Elimination of erythromycin in milk after intramammary administration in cows with specific mastitis: relation to dose,milking frequency and udder health

Elimination of erythromycin in milk following intramammary therapy of specific mastitis in cows was studied. Five cows received therapy in one quarter (G1), and eight in two quarters with five milked twice (G2) and three thrice a day (G3). Dose infused was 300 mg/quarter 12 h × 5 times. The drug concentrations in milk were determined using microbial assay technique with Micrococcus luteus as the test organism. Considerable variations occurred in the excretion of drug; levels for treated quarters being 8.25 to 37.61 μg/ml at first milking that declined rapidly at 24 h and no drug activity was observed beyond 36 h post treatment. In total, about 6–25% of the last infused dose appeared in the milk. Drug crossed to 1/15 quarter (G1), 6/10 quarters (G2) and all the six untreated quarters (G3). Crossover levels were significantly higher in mastitic quarters and for G3 cows, but duration of excretion remained same in all cases. It seems that crossover of erythromycin to untreated quarters is related to the udder health and dose infused.     

Effects of intramammary infusion of Bifidobacterium breve on mastitis pathogens and somatic cell response in quarters from dairy cows with chronic subclinical mastitis

The present study assessed the effects of intramammary infusion of Bifidobacterium breve (B. breve) on mastitis‐causing pathogens and on the somatic cell counts (SCC) in lactating cows with chronic subclinical mastitis. The bacteriological cure rates of 42 quarters from 42 cows infected with Staphylococcus aureus, Corynebacterium bovis, coagulase‐negative staphylococci, and environmental streptococci were 18.2% (2/11), 14.3% (1/7), 58.8% (10/17), and 28.6% (2/7), respectively, on day 14 after B. breve infusion. In a second trial, B. breve was infused into 18 quarters from 18 cows with chronic subclinical mastitis from which pathogens had not been isolated; the rates of quarters showing SCC > 50 × 10⁴ cells/ml prior to B. breve infusion that decreased to < 30 × 10⁴ cells/ml after infusion were significantly (p < .01) increased to 61.1% (11/18) on day 14 compared to that prior to infusion (0/18). The intramammary infusion of B. breve appears to be a non‐antibiotic approach for elimination of minor pathogens and decreasing SCC in quarters with chronic subclinical mastitis in dairy cows.     

Disposition Kinetics of Difloxacin After Intravenous,Intramuscular and Subcutaneous Administration in Calves

The pharmacokinetics of difloxacin (Dicural) was studied in a crossover study using three groups (n = 4) of male and female Friesian calves after intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administrations of 5 mg/kg body weight. Drug concentration in plasma was determined by high-performance liquid chromatography using fluorescence detection. The plasma concentration–time data following i.v. administration were best fitted to a two-compartment open model and those following i.m. and s.c. routes were best fitted using one-compartment open model. The collected data were subjected to a computerized kinetic analysis. The mean i.v., i.m. and s.c. elimination half-lives (t _1/2β) were 5.56 ± 0.33 h, 6.12 ± 0.42 h and 7.26 ± 0.6 h, respectively. The steady-state volume of distribution (V _dss) was 1.12 ± 0.09 L/kg and total body clearance (Cl_B) was 2.19 ± 0.1 ml/(min. kg). The absorption half lives (t _1/2ab) were 0.38 ± 0.027 h and 2.1 ± 0.09 h, with systemic bioavailabilities (F) of 96.5% ± 6.4% and 84% ± 5.5% after i.m. and s.c. administration, respectively. After i.m. and s.c. dosing, peak plasma concentrations (C _max) of 3.38 ± 0.13 μg/ml and 2.18 ± 0.12 μg/ml were attained after (t _max) 1.22 ± 0.20 h and 3.7 ± 0.52 h. The MIC₉₀ of difloxacin for Mannheimia haemolytica was 0.29 ± 0.04 μg/ml. The AUC/MIC₉₀ and C _max/MIC₉₀ ratios for difloxacin following i.m. administration were 120 and 11.65, respectively and following s.c. administration were 97.58 and 7.51, respectively. Difloxacin was 31.7–36.8% bound to calf plasma protein. Since fluoroquinolones display concentration-dependent activities, the doses of difloxacin used in this study are likely to involve better pharmacodynamic characteristics that are associated with greater clinical efficacy following i.m. administration than following s.c. administration.     

Plasma Concentrations,Pharmacokinetics and Urinary Excretion of Gatifloxacin after Single Intravenous Injection in Buffalo Calves

The pharmacokinetics and urinary excretion of gatifloxacin were investigated after a single intravenous injection of 4 mg/kg body weight in buffalo calves. The therapeutic plasma drug concentration was maintained for up to 12 h. Gatifloxacin rapidly distributed from blood to tissue compartments, which was evident from the high values of the distribution rate constant, α₁ (11.1 ± 1.06 h⁻¹) and the rate constant of transfer of drug from central to peripheral compartment, k ₁₂ (6.29 ± 0.46 h⁻¹). The area under the plasma drug concentration–time curve and apparent volume of distribution were 17.1 ± 0.63 (μg.h)/ml and 3.56 ± 0.95 L/kg, respectively. The elimination half-life (t _{1/2 β}), total body clearance (Cl_B) and the ratio of drug present in tissues and plasma (T/P) were 10.4 ± 2.47 h, 235.1 ± 8.47 ml/(kg.h) and 10.1 ± 2.25, respectively. About 19.7% of the administered drug was excreted in urine within 24 h. A satisfactory intravenous dosage regimen for gatifloxacin in buffalo calves would be 5.3 mg/kg at 24 h intervals. Abbreviations for pharmacokinetic parameters are given in the footnote of Table I     

Pharmacokinetics,urinary excretion and plasma protein binding of danofloxacin following intravenous administration in buffalo calves (Bubalus bubalis)

Pharmacokinetics, urinary excretion and plasma protein binding of danofloxacin was investigated in buffalo calves following intravenous administration at the dose rate of 1.25 mg/kg to select the optimal dosage regimen of danofloxacin. Drug concentrations in plasma and urine were measured by microbiological assaying. In vitro plasma protein binding was determined employing the equilibrium dialysis technique. The distribution and elimination of danofloxacin were rapid, as indicated by values (mean ±SD) of distribution half-life (t_1/2α = 0.16 ± 0.07 h) and elimination half-life (t_1/2β = 4.24 ± 1.78 h), respectively. Volume of distribution at steady state (Vss) = 3.98 ± 1.69 L/kg indicated large distribution of drug. The area under plasma drug concentration versus time curve (AUC) was 1.79 ± 0.28 μg/mlxh and MRT was 8.64 ± 0.61 h. Urinary excretion of danofloxacin was 23% within 48 h of its administration. Mean plasma protein binding was 36% at concentrations ranging from 0.0125 μg/ml to 1 μg/ml. On the basis of pharmacokinetic parameters obtained, it is concluded that the revision of danofloxacin dosage regimen in buffalo calves is needed because the current dosage schedule (1.25 mg/kg) is likely to promote resistance.     

Comparative Pharmacokinetics of Gentamicin after Intravenous,Intramuscular, Subcutaneous and Oral Administration in Broiler Chickens

The pharmacokinetics and bioavailability of gentamicin sulphate (5 mg/kg body weight) were studied in 50 female broiler chickens after single intravenous (i.v.), intramuscular (i.m.), subcutaneous (s.c.) and oral administration. Blood samples were collected at time 0 (pretreatment), and at 5, 15 and 30 min and 1, 2, 4, 6, 8, 12, 24 and 48 h after drug administration. Gentamicin concentrations were determined using a microbiological assay and Bacillus subtillis ATCC 6633 as a test organism. The limit of quantification was 0.2 μg/ml. The plasma concentration–time curves were analysed using non-compartmental methods based on statistical moment theory. Following i.v. administration, the elimination half-life (t _1/2β), the mean residence time (MRT), the volume of distribution at steady state (V _ss), the volume of distribution (V _d,area) and the total body clearance (Cl_B) were 2.93 ± 0.15 h, 2.08 ± 0.12 h, 0.77 ± 0.05 L/kg, 1.68 ± 0.39 L/kg and 5.06 ± 0.21 ml/min per kg, respectively. After i.m. and s.c. dosing, the mean peak plasma concentrations (C _max) were 11.37 ± 0.73 and 16.65 ± 1.36 μg/ml, achieved at a post-injection times (t _max) of 0.55 ± 0.05 and 0.75 ± 0.08 h, respectively. The t _1/2β was 2.87 ± 0.44 and 3.48 ± 0.37 h, respectively after i.m. and s.c. administration. The V _d,area and Cl_B were 1.49 ± 0.21 L/kg and 6.18 ± 0.31 ml/min per kg, respectively, after i.m. administration and were 1.43 ± 0.19 L/kg and 4.7 ± 0.33 ml/min per kg, respectively, after s.c. administration. The absolute bioavailability (F) of gentamicin after i.m. administration was lower (79%) than that after s.c. administration (100%). Substantial differences in the resultant kinetics data were obtained between i.m. and s.c. administration. The in vitro protein binding of gentamicin in chicken plasma was 6.46%.     

Plasma pharmacokinetics and milk levels of ceftriaxone following single intravenous administration in healthy and endometritic cows

Pharmacokinetics and milk levels of ceftriaxone were studied in healthy and endometritic cows following single intravenous administration. The drug was detected up to 8 h of dosing in plasma of healthy and endometritic cows and the drug disposition followed three-compartment open model. The values of Vd_area, AUC, t_1/2β, Cl_B, MRT and P/C ratio were 0.50 ± 0.19 L.kg⁻¹, 62.2 ± 23.3 μg.ml⁻¹.h, 1.02 ± 0.07 h, 0.30 ± 0.09 L.kg⁻¹.h⁻¹, 1.55 ± 0.25 h and 0.52 ± 0.27, respectively, in healthy and 1.55 ± 0.52 L.kg⁻¹, 37.0 ± 17.1 μg.ml⁻¹.h, 1.56 ± 0.25 h, 0.56 ± 0.14 L.kg⁻¹.h⁻¹, 2.14 ± 0.34 h and 1.44 ± 0.60, respectively, in endometritic cows. The drug was detected in milk for 36 h after administration. For MIC₉₀ of 0.5 μg.ml⁻¹ the most appropriate dosage for ceftriaxone, would be 9.0 mg.kg⁻¹ repeated at 6 h intervals for the treatment of endometritis in cows.     

Bioequivalence Study of Two Long-acting Oxytetracycline Formulations in Sheep

Two commercially available long-acting oxytetracycline hydrochloride formulations (Primamycin LA (Pfizer) and Terralent 20% LA (İ.E. Ulagay)) were administered by the intramuscular route to 20 clinically healthy sheep at a dose of 20 mg/kg. The study was performed in a two-period crossover design. Plasma samples were analysed by high-pressure liquid chromatography. The mean maximum concentrations (C _max) was 8.00 ± 2.05 μg/mland 8.61 ± 1.42 μg/ml, respectively. The mean area under the concentration time curve (AUC) values were 154.95 ± 50.37(μg h)/ml and 161.70 ± 47.02(μg h)/ml, respectively. The 90%confidence intervals for the ratio of C _max and AUC values for the test and reference product are with in the interval 70−143% for C _max and interval 80-−125% for AUC proposed by EMEA. It was concluded that Primamycin LA and Terralent 20% LA formulations are bioequivalent in their rate and extent of drug absorbtion. Ozdemir N. and Yıldırım, M., 2006. Bioequivalence study of two long-acting oxytetracycline formulations in sheep. Veterinary Research Communications, 30(8), 929–934     

Plasma Disposition and Faecal Excretion of Netobimin Metabolites and Enantiospecific Disposition of Albendazole Sulphoxide Produced in Ewes

Netobimin (NTB) was administered orally to ewes at 20 mg/kg bodyweight. Blood and faecal samples were collected from 1 to 120 h post-treatment and analysed by high-performance liquid chromatography (HPLC). Using a chiral phase-based HPLC, plasma disposition of albendazole sulphoxide (ABZSO) enantiomers produced was also determined. Neither NTB nor albendazole (ABZ) was present and only ABZSO and albendazole sulphone (ABZSO₂) metabolites were detected in the plasma samples. Maximum plasma concentrations (C<_max) of ABZSO (4.1 ± 0.7 μg/ml) and ABZSO₂ (1.1 ± 0.4 μg/ml) were detected at (t _max) 14.7 and 23.8 h, respectively following oral administration of netobimin. The area under the curve (AUC) of ABZSO (103.8 ± 22.8 (μg h)/ml) was significantly higher than that ABZSO₂(26.3± 10.1 (μg h)/ml) (p<0.01). (−)−ABZSO and (+)-ABZSO enantiomers were never in racemate proportions in plasma. The AUC of (+)-ABZSO (87.8±20.3 (μg h)/ml) was almost 6 times larger than that of (−)−ABZSO (15.5 ±5.1 (μg h)/ml) (p < 0.001). Netobimin was not detected, and ABZ was predominant and its AUC was significantly higher than that of ABZSO and ABZSO₂, following NTB administration in faecal samples (p > 0.01). Unlike in the plasma samples, the proportions of the enantiomers of ABZSO were close to racemic and the ratio of the faecal AUC of (−)−ABZSO (172.22 ±57.6 (μg h)/g) and (+)-ABZSO (187.19 ±63.4 (μg h)/g) was 0.92. It is concluded that NTB is completely converted to ABZ by the gastrointestinal flora and absorbed ABZ is completely metabolized to its sulphoxide and sulphone metabolites by first-pass effects. The specific behaviour of the two enantiomers probably reflects different enantioselectivity of the enzymatic systems of the liver that are responsible for sulphoxidation and sulphonation of ABZ.     

Pharmacokinetics of Tilmicosin (Provitil Powder and Pulmotil Liquid AC) Oral Formulations in Chickens

A bioavailability and pharmacokinetics study of powder and liquid tilmicosin formulations was carried out in 18 healthy chickens according to a single-dose, two-period, two-sequence, crossover randomized design. The two formulations were Provitil and Pulmotil AC. Both drugs were administered to each chicken after an overnight fast on two treatment days separated by a 2-week washout period. A modified rapid and sensitive HPLC method was used for determination of tilmicosin concentrations in chicken plasma. Various pharmacokinetic parameters including area under plasma concentration–time curve (AUC₀₋₇₂), maximum plasma concentration (C _max), time to peak concentration (t _max), elimination half-life (t _1/2β), elimination rate (k _el), clearance (Cl_B), mean residence time (MRT) and volume of distribution (V _d,area) were determined for both formulations. The average means of AUC₀₋₇₂ for Provitil and Pulmotil AC were very close (24.24 ± 3.86, 21.82 ± 3.14 (μg.h)/ml, respectively), with no significant differences based on ANOVA. The relative bioavailability of Provitil as compared to Pulmotil AC was 111%. In addition, there were no significant differences in the C _max (2.09 ± 0.37, 2.12 ± 0.40 μg/ml), t _max (3.99 ± 0.84, 5.82 ± 1.04 h), t _1/2β (47.4 ± 9.32, 45.0 ± 5.73 h), k _el (0.021 ± 0.0037, 0.022 ± 0.0038 h⁻¹), Cl_B (19.73 ± 3.73, 21.37 ± 4.54 ml/(min/kg)), MRT (71.20 ± 12.87, 67.15 ± 9.01 h) and V _d,area (1024.8 ± 87.5, 1009.8 ± 79.5 ml/kg) between Pulmotil AC and Provitil, respectively. In conclusion, tilmicosin was rapidly absorbed and slowly eliminated after oral administration of single dose of tilmicosin aqueous and powder formulations. Provitil and Pulmotil AC can be used as interchangeable therapeutic agents.     

Influence of <Emphasis Type="Italic">E. coli</Emphasis> lipopolysaccharide induced fever on the plasma kinetics of cefepime in cross-bred calves

The pharmacokinetic behavior of cefepime was studied in healthy and febrile cross-bred calves after single intravenous administration (10 mg/kg). The fever was induced with E. coli lipopolysaccharide (1 μg/kg, IV). The drug concentration in plasma was detected by microbiological assay method using E. coli (MTCC 739) test organism. Pharmacokinetic analysis of disposition data indicated that intravenous administration data were best described by 2 compartment open model. At 1 min the concentration of cefepime in healthy and febrile animals were 55.3 ± 0.54 μg/ml and 50.0 ± 0.48 μg/ml, respectively and drug was detected up to 12 h. The elimination half-life of cefepime was increased from 1.26 ± 0.01 h in healthy animals to 1.62 ± 0.09 h in febrile animals. Drug distribution was altered by fever as febrile animals showed volume of distribution (0.27 ± 0.02 L/kg) higher than normal animal (0.19 ± 0.01 L/kg). Total body clearances in healthy and febrile animals were 104.4 ± 2.70 and 114.2 ± 1.20 ml/kg/h, respectively. To maintain minimum therapeutic concentration of 1 μg/ml, a satisfactory dosage regimen of cefepime in healthy and febrile cross-bred calves would be 15.5 mg/kg and 8.2 mg/kg body weight, respectively, to be repeated at 8 h intervals. The T>MIC values (8 h) of cefepime suggested that this agent is clinically effective in the treatment of various infections.     

Pharmacokinetic Parameters of (R)-(−) and (S)-(+)-Flurbiprofen in Dairy Bovines

The aim of the study was to evaluate the pharmacokinetics of flurbiprofen (FBP) in different age groups and physiological status groups in dairy cattle. Ten Argentine Holstein bovines were divided into three different groups: 3 cows in early lactation, 3 cows in gestation and 4 newborn calves. Based on previous experience, all the animals received racemic FBP (50:50) at a dose of 0.5 mg/kg by intravenous administration. Blood samples were taken at predetermined times after administration of flurbiprofen. Plasma enantiomer concentrations were measured by HPLC. Total body clearance (ClB) of (S)-(+)-FBP was higher in calves than in cows (114.5, 136.4, 121.4, 128.9 μg/ml vs 22.0, 24.2, 46.5 μg/ml and 27.6, 25.3, 34.6 μg/ml). In calves the disposition kinetics showed stereoselective behaviour. Area under the concentration–time curve (AUC) was higher and Cl_B and steady-state volume of distribution (V_ss) were lower for (R)-(−)-FBP than for (S)-(+)-FBP. In cows, stereoselectivity was observed in Cl_B and elimination half-life (fract₁2)(frac{t_1}{2}) only in the early lactation group. In this study, enantioselective metabolic behaviour of FBP under the physiological situations studied was found. Hence, it is possible that both enantiomers of flurbiprofen may contribute to the drug's therapeutic effects, but further studies with the administration of separate enantiomers will be required to elucidate their metabolism.     

Pharmacokinetic-Pharmacodynamic Modelling of Danofloxacin in Turkeys

Colibacillosis is a systemic disease responsible for important economic losses in poultry breeding; fluoroquinolones, including danofloxacin, are used to treat diseased animals. The purpose of the present study was to estimate pharmacokinetic–pharmacodynamic (PK-PD) surrogates for bacteriostasis, bactericidal activity and bacterial elimination against Escherichia coli O78/K80, using a PK-PD approach, for danofloxacin in turkeys after oral administration. Eight healthy turkeys, breed BUT 9, were included in a two-way crossover study. The drug was administered intravenously (i.v.) and orally at a dose rate of 6 mg/kg bw. The values of the elimination half-life and the total body clearance after i.v. administration were 8.64 ± 2.35 h and 586.76 ± 136.67 ml kg^-1h^-1, respectively. After oral administration, the values of the absolute bioavailability and the elimination half-life were 78.37± 17.35% and 9.74± 2.93 h, respectively. The minimum inhibitory concentration against the investigated strain in turkey serum was 0.25 μg/ml, four times higher than in broth. The lowest effective ex vivo AUC₂₄/MIC ratios required for bacteriostasis, bactericidal activity, and total killing of E. coliO78/K80 were 0.416 h, 1.9 h and 6.73 h, respectively. The oral dose of 6 mg/kg used in the present study could be interpreted as being sufficient to eliminate E. coli with an MIC 0.25 μ g/ml. However, considering the demand that antimicrobial resistance should be avoided by complete bacterial elimination, PK-PD considerations suggest that an even higher dose of 32 mg/kg per day or 0.7 mg/kcal per day should be evaluated in clinical trials.     

Impact of intramammary tilmicosin infusion as a dry cow therapy

Three hundred subclinically infected quarters of 259 Holstein cows infected with gram‐positive bacteria were selected via quota sampling based on the California Mastitis Test (CMT) result and were divided randomly and equally into treatment and test groups. Quarters of test group (n = 150 in 128 cows) were treated with an intramammary infusion of tilmicosin, and quarters of the control group (n = 150 in 131 cows) were treated with cloxacillin as a traditional intramammary infusion of dry cow (DC) ointment. Cows with more than one infected quarter were randomly assigned to the same group, and adjacent quarters were treated the same. The milk samples of all quarters were obtained, and bacterial cultures and somatic cell count (SCC) were tested before dry cow therapy (DCT) (50 ± 15 days before parturition), and finally on day 2 of the next lactation. Results have shown that total bacteriological cure rates on day 2 of the next lactation were 45% and 78%, (p = .01), new infection rates were 43.3% and 56.6%, and SCC was (6.732 × 10⁵ ± 3.124 × 10⁵) and (5.025 × 10⁵ ± 2.935 × 10⁵), (p > .05) in test and control groups, respectively. Tilmicosin had less effect on reducing IMI due to Corynebacterium bovis, and had no effect on Streptococcus agalactiae, but had a potent effect against Staphylococcus aureus. It was concluded that tilmicosin alone should not be infused as an alternative to conventional dry cow therapy. However, it had a significant effect against S. aureus, and the potential of tilmicosin to treat S. aureus IMI should be confirmed in further studies.     

Depletion of florfenicol in lactating dairy cows after intramammary and subcutaneous administration

Eighteen Holstein dairy cows ranging in body weight from 500–700 kg and with an average milk yield of 37 ± 6 kg/day were used to investigate the depletion of florfenicol (FFL) in milk and plasma of dairy cows. Three groups of six were administered FFL: Group A, intramammary (IMM) infusion of ~2.5 mg FFL/kg BW at three consecutive milking intervals (total amount of ~7.5 mg/kg BW); Group B, one IMM infusion (20 mg/kg BW) into one quarter and Group C, one subcutaneous (SC) treatment (40 mg/kg BW). IMM infusions were into the right front quarter. Cows were milked daily at 06:00 and 18:00 h. The highest concentrations (C_max) and time to C_max (T_max) were: 1.6 ± 2.2 μg·FFL/mL milk at 22 h (Group A), 5.5 ± 3.6 μg·FFL/mL milk at 12 h (Group B), and 1.7 ± 0.4 μg·FFL/mL milk at 12 h (Group C). The half‐lives (t_1/2) were ~19, 5.5, and 60 h, for Groups A, B, and C, respectively. FFL was below the limit of detection (LOD) by 60 h in three Group B cows, but above the LOD at 72, 84, and 120 h in three cows. FFL was above the LOD in milk from Group C's cows for 432–588 h. Plasma values followed the same trends as milk. The results demonstrate that IMM‐infused FFL is bioavailable and below the LOD within 72–120 h. The concentration of FFL was detectable in both plasma and milk over the course of 2–3 weeks after SC administration. The absence of residue depletion data presents problems in determining safe levels of FFL residues in milk and edible tissues. The data presented here must not be construed as approval for extra‐label use in food animals.     

Response of lactating dairy cows fed different supplemental zinc sources with and without evaporative cooling to intramammary lipopolysaccharide infusion: metabolite and mineral profiles in blood and milk

The objective of this study was to determine the effect of evaporative cooling and dietary supplemental Zn source on blood metabolites, insulin and mineral concentrations, and milk mineral concentrations following intramammary lipopolysaccharide (LPS) infusion. Seventy-two multiparous Holstein cows were assigned to one of four treatments with a 2 × 2 factorial arrangement. Treatments included two environments: with or without evaporative cooling using fans and misters over the freestall and feedbunk, and two dietary sources of supplemental Zn: 75 mg/kg of dry matter (DM) supplied by Zn hydroxychloride (inorganic Zn; IOZ) or Zn hydroxychloride (35 mg of Zn/kg of DM) + Zn–Met complex (ZMC; 40 mg of Zn/kg of DM). A subset of cows (n = 16; 263 ± 63 d in milk) was infused with 10 μg of LPS or a saline control in the left or right rear quarters on day 34 of the environmental treatment. Individual milk samples collected from LPS-infused quarters at −4, 0, 6, 12, 24, 48, 72, 96, and 144 h relative to infusion were analyzed for minerals. Blood samples were collected at the same time with an additional sample collected at 3 h post-infusion to analyze glucose, nonesterified fatty acids (NEFA), insulin, and minerals. Cooling by time interactions (P ≤ 0.07) were observed for plasma glucose, NEFA, and serum insulin. Compared with cooled cows, non-cooled cows had lower concentrations of plasma glucose except at 3 h following intramammary LPS infusion, greater serum insulin at 3 and 12 h, and lower plasma NEFA at 24 and 48 h after infusion. Relative to cooled cows, non-cooled cows tended (P = 0.07) to have lower serum K concentration and had lower (P < 0.01) serum Zn 6 h following infusion (cooling by time interaction: P < 0.01). Relative to ZMC cows, IOZ cows had greater (P ≤ 0.09) concentrations of plasma Se, skim milk Na and Se, and skim milk Na to K ratio. Regardless of treatment, intramammary LPS infusion reduced (P < 0.01) serum or plasma concentrations of Ca, Mg, Zn, Fe, and Se, but increased (P < 0.01) their concentration in skim milk. In conclusion, deprivation of cooling resulted in more rapid and prolonged insulin release and influenced the systemic and mammary mineral metabolism during mammary inflammation induced by LPS of lactating dairy cows. Dietary supplementation of Zn–Met complex reduced blood and milk Se concentrations compared with cows fed Zn from an inorganic source.     

Pharmacokinetics of allopurinol in Dalmatian dogs

The pharmacokinetics of allopurinol were studied in Dalmatian dogs. Eight dogs were given allopurinol orally at a dose of 10 mg/kg for seven doses prior to sample collection. After a period of at least two weeks, four of these dogs and four additional Dalmatians were later given a single intravenous (i.v.) dose of allopurinol (6 mg/kg) prior to sample collection.Allopurinol was found to follow first-order absorption and elimination kinetics. In the i.v. kinetic study, the elimination constant (K_el) = 0.31±0.03 per h, the half-life (t_½) = 2.22±0.20 h, the initial concentration (C₀) = 5.26±0.34 μg/mL and the specific volume (V_d) = 1.14±0.07 L/kg. Clearance of allopurinol was estimated to be 0.36±0.03 L/kg·h. In the oral kinetic study, the absorption rate constant (K_ab) = 1.06±0.13 per h, the elimination rate constant (K_el) = 0.26±0.01 per h, the absorption half-life (t_½ab) = 0.66±0.06 h, and the elimination half-life (t_½el) = 2.69±0.14 h. Peak plasma concentrations (C_max) = 6.43±0.18 μg/mL were obtained within 1 to 3 h (mean time of maximum concentration (T_max) = 1.9±0.1 h). The volume of distribution corrected by the fraction of dose absorbed (V_d/F) was estimated to be 1.17±0.07 L/kg.Good agreement was obtained between mean kinetic parameters in the oral and i.v. studies. There was little variation between individual dogs in the i.v. study, whereas the rate of absorption and elimination of orally administered allopurinol was more varied among individual dogs. Because of this, and the fact that the magnitude of hyperuricosuria varies among Dalmatians, it is not possible to specify an exact dose of allopurinol that will effectively lower the urinary uric acid concentration to acceptable values in all Dalmatians with hyperuricosuria; rather, the dose must be titrated to the needs of each dog.     

Phmacodynamics and pharmacokinetics of carprofen, a non-steroidal anti-inflammatory drug, in healthy cows and cows with Escherichia coli endotoxin-induced mastitis

The pharmacodynamics of carprofen and its pharmacokinetics in plasma and milk of healthy cows and cows with endotoxin-induced mastitis were studied after a single intravenous dose of 0.7 mg/kg body weight. Carprofen was administered to five clinically healthy cows and to the same cows 3 weeks later, 2 h after intramammary infusion of endotoxin. Mastitis developed in all endotoxin-infused quarters. The pharmacokinetic characteristics of carprofen in healthy cows were a small volume of distribution (0.09 l/kg), a relatively low systemic clearance (2.4 ml/h kg), and a long elimination half-life (30.7 h). In the mastitic cows, systemic clearance (1.4 ml/h kg) was significantly lower (P less than 0.01), and elimination half-life (43.0 h) was significantly longer (P less than 0.01) than in the normal animals. Concentrations of carprofen in milk from healthy quarters were below the limit of detection for the assay (0.022 micrograms/ml). In milk from mastitic quarters, concentrations of carprofen increased up to 0.164 micrograms/ml during the first 12 h after induction of mastitis, but were less than 0.022 micrograms/ml at 24 to 48 h. Compared with the untreated mastitic controls, carprofen treatment significantly reduced heart rate (P less than 0.01), rectal temperature (P less than 0.001), quarter swelling (P less than 0.01) and other parameters measured. Local and systemic adverse reactions to carprofen were not observed.     

The pharmacokinetics of thiamphenicol in lactating cows

The pharmacokinetics of thiamphenicol were studied after intravenous and intramuscular administration of 25 mg/kg body weight in lactating cows. Distribution (t _1/2) and elimination (t _1/2) half-lives of 6.10±1.39 min and 1.60±0.30 h, respectively, were obtained after intravenous administration. The body clearance was 3.9±0.077 ml/kg per min and the apparent volume of distribution was 1220.79±256.67 ml/kg. The rate at which thiamphenicol appeared in the milk, as indicated by the penetration half-life (t _1/2P) (serum to quarters), was found to be 36.89±11.14 min. The equivalent elimination half-life (t _1/2E) (quarters to serum) from the milk was 3.62±1.06 h and the peak thiamphenicol concentration in the milk was 23.09±3.42 µg/ml at 2.5±0.32 h.After intramuscular injection, the elimination half-life was 2.2±0.40 h, the absorption half-life was 4.02±1.72 min and the peak concentration in the serum was 30.90±5.24 µg/ml at 23±8.4 min. The bioavailability after intramuscular administration approached 100%. The penetration half-life was 50.59±6.87 min, the elimination half-life was 5.91±4.97 h and the mean peak concentration in the milk was 17.37±2.20 µg/ml at 3.4±0.22 h.Abbreviations AUC area under the concentration-time curve - CAP chloramphenicol - C _max peak concentration - IM intramuscular - IV intravenous - TAP thiamphenicol - t _1/2 distribution half-life - t _1/2 elimination half-life - V _c volume of central compartment - V _d volume of distribution     

Pharmacokinetic profile of Ceftiofur Hydrochloride Injection in lactating Holstein dairy cows

Ceftiofur (CEF), a broad‐spectrum third‐generation cephalosporin, exhibits a good activity against a broad range of gram‐negative and gram‐positive bacteria, including many that produce β‐lactamase. To design a rational dosage regimen for the drug in lactating Holstein dairy cows, the pharmacokinetic properties of ceftiofur hydrochloride injection were investigated in six cows after intravenous, intramuscular, and subcutaneous administration of single dose of 2.2 mg/kg BW (body weight). Plasma concentration–time curves and relevant parameters were best described by noncompartmental analysis through WinNonlin 6.3 software. After subcutaneous administration, the absolute bioavailability was 61.12% and the T_1/2λz (elimination half‐life) was 8.67 ± 0.72 hr. The C_max (maximum plasma concentration) was 0.88 ± 0.21 μg/ml and T_max (the time after initial injection to when C_max occurs) was 1.50 ± 0.55 hr. The MRT (mean residence time) was 11.00 ± 0.30 hr. Following intramuscular administration, the C_max (1.09 ± 0.21 μg/ml) was achieved at T_max (1.20 ± 0.26 hr) with an absolute availability of 70.52%. In this study, the detailed pharmacokinetic profiles of free and total CEF showed that this drug is widely distributed and rapidly eliminated and may contribute to a better understanding of the usage of ceftiofur hydrochloride injection in Holstein dairy cows.