specifically, if the long duration of exposure is attributable to formulation effects, Cmax and Tmax may not be adequate to compare the rate of drug absorption, especially when there are multiphasic absorption processes. In this case, it may be appropriate to use partial (segmented areas) for comparing product profiles. However, the decision of how the curves are segmented is not straightforward. Points to consider are discussed in this manuscript. Alternatively, if the long half-life is due to the pharmacokinetics (PK) of the active pharmaceutical ingredient and not to formulation effects, Cmax and Tmax may be appropriate metrics for the rate of absorption but decisions regarding the duration of blood sampling needed to capture the AUC should be based upon an assessment of the inherent variability in drug absorption and elimination. Furthermore, it is important to be confident that the absorption phase is complete. In this manuscript, we explore some of the difficulties associated with determining optimal metrics for comparing the rate and extent of product release for long half life drugs when the long duration of exposure is attributable to either the inherent drug PK or to formulation effects. [ABSTRACT FROM AUTHOR]

Bergamasco, L., Coetzee, J. F., Gehring, R., Murray, L., Song, T., Mosher, R. A. Effect of intravenous sodium salicylate administration prior to castration on plasma cortisol and electroencephalography parameters in calves. J. vet. Pharmacol. Therap. 34, 565-576. Nociception is an unavoidable consequence of many routine management procedures such as castration in cattle. This study investigated electroencephalography (EEG) parameters and cortisol levels in calves receiving intravenous sodium salicylate in response to a castration model. Twelve Holstein calves were randomly assigned to the following groups: (i) castrated, untreated controls, (ii) 50 mg/kg sodium salicylate IV precastration, were blood sampled at 0, 5, 10, 20, 30, 45, 60, 90, 120, 150, 180, 240, 360, and 480 min postcastration. The EEG recording included baseline, castration, immediate recovery (0-5 min after castration), middle recovery (5-10 min after castration), and late recovery (10-20 min after castration). Samples were analyzed by competitive chemiluminescent immunoassay and fluorescence polarization immunoassay for cortisol and salicylate, respectively. EEG visual inspection and spectral analysis were performed. Statistical analyses included anova repeated measures and correlations between response variable. No treatment effect was noted between the two groups for cortisol and EEG measurements, namely an attenuation of acute cortisol response and EEG desynchronization in sodium salicylate group. Time effects were noted for EEG measurements, cortisol and salicylates levels. Significant correlations between cortisol and EEG parameters were noted. These findings have implications for designing effective analgesic regimens, and they suggest that EEG can be useful to monitor pain attributable to castration. [ABSTRACT FROM AUTHOR]

The rain garden is an urban storm water best management practice that is used to infiltrate runoff close to its source thereby disconnecting impervious area while providing an avenue for groundwater recharge. Groundwater recharge may provide additional benefits to aquatic ecosystems via enhancement of stream base flow. Yet, soil conditions can impact on certain aspects of rain garden performance and its provision of ecosystem services. In the context of a watershed-level study to determine the effectiveness of decentralized storm water management, we performed an order 1 soil survey of the Shepherd Creek watershed (Cincinnati, Ohio) to delineate soils and identify and describe representative soil pedons, and then we assessed subsoil saturated hydraulic conductivity (Ksat) in each of the three dominant subsoils with qualitative estimation methods and directly with constant-head permeametry. We next simulated the effect of subsoil hydrology of a hypothetical implementation of a parcel- level rain garden on groundwater recharge in this watershed. Measured subsoil Ksat were overall very low with a mean of 0.01 cm hr-1 (4 x 10-3 in hr-1) for Eden soil and a mean of 0.2 cm hr-1 (0.08 in hr-1) for both the fine-silty family and Switzerland soils. Compared with the measured values, qualitative measures overestimated Ksat and depth of recharge for Eden and fine-silty, and underestimated the same for Switzerland. Based on median parcel features and 2004 warm-season storm records, rain gardens in the fine-silty family and Switzerland subsoils would be expected to contribute about 6 cm (2.4 in) of recharge as compared to the 2 cm (0.8 in) expected in Eden soils. Our results also suggest the highest potential for abatement of storm water quantity abatement in Eden soils, with some partitioning of this water to recharge as an added benefit. Our approach and results form the basis for a comprehensive understanding of how storm water management decentralized at the watershed level play positively impact ecosystem services. [ABSTRACT FROM AUTHOR]

As particle accelerator technology advances, rapid cycling machines become more common. An increase in ramping speed of the magnets will draw more pulsed power from the utilities grid up to non acceptable levels. An intermediate storage of active and reactive power with fast reaction times and excellent cycling capabilities becomes more and more important. A study has been performed for the conceivable replacement of the existing magnet power supply of the PS (Proton Synchrotron) of CERN. A possible solution is a SMES-based modular compensator system, which allows a step-by-step build-up of the system in turn with test operations during regular shut-down phases while continuing operation of the existing power supply. [ABSTRACT FROM AUTHOR]

The rate and extent of dermal absorption are important in the analysis of risk from dermal exposure to toxic chemicals and for the development of topically applied drugs, barriers, insect repellents, and cosmetics. In vitro flow-through cells offer a convenient method for the study of dermal absorption that is relevant to the initial processes of dermal absorption. This study describes a physiologically based pharmacokinetic (PBPK) model developed to simulate the absorption of organophosphate pesticides, such as parathion, fenthion, and methyl parathion through porcine skin with flow-through cells. Parameters related to the structure of the stratum corneum and solvent evaporation rates were independently estimated. Three parameters were optimized based on experimental dermal absorption data, including solvent evaporation rate, diffusivity, and a mass transfer factor. Diffusion cell studies were conducted to validate the model under a variety of conditions, including different dose ranges (6.3–106.9 μg/cm2 for parathion; 0.8–23.6 μg/cm2 for fenthion; 1.6–39.3 μg/cm2 for methyl parathion), different solvents (ethanol, 2-propanol and acetone), different solvent volumes (5–120 μl for ethanol; 20–80 μl for 2-propanol and acetone), occlusion versus open to atmosphere dosing, and corneocyte removal by tape-stripping. The study demonstrated the utility of PBPK models for studying dermal absorption, which can be useful as explanatory and predictive tools that may be used for in silico hypotheses generation and limited hypotheses testing. The similarity between the overall shapes of the experimental and model-predicted flux/time curves and the successful simulation of altered system conditions for this series of small, lipophilic compounds indicated that the absorption processes that were described in the model successfully simulated important aspects of dermal absorption in flow-through cells. These data have direct relevance to topical organophosphate pesticide risk assessments. [ABSTRACT FROM AUTHOR]

All drugs approved for use in food-producing animals have a withdrawal interval to prevent residues in food of animal origin that are potentially harmful to consumers. These withdrawal times must be appropriately extended if the drug is used in an extralabel manner. This paper describes a web-based application that was developed to facilitate the calculation of extended withdrawal intervals based on information in the databases maintained by members of the Food Animal Residue Avoidance Databank (FARAD) and using the Extrapolated Withdrawal Interval Estimator (EWE) algorithm. The implementation of this application was illustrated using a group of antimicrobials that are used in cattle and swine. The use of this application has been limited to staff veterinarians working for FARAD since limitations in the available pharmacokinetic data require that results are interpreted by personnel with in-depth knowledge of the pharmacokinetics of drugs in food-producing animals. [Copyright &y& Elsevier]