Pharmacokinetics of oral chlortetracycline in nonpregnant adult ewes

The objectives of this study were to determine plasma concentrations and pharmacokinetic parameters of feed‐grade chlortetracycline (CTC) in sheep after oral administration of 80 or 500 mg/head daily, divided into two equal doses given at 12‐h intervals for 8 days. These are the approved, and commonly used but unapproved, feed additive doses, respectively, in the United States for the prevention of ovine infectious abortion. Blood samples were collected just prior to dosing at 0, 12, 24, 72, 96, and 192 h, as well as 4, 8, 12, 24, and 36 h after the last dose, and noncompartmental pharmacokinetic analysis was performed to estimate elimination half‐life and area under the plasma concentration–time curve (AUC). Mean observed maximum CTC concentrations (C_max) were 20.0 ng/mL (80 mg dose) and 101 ng/mL (500 mg dose). Mean apparent elimination half‐life was 18 h (80 mg dose) and 20 h (500 mg dose). Although published data do not exist to estimate plasma CTC concentrations necessary for the prevention of ovine infectious abortion, concentrations reached in our study suggest that either the FDA‐approved and FDA‐unapproved dosages are not high enough or that the pharmacodynamic parameter relating preventive dose to pathogen minimum inhibitory concentrations is yet to be determined.     

Pharmacokinetics of tulathromycin in fetal sheep and pregnant ewes

Macrolides are important antimicrobials frequently used in human and veterinary medicine in the treatment of pregnant women and pregnant livestock. They may be useful for the control of infectious ovine abortion, which has economic, animal health, and human health impacts. In this study, catheters were surgically placed in the fetal vasculature and amnion of pregnant ewes at 115 (±2) days of gestation. Ewes were given a single dose of 2.5 mg/kg tulathromycin subcutaneously, and drug concentrations were determined in fetal plasma, maternal plasma, and amniotic fluid at 4, 8, 12, 24, 36, 48, 72, 144, and 288 hr after drug administration. Pharmacokinetic parameters in maternal plasma were estimated using noncompartmental analysis and were similar to those previously reported in nonpregnant ewes. Tulathromycin was present in fetal plasma and amniotic fluid, indicating therapeutic potential for use against organisms in these compartments, though concentrations were lower than those in maternal plasma. Time‐course of drug concentrations in the fetus was quite different than that in the ewe, with plasma concentrations reaching a plateau at 4 hr and remaining at this concentration for the remainder of the sampling period (288 hr), raising questions about how tulathromycin may be transported into or metabolized and eliminated by the fetus.     

Hormonal induction of lactation in nonpregnant ewes

Exogenous hormone treatments designed to induce nonpregnant ewes to lactate at levels sufficient to rear orphan lambs were investigated in three breeds (Blackface, Dorset and Greyface) and in a total of 14 groups. The hormone treatments consisted of an induction phase lasting 1–6 weeks during which most ewes received daily subcutaneous injections of 75 mg of progesterone and 100 µg of oestradiol-17β and a trigger phase lasting 1 or 2 weeks during which 5 mg of oestradiol-17β and/or 10 mg of dexamethasone were given daily and the daily dose of progesterone was reduced to zero. From the end of the trigger phase for at least 2 weeks, milk production was determined three times daily by hand milking after prior intravenous injections of 5 IU of oxytocin. The linear dimensions of the udder were measured in each ewe at 5–6 day intervals throughout the induction and trigger phases.

Udder sizes increased in response to hormone treatment in all cases, and the rate of increase was usually 1.75–11.3 times greater during the trigger phase than during the induction phase. Accumulation of milk in the udder during the trigger phase resulted in mean milk yields of 212–763 ml on the first day of milking, which were higher than the mean yields of 130–354 ml on the second day. Thereafter the mean daily milk yields increased progressively to reach 579–1301 ml after 14 days of milking. Group comparisons revealed the following: an induction phase of at least 4 weeks duration was required to ensure that all hormone-treated ewes produced 800 ml or more of milk/day by 14 days of milking; during the trigger phase, oestadiol-17β alone was a more effective lactogenic agent than dexamethasone alone, and dexamethasone apparently hindered the lactogenic actions of oestradiol-17β when both hormones were given together; extending the duration of the trigger phase from 1 to 2 weeks did not improve subsequent milk yields; and there were no significant breed differences in milk yield responses to similar hormone treatments.

It is concluded that a 4–6 week induction phase followed by a l-week trigger phase using the progesterone and oestradiol-17β doses noted above but excluding dexamethasone would induce in most nonpregnant ewes lactation at levels sufficient to rear orphan lambs. Compared to the compositions of normal colostrum and milk, the milk from some of the present ewes had lower dry matter contents, fat concentrations and immunoglobulin-G concentrations and generally similar lactose concentrations. These differences were not considered to be sufficient to jeopardise the survival of lambs reared by such ewes.     

Pharmacokinetics and lung tissue concentrations of tulathromycin in swine

The absolute bioavailability and lung tissue distribution of the triamilide antimicrobial, tulathromycin, were investigated in swine. Fifty-six pigs received 2.5 mg/kg of tulathromycin 10% formulation by either intramuscular (i.m.) or intravenous (i.v.) route in two studies: study A (10 pigs, i.m. and 10 pigs, i.v.) and study B (36 pigs, i.m.). After i.m. administration the mean maximum plasma concentration (C(max)) was 616 ng/mL, which was reached by 0.25 h postinjection (t(max)). The mean apparent elimination half-life (t(1/2)) in plasma was 75.6 h. After i.v. injection plasma clearance (Cl) was 181 mL/kg.h, the volume of distribution at steady-state (V(ss)) was 13.2 L/kg and the elimination t(1/2) was 67.5 h. The systemic bioavailability following i.m. administration was >87% and the ratio of lung drug concentration for i.m. vs. i.v. injection was > or =0.96. Following i.m. administration, a mean tulathromycin concentration of 2840 ng/g was detected in lung tissue at 12 h postdosing. The mean lung C(max) of 3470 ng/g was reached by 24 h postdose (t(max)). Mean lung drug concentrations after 6 and 10 days were 1700 and 1240 ng/g, respectively. The AUC(inf) was 61.4 times greater for the lung than for plasma. The apparent elimination t(1/2) for tulathromycin in the lung was 142 h (6 days). Following i.m. administration to pigs at 2.5 mg/kg body weight, tulathromycin was rapidly absorbed and highly bioavailable. The high distribution to lung and slow elimination following a single dose of tulathromycin, are desirable pharmacokinetic attributes for an antimicrobial drug indicated for the treatment of respiratory disease in swine.     

Pharmacokinetics of tulathromycin following subcutaneous administration in meat goats

Tulathromycin is a triamilide antibiotic that maintains therapeutic concentrations for an extended period of time. The drug is approved for the treatment of respiratory disease in cattle and swine and is occasionally used in goats. To investigate the pharmacokinetics of tulathromycin in meat goats, 10 healthy Boer goats were administered a single 2.5 mg/kg subcutaneous dose of tulathromycin. Plasma concentrations were measured by ultra-high pressure liquid chromatography tandem mass spectrometry (UPLC–MS/MS) detection. Plasma maximal drug concentration (C_max) was 633 ± 300 ng/ml (0.40 ± 0.26 h post-subcutaneous injection). The half-life of tulathromycin in goats was 110 ± 19.9 h. Tulathromycin was rapidly absorbed and distributed widely after subcutaneous injection 33 ± 6 L/kg. The mean AUC of the group was 12,500 ± 2020 h ng/mL for plasma. In this study, it was determined that the pharmacokinetics of tulathromycin after a single 2.5 mg/kg SC injection in goats were very similar to what has been previously reported in cattle.     

Pharmacokinetics of ivermectin in pregnant and nonpregnant sheep

The plasma kinetic profile of ivermectin during the last trimester of pregnancy was studied in ewes after a single subcutaneous administration of 0.2 mg/kg body weight (BW). Sheep were randomly distributed into two groups. Ewes in group 1 (control, n=6) were left unmated, whereas in group 2 (pregnant, n=6) ewes were estrus-synchronized and mated with rams. Both groups were housed under similar conditions of management and feeding. At 120 days of pregnancy, both groups were given a subcutaneous injection of 0.2 mg/kg BW of ivermectin. Blood samples were taken by jugular puncture according to a fixed protocol between 1 h and 40 days post-treatment. After plasma extraction and derivatization, samples were analyzed by high performance liquid chromatography with fluorescence detection. A computerized pharmacokinetic analysis was performed, and the data were compared by means of the Student t-test. The results showed that plasma concentrations of ivermectin remained longer in the pregnant than in the control group. The mean values of pharmacokinetic parameters C(max), t(max), and area under the concentration-time curve (AUC) were similar for both groups of sheep. The mean residence time (MRT) values for the pregnant group (8.8+/-1.4 days) were higher (P<0.05) than those observed in the control group (5.3+/-1.9 days). It can be concluded that pregnancy increases the residence time of ivermectin in the plasma of pregnant sheep when it is administered subcutaneously.     

Characterization of local and peripheral immune system in pregnant and nonpregnant ewes

Modulation of the immune system is known to be important for successful pregnancy but how immune function might differ between the lymph nodes draining the reproductive tract and peripheral lymph nodes is not well understood. Additionally, if immune system changes in response to the presence of an embryo during early pregnancy, and if this response differs in local versus peripheral immune tissue, has not been well characterized. To address these questions, we examined expression of genes important for immune function using NanoString technology in the ampulla and isthmus of the oviduct, endometrium, lymph nodes draining the reproductive tract (lumbo-aortic and medial iliac) as well as a peripheral lymph node (axillary), the spleen, and circulating immune cells from ewes on day 5 of the estrous cycle or pregnancy. Concentrations of estradiol and progesterone in plasma were also determined. Principal component analysis revealed separation of the local from the peripheral lymph nodes (MANOVA P = 3.245e-08, R² = 0.3) as well as separation of tissues from pregnant and nonpregnant animals [lymph nodes (MANOVA P = 2.337e-09, R² = 0.5), reproductive tissues (MANOVA P = 2.417e-14, R² = 0.47)]. Nine genes were differentially (FDR < 0.10) expressed between lymph node types, with clear difference in expression of these genes between the lumbo-aortic and axillary lymph nodes. Expression of these genes in the medial iliac lymph node was not consistently different to either the axillary or the lumbo-aortic lymph node. Expression of IL10RB was increased (FDR < 0.05) by 24% in the reproductive tissue of the pregnant animals compared to nonpregnant animals. Analysis of gene categories revealed that expression of genes of the T-cell receptor pathway in reproductive tract tissues was associated (P < 0.05) with pregnancy status. In conclusion, assessment of gene expression of reproductive and immune tissue provides evidence for a specialization of the local immune system around the reproductive tract potentially important for successful establishment of pregnancy. Additionally, differences in gene expression patterns in reproductive tissue from pregnant and nonpregnant animals could be discerned as early as day 5 of pregnancy. This was found to be associated with expression of genes important for T-cell function and thus highlights the important role of these cells in early pregnancy.     

Pharmacokinetics of toltrazuril and its metabolites in pregnant and nonpregnant ewes and determination of their concentrations in milk,allantoic fluid,and newborn plasma

The objectives of this study were to determine the pharmacokinetics of toltrazuril and its metabolites in pregnant and nonpregnant ewes following a single oral dose and to determine the plasma concentrations of these compounds in milk, allantoic fluid, and newborn plasma. Eighteen healthy ewes were randomly divided into three groups (n = 6 each): pregnant ewes at 12–13 weeks of gestation (group A), nonpregnant ewes (group B), and pregnant ewes at 1–2 weeks before expected lambing date (group C). Ewes in all groups received a single oral dose of toltrazuril at 20 mg/kg body weight. In groups A and B, blood samples were collected at 1, 3, 5, 7, 9, 12, 15, 18 hr, every 6 hr to day 3, every 12 hr to day 7 and thereafter every 24 hr to day 14 post-toltrazuril administration. In group C, parturition was induced 24–36 hr after toltrazuril administration then milk, allantoic fluid, and newborn plasma samples were collected immediately after birth. Drug metabolites were assayed using ultra high-performance liquid chromatography–ultraviolet detection method (UHPLC-UV). The maximum concentration (C_max), area under the plasma concentration-time curve (AUC_0–t), AUC to 24 and 48 hr (AUC_0–24), and (AUC_0–48) were significantly higher in pregnant ewes. Longer apparent half-life (T_1/2), significantly higher apparent volume of distribution (Vd/F) and total clearance (Cl/F) were observed in nonpregnant ewes. The time to maximum plasma concentration (T_max), mean residence time (MRT) and elimination rate constant (K_el) were similar in both groups. The AUC_0–24 and AUC_0–48 were significantly higher in nonpregnant ewes. The AUC_0–t was significantly higher in pregnant ones. The ratio of plasma toltrazuril concentrations in ewes and toltrazuril concentrations in newborn lambs' plasma, allantoic fluid, and milk were 68%, 2.3%, and 5.3%, respectively. Results of this study showed that toltrazuril is well absorbed after a single oral dose in ewes with widespread distribution in different body tissues.     

Pharmacokinetics of tulathromycin after subcutaneous injection in North American bison (Bison bison)

Tulathromycin is approved for the treatment of respiratory disease in cattle and swine. It is intended for long‐acting, single‐dose injection therapy (Draxxin), making it particularly desirable for use in bison due to the difficulty in handling and ease of creating stress in these animals. The pharmacokinetic properties of tulathromycin in bison were investigated. Ten wood bison received a single 2.5 mg/kg subcutaneous injection of Draxxin. Serum concentrations were measured by liquid chromatography–mass spectrometry (LC‐MS) detection. Tulathromycin demonstrated early maximal serum concentrations, extensive distribution, and slow elimination characteristics. The mean maximum serum concentration (C_max) was 195 ng/mL at 1.04 h (t_max) postinjection. The mean area under the serum concentration–time curve, extrapolated to infinity (AUC_0–inf), was 9341 ng·h/mL. The mean apparent volume of distribution (V_d/F) and clearance (Cls/F) was 111 L/kg and 0.4 L/h/kg, respectively, and the mean half‐life (t_1/2) was 214 h (8.9 days). Compared to values for cattle, C_max and AUC_0–inf were lower in bison, while the V_d/F was larger and the t_1/2 longer. Tissue distribution and clinical efficacy studies in bison are needed to confirm the purported extensive distribution of tulathromycin into lung tissue and to determine whether a 2.5 mg/kg subcutaneous dosage is adequate for bison.     

Pharmacokinetics and lung tissue concentrations of tulathromycin, a new triamilide antibiotic, in cattle

The pharmacokinetics of the new triamilide antibiotic tulathromycin was investigated in two cattle studies. Following a single subcutaneous injection, the drug was rapidly absorbed and bioavailability was excellent. High and persistent levels of the drug in lung tissue were observed as well. These attributes are advantageous for an antimicrobial drug indicated for the treatment of bacterial and mycoplasmal respiratory diseases in cattle.     

Peritoneal fluid analysis in adult, nonpregnant Awassi sheep

BACKGROUND: To the authors' knowledge, there is no information in the literature about normal peritoneal fluid values in ovine species. OBJECTIVES: The purpose of the study reported here was to establish reference intervals for peritoneal fluid from clinically normal Awassi sheep and to compare the values to those in blood. METHODS: Peritoneal fluid and blood samples were collected into tubes containing EDTA, from 40 clinically healthy, nonpregnant, female Awassi sheep, aged 2 to 7 years. Total nucleated cell count (TNCC) was determined using an electronic cell counter. Total protein, albumin, urea, creatinine, and glucose concentrations and aspartate transaminase activity were analyzed using commercially available kits. RESULTS: TNCC (mean +/- SD) of peritoneal fluid was 1.1 +/- 0.87 X 10(3)/microl, with neutrophils (3.9%), lymphocytes (33.5%), macrophages/monocytes (61.2%), and eosinophils (1.4%). Biochemical results in peritoneal fluid were: total protein, 1.7 +/- 0.74 g/dL; albumin, 1.0 +/- 0.04 g/dL; urea, 12.6 +/- 3.95 mg/dL; creatinine, 0.6 +/- 0.19 mg/dL; glucose, 54.8 +/- 6.11 mg/dL; and aspartate transaminase, 23.5 +/- 8.82 U/L. Eosinophil percentage and creatinine concentration did not differ significantly from blood values. CONCLUSION: Baseline values for cytologic and biochemical parameters in peritoneal fluid of Awassi sheep, with comparison to blood, have been generated. Such data may be applicable to other ovine species and can be used in the clinical investigation of ovine abdominal disorders.     

Pharmacokinetics and mammary residual depletion of erythromycin in healthy lactating ewes

The aim of this investigation was to examine the pharmacokinetics and mammary excretion of erythromycin administered to lactating ewes (n = 6) by the intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) routes at a dosage of 10 mg/kg. Blood and milk samples were collected at pre-determined times, and a microbiological assay method was used to measure erythromycin concentrations in serum and milk. The concentration-time data were analysed by compartmental and non-compartmental kinetic methods. The serum concentration-time data of erythromycin were fit to a two-compartment model after i.v. administration and a one-compartment model with first-order absorption after i.m. and s.c. administration. The elimination half-life (t(1/2beta)) was 4.502 +/- 1.487 h after i.v. administration, 4.874 +/- 0.296 h after i.m. administration and 6.536 +/- 0.151 h after s.c. administration. The clearance value (Cl tot) after i.v. dosing was 1.292 +/- 0.121 l/h/kg. After i.m. and s.c. administration, observed peak erthyromycin concentrations (Cmax) of 0.918 +/- 0.092 microg/ml and 0.787 +/- 0.010 microg/ml were achieved at 0.75 and 1.0 h (Tmax) respectively. The bioavailability obtained after i.m. and s.c. administration was 91.178 +/- 10.232% and 104.573 +/- 9.028% respectively. Erythromycin penetration from blood to milk was quick for all the routes of administration, and the high AUC milk/AUC serum (1.186, 1.057 and 1.108) and Cmax-milk/Cmax-serum ratios reached following i.v., i.m. and s.c. administration, respectively, indicated an extensive penetration of erythromycin into the milk.     

Pharmacokinetics of acyclovir in adult horses

Objective: To determine the pharmacokinetics of acyclovir administered intravenously (IV) and orally to healthy adult horses. Design: Random cross‐over with an approximate 1‐week washout period between trials. Setting: University veterinary medical teaching hospital. Animals: Six healthy adult research herd horses. Interventions and main results: Acyclovir was administered IV (10 mg/kg in 1 L isotonic crystalloid solution over 60 minutes) and orally (20 mg/kg) to healthy adult horses. Plasma samples were obtained and acyclovir concentrations were determined by high‐pressure liquid chromatography. Peak concentration (mean±SD) for IV acyclovir was 13.74±5.88 μg/mL at the completion of the 1‐hour infusion. The half‐life of the distribution phase (α) was 0.16 hours while the half‐life of the elimination phase (β) was 9.6 hours. The steady‐state volume of distribution was 3.93±1.21 L/kg. We were unable to measure pharmacokinetics after PO acyclovir as plasma concentrations were below the lower limits of detection in all 6 horses. Conclusions: IV administration of acyclovir to healthy adult horses achieves concentrations within the sensitivity range described for equine herpes virus‐type 1. The oral bioavailability of acyclovir in horses is low and additional studies are required.     

Successful fostering of orphan lambs by nonpregnant ewes induced to lactate using exogenous hormone treatment

Six nonpregnant ewes were induced to lactate by an exogenous hormone treatment lasting 6 weeks. At the end of the treatment one alien lamb was adopted by each ewe. Each ewe was initially indifferent to the alien lamb and required only mild restraint to allow the lambs to suck successfully. Maternal interest subsequently increased and strong ewe-lamb bonding was evident by 80 minutes (n=l), 10 hours (n=4) or 24 hours (n=l) in different cases. The lambs required supplementary milk for 4–6 days while milk production by the ewes increased to adequate levels. Thereafter they were reared entirely by the ewes. Another four nonpregnant ewes were induced to lactate by a similar hormone treatment and were then hand-milked thrice daily for 2-3 weeks. One alien lamb was then introduced to each ewe. All four ewes were aggressive towards the lambs which were removed after 10–30 minutes. The ewes were then injected subcu- taneously with 5 mg of oestradiol-17β and were placed in fostering stocks. After a further 3–5 hours the lambs were re-introduced. Strong ewe-lamb bonding occurred during the subsequent 10 hours in all cases. All 10 lambs were reared successfully by these ewes until at least 3 months of age, when observations stopped. It was concluded firstly that nonpregnant ewes induced to lactate artificially will adopt and rear orphan lambs successfully, provided that additional milk is given to meet shortfalls during the first 4–6 days; and secondly that a 5 mg injection of oestradiol-17β may facilitate fostering of lambs by ewes in established lactation whether the lactation is induced artificially or not.