Pharmacokinetic Parameters and Estimated Milk Withdrawal Intervals for Domestic Goats (Capra Aegagrus Hircus) After Administration of Single and Multiple Intravenous and Subcutaneous Doses of Flunixin Meglumine.

Introduction: The study objectives were to estimate plasma flunixin (FLU) pharmacokinetic parameters and milk depletion profiles for FLU and its metabolite (5-hydroxy flunixin; 5-OH) after subcutaneous (SC) and intravenous (IV) administration of single and multiple flunixin meglumine (FM) doses to non-lactating (nulliparous and pregnant does) and lactating dairy goats. Analytical methods (ELISA and UPLC-MS/MS) for quantifying plasma FLU concentrations were compared. The final objective was to use regulatory (FDA and EMA) methods to estimate milk withdrawal intervals following extra-label drug use in goats. Methods: FM was administered IV and SC to commercial dairy goats at 1.1 mg/kg for single and multiple doses. Plasma and milk samples were analyzed for FLU and 5-OH via UPLC-MS/MS. Plasma samples were also analyzed for FLU concentrations via ELISA. Using statistical approaches recommended by regulatory agencies, milk withdrawal intervals were estimated following FM extra-label use. Results: Following IV administration of a single FM dose, clearances were 127, 199, and 365 ml/kg/h for non-lactating (NL) pregnant does, NL nulliparous does, and lactating dairy does, respectively. Following multiple SC doses, clearance/F was 199 ml/kg/h for lactating does. After IV administration of a single FM dose, terminal elimination half-lives were 4.08, 2.87, and 3.77 h for NL pregnant does, NL nulliparous does, and lactating dairy does, respectively. After multiple SC doses, the terminal elimination half-life was 3.03 h for lactating dairy does. No significant differences were noted for samples analyzed by UPLC-MS/MS or ELISA. Milk withdrawal intervals ranged from 36 to 60 h depending on the regulatory statistical method and dosage regimen. Conclusions: Subcutaneous administration of FM to goats results in similar plasma pharmacokinetic parameters as IV administration. ELISA analysis is an alternative method to UPLC-MS/MS for quantifying FLU concentrations in caprine plasma samples. Following FM extra-label administration to dairy goats, clinicians could consider 36-60 h milk withdrawal intervals.

Sixth Drag Prediction Workshop Results Using FUN3D with k-kL-MEAH2015 Turbulence Model.

The Common Research Model wing/body configuration is investigated with the k-kL-MEAH2015 turbulence model implemented in FUN3D. This includes results presented at the Sixth Drag Prediction Workshop and additional results generated after the workshop with a nonlinear quadratic constitutive relation variant of the same turbulence model. The workshop-provided grids are used, and a uniform grid refinement study is performed at the design condition. A large variation between results with and without a reconstruction limiter is exhibited on "medium" grid sizes, indicating that the medium grid size is too coarse for drawing conclusions in comparison with experiment. This variation is reduced with grid refinement. At a fixed angle of attack near design conditions, the quadratic constitutive relation variant yielded decreased lift and drag compared with the linear eddy-viscosity model by an amount that was approximately constant with grid refinement. The k-kL-MEAH2015 turbulence model produced wing-root junction flow behavior consistent with wind-tunnel observations.

Estimation of tulathromycin depletion in plasma and milk after subcutaneous injection in lactating goats using a nonlinear mixed-effects pharmacokinetic modeling approach.

BACKGROUND: Extra-label use of tulathromycin in lactating goats is common and may cause violative residues in milk. The objective of this study was to develop a nonlinear mixed-effects pharmacokinetic (NLME-PK) model to estimate tulathromycin depletion in plasma and milk of lactating goats. Eight lactating goats received two subcutaneous injections of 2.5 mg/kg tulathromycin 7 days apart; blood and milk samples were analyzed for concentrations of tulathromycin and the common fragment of tulathromycin (i.e., the marker residue CP-60,300), respectively, using liquid chromatography mass spectrometry. Based on these new data and related literature data, a NLME-PK compartmental model with first-order absorption and elimination was used to model plasma concentrations and cumulative excreted amount in milk. Monte Carlo simulations with 100 replicates were performed to predict the time when the upper limit of the 95% confidence interval of milk concentrations was below the tolerance. RESULTS: All animals were healthy throughout the study with normal appetite and milk production levels, and with mild-moderate injection-site reactions that diminished by the end of the study. The measured data showed that milk concentrations of the marker residue of tulathromycin were below the limit of detection (LOD = 1.8 ng/ml) 39 days after the second injection. A 2-compartment model with milk as an excretory compartment best described tulathromycin plasma and CP-60,300 milk pharmacokinetic data. The model-predicted data correlated with the measured data very well. The NLME-PK model estimated that tulathromycin plasma concentrations were below LOD (1.2 ng/ml) 43 days after a single injection, and 62 days after the second injection with a 95% confidence. These estimated times are much longer than the current meat withdrawal time recommendation of 18 days for tulathromycin in non-lactating cattle. CONCLUSIONS: The results suggest that twice subcutaneous injections of 2.5 mg/kg tulathromycin are a clinically safe extra-label alternative approach for treating pulmonary infections in lactating goats, but a prolonged withdrawal time of at least 39 days after the second injection should be considered to prevent violative residues in milk and any dairy goat being used for meat should have an extended meat withdrawal time.

Pharmacokinetics of ceftiofur crystalline free acid after single subcutaneous administration in lactating and nonlactating domestic goats (Capra aegagrus hircus).

Six nonlactating and six lactating adult female goats received a single subcutaneous injection of ceftiofur crystalline free acid (CCFA) at a dosage of 6.6 mg/kg. Blood samples were collected from the jugular vein before and at multiple time points after CCFA administration. Milk samples were collected twice daily. Concentrations of ceftiofur and desfuroylceftiofur-related metabolites were measured using high-performance liquid chromatography. Data were analyzed using compartmental and noncompartmental approaches. The pharmacokinetics of CCFA in the domestic goat was best described by a one compartment model. Mean (±SD) pharmacokinetic parameters were as follows for the nonlactating goats: area under the concentration time curve(0-∞) (159 h·µg/mL ± 19), maximum observed serum concentration (2.3 µg/mL ± 1.1), time of maximal observed serum concentration (26.7 h ± 16.5) and terminal elimination half life (36.9 h; harmonic). For the lactating goats, the pharmacokinetic parameters were as follows: area under the concentration time curve(0-∞) (156 h·µg/mL ± 14), maximum observed serum concentration (1.5 µg/mL ± 0.4), time of maximal observed serum concentration (46 h ± 15.9) and terminal elimination half life (37.3 h; harmonic). Ceftiofur and desfuroylceftiofur-related metabolites were only detectable in one milk sample at 36 h following treatment. There were no significant differences in the pharmacokinetic parameter between the nonlactating and lactating goats.

Impact of gender on incident diabetes mellitus in obstructive sleep apnea: a 16-year follow-up.

STUDY OBJECTIVE: To address the influence of gender and obstructive sleep apnea (OSA) on development of diabetes mellitus (DM) in a sleep clinic cohort. DESIGN: A longitudinal observational study. PARTICIPANTS: A consecutive middle-aged (30-69 years) sleep clinic cohort from 1991 (n=318; 254 men, 64 women) with eligible baseline characteristics, clinical charts, and information from the Swedish Hospital Discharge Registry were identified. Ten individuals with DM at baseline and 47 patients who died during the follow-up period were excluded. MEASUREMENTS: The remaining 261 subjects were asked to complete a postal questionnaire regarding concomitant diseases including DM, diagnosed by a physician. RESULTS: In total, 168 patients (64.4%) replied. The incidence of DM was 24.9% in patients with OSA (overnight oxygen desaturations > or =30 in 1991) compared with 10.8% in subjects without OSA (p = 0.020). New-onset DM in men was 19.1% in OSA vs. 11.1% in non-OSA (n.s.), while the corresponding values in women were 50.0% in OSA and 9.5% in non-OSA (p = 0.022). In a multivariate analysis, DM was predicted by OSA in women with an odds ratio (OR) of 11.8, but not by age, body mass index (BMI) at baseline, or weight change at followup. In men, only BMI (OR 1.16) predicted DM. CONCLUSION: The contribution of OSA to DM development seems to be gender-dependent and higher in women than in men.

The effects of hypoxia and hypercapnia on renal and heart function, haemodynamics and plasma hormone levels in stable COPD patients.

BACKGROUND: Fluid retention with oedema is an important clinical problem in advanced chronic obstructive pulmonary disease (COPD). OBJECTIVE: The aim of this study was to investigate cardiovascular, hormonal, renal and pulmonary function data and their possible relation to fluid retention in COPD. METHODS: The study group consisted of 25 stable outpatients with COPD. The presence of oedema was assessed by clinical examination and the intake of diuretics was recorded. Glomerular filtration rate (GFR) and the renal blood flow (RBF) were measured. Lung function was assessed with standard spirometry. Cardiac function and haemodynamic variables were studied using echocardiography and equilibrium radionucleotide angiography. The plasma levels of noradrenaline, plasma renin activity, angiotensin II, aldosterone, atrial natriuretic peptide, brain natriuretic peptide and antidiuretic hormone were measured. RESULTS: Systolic and diastolic cardiac functions were found to be well preserved in the patients. Hypercapnia and impaired lung function, but not hypoxia, were clearly associated with oedema/intake of diuretics, low diuresis, low GFR, low RBF and high renal vascular resistance. These effects had no significant relationship to central haemodynamics or the measured plasma hormone levels. CONCLUSIONS: In stable COPD, renal fluid retention and oedema are enhanced by hypercapnia-induced renal vasoconstriction and antidiuresis. In contrast to some earlier reports, this effect does not seem to be mediated via the central haemodynamic reflex systems or the measured plasma hormones. In addition, hypoxia had no significant effect on fluid retention in this group of patients.

Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a 7-year follow-up.

The incidence of a cardiovascular disease (CVD) was explored in a consecutive sleep clinic cohort of 182 middle-aged men (mean age, 46.8 +/- 9.3; range, 30-69 years in 1991) with or without obstructive sleep apnea (OSA). All subjects were free of hypertension or other CVD, pulmonary disease, diabetes mellitus, psychiatric disorder, alcohol dependency, as well as malignancy at baseline. Data were collected via the Swedish Hospital Discharge Register covering a 7-year period before December 31, 1998, as well as questionnaires. Effectiveness of OSA treatment initiated during the period as well as age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP) at baseline, and smoking habits were controlled. The incidence of at least one CVD was observed in 22 of 60 (36.7%) cases with OSA (overnight oxygen desaturations of 30 or more) compared with in 8 of 122 (6.6%) subjects without OSA (p < 0.001). In a multiple logistic regression model, significant predictors of CVD incidence were OSA at baseline (odds ratio [OR] 4.9; 95% confidence interval [CI], 1.8-13.6) and age (OR 23.4; 95% CI, 2.7-197.5) after adjustment for BMI, SBP, and DBP at baseline. In the OSA group, CVD incidence was observed in 21 of 37 (56.8%) incompletely treated cases compared with in 1 of 15 (6.7%) efficiently treated subjects (p < 0.001). In a multiple regression analysis, efficient treatment was associated with a significant risk reduction for CVD incidence (OR 0.1; 95% CI, 0.0-0.7) after adjustment for age and SBP at baseline in the OSA subjects. We conclude that the risk of developing CVD is increased in middle-aged OSA subjects independently of age, BMI, SBP, DBP, and smoking. Furthermore, efficient treatment of OSA reduces the excess CVD risk and may be considered also in relatively mild OSA without regard to daytime sleepiness.