Reproductive and margin of safety of a fixed-dose combination injectable endectocide (0.2 mg/kg doramectin; 6.0 mg/kg levamisole hydrochloride) in cattle.

We present a fixed-dose combination injectable (FDCI) solution for cattle formulated for a single subcutaneous administration at a dose rate of 1 ml/25 kg of body weight to deliver a dose of 0.2 mg/kg of doramectin and 6.0 mg/kg of levamisole hydrochloride (5.1 mg/kg base equivalent). This drug product is marketed in the United States under the tradename Valcor® and in Australia and New Zealand under the tradename Dectomax V®. Both levamisole and doramectin have histories of safe and effective use in ruminants, with safety margins of 3X and 25X, respectively. Three studies were conducted to demonstrate the safety of the new FDCI: margin of safety (Study 1), and reproductive safety in sexually nulliparous beef heifers (Studies 2 and 3). In Study 1, 3-month-old sexually intact male and female calves were given either saline (control) or 1X, 2X, or 3X FDCI on Days 0, 14, and 28. General health, clinical, and neurological observations were made throughout the study, and clinical and pathology evaluations were made at study end. Studies 2 and 3 demonstrated the reproductive safety of the FDCI on sexually nulliparous beef heifers using estrus synchronization and timed artificial insemination. Treatments of either saline (control) or 3X FDCI were administered to coincide with either folliculogenesis, implantation, organogenesis, early gestation, or late gestation. Reproductive safety was demonstrated by evaluating rates of conception, calving, abortion, and stillbirth, dystocia scores, and calf health. In all studies, the FDCI at 1X, 2X, or 3X dosages was well tolerated. In the margin of safety study, 3X calves showed increased incidence of salivation for up to 8 h post-dosing compared to other groups. Injection sites were palpable post-dosing in all three FDCI groups but resolved by Day 28 in all but one animal each in 2X and 3X. In the reproductive safety studies, the FDCI had no effect on conception, pregnancy, fetal development, or postnatal viability. Injection site swelling was increased in frequency and duration compared to controls. The studies demonstrate the safety of the new FDCI in cattle from 3 months of age and in reproducing heifers during all reproductive stages from folliculogenesis through gestation and up to a month post-partum.

Pharmacokinetics, Milk Residues, and Toxicological Evaluation of a Single High Dose of Meloxicam Administered at 30 mg/kg per os to Lactating Dairy Cattle.

Adverse effects associated with overdose of NSAIDs are rarely reported in cattle, and the risk level is unknown. If high doses of NSAIDs can be safely administered to cattle, this may provide a longer duration of analgesia than using current doses where repeated administration is not practical. Meloxicam was administered to 5 mid-lactation Holstein dairy cows orally at 30 mg/kg, which is 30 times higher than the recommended 1 mg/kg oral dose. Plasma and milk meloxicam concentrations were determined using high-pressure liquid chromatography with mass spectroscopy (HPLC-MS). Pharmacokinetic analysis was performed by using noncompartmental analysis. The geometric mean maximum plasma concentration (Cmax) was 91.06 µg/mL at 19.71 h (Tmax), and the terminal elimination half-life (T1/2) was 13.79 h. The geometric mean maximum milk concentration was 33.43 µg/mL at 23.74 h, with a terminal elimination half-life of 12.23 h. A thorough investigation into the potential adverse effects of a meloxicam overdose was performed, with no significant abnormalities reported. The cows were humanely euthanized at 10 d after the treatment, and no gross or histologic lesions were identified. As expected, significantly higher plasma and milk concentrations were attained after the administration of 30 mg/kg meloxicam with similar half-lives to previously published reports. However, no identifiable adverse effects were observed with a drug dose 30 times greater than the industry uses within 10 days of treatment. More research is needed to determine the tissue withdrawal period, safety, and efficacy of meloxicam after a dose of this magnitude in dairy cattle.

Innate and acquired immune responses of colostrum-fed neonatal Holstein calves following intranasal vaccination with two commercially available modified-live virus vaccines.

OBJECTIVE: To compare immune responses induced by 2 commercially available vaccines with a bovine herpesvirus type 1 (BHV1) component following intranasal (IN) administration to colostrum-fed calves. ANIMALS: 90 male Holstein calves (ages, 5 to 14 days). PROCEDURES: In a randomized complete block design, each calf received 2 mL (1 mL/nostril) of vaccine A (n = 30), vaccine B (30), or saline (0.9% NaCl) solution (30) on day 0. Blood samples were collected for determination of serum anti-BHV1 IgG titer, and nasal fluid (NF) samples were collected for determination of interferon (IFN)-α and IFN-γ concentrations and for secretory IgA titers against BHV1, Mannheimia haemolytica, and Pasteurella multocida at predetermined times for 42 days after vaccination. RESULTS: All calves were seropositive for anti-BHV1 IgG, and the mean anti-BHV1 IgG titer did not differ significantly among the 3 groups at any time. Both vaccines induced significant transient increases in NF IFN-α and IFN-γ concentrations. On day 5, mean IFN-α concentration and the proportion of calves with detectable IFN-α concentrations for the vaccine A group were significantly greater than those for the vaccine B and control groups. On day 42, the mean NF anti-P multocida IgA titers for both vaccine groups were significantly greater than that of the control group. CONCLUSIONS AND CLINICAL RELEVANCE: Both vaccines induced innate and acquired immune responses in calves with colostral antibodies. The magnitude of the IFN-α response and proportion of calves with detectable IFN-α differed between the 2 vaccine groups. Both vaccines appeared to enhance the IgA response against P multocida.

A field trial comparing four oral nonsteroidal anti-inflammatory drugs on controlling cautery dehorning pain and stress in calves.

The purpose of this study was to compare the analgesic effect of four nonsteroidal anti-inflammatory drugs (NSAIDs) administered as a single, standardized, oral dose in dairy calves at the time of cautery dehorning. The NSAIDs investigated have pharmacokinetic properties in cattle that produce persistent plasma concentrations that may provide prolonged analgesia with the added practicality of a simple administration regimen. One hundred and eighty-five Holstein calves aged approximately 50 d old were either sham dehorned (n = 31) or cautery dehorned following oral administration of carprofen (n = 31), firocoxib (n = 31), flunixin meglumine (n = 30), meloxicam (n = 31) or placebo (n = 31) in a randomized, controlled trial. A standard dose of 2.0 mg/kg was administered to all calves receiving an oral NSAID. All calves received local anesthesia prior to actual or sham dehorning. Cortisol concentrations, heart rate, mechanical nociception thresholds, ocular and dehorning area temperatures, and average daily gains were evaluated. A linear mixed-effects model with repeated measures was used for statistical analysis. Administration of oral meloxicam, flunixin meglumine, and firocoxib at 2.0 mg/kg resulted in decreased cortisol concentrations compared to placebo-treated controls for the first 24 h postdehorning (AUEC0-24) (P = 0.03). Moreover, firocoxib, flunixin meglumine, and meloxicam attenuated the maximum cortisol concentrations compared to placebo-treated calves (P = 0.04, P= 0.02). In calves treated with flunixin meglumine, cortisol concentrations was reduced at 4 h (P = 0.04) and 8 h (P = 0.02). In addition, analgesic administration was associated with changes in ocular and dehorning area temperature differences (P = 0.09). Carprofen and meloxicam reduced heart rates during the entire study period (P = 0.003). Although a treatment effect (P < 0.0001) was observed in the determination of mechanical nociception threshold among all treatment groups, meloxicam expressed marginally significant effects (P = 0.09) among NSAID treated groups dehorned. A single dose of oral meloxicam, flunixin meglumine, or firocoxib administered at 2.0 mg/kg reduced the acute stress response associated with cautery dehorning. However, carprofen administration was associated with increased cortisol concentrations and dehorning area temperatures for the initial 24 h. Given the changes in pain and stress outcome variables assessed in this study, NSAIDs should be administered at the time of dehorning.

Effect of ractopamine hydrochloride on environmental gas emissions, growth performance, and carcass characteristics in feedlot steers.

With a growing global population and increased environmental concerns around animal agriculture, it is essential to humanely maximize animal performance and reduce environmental emissions. This study aims to determine the efficacy of feeding ractopamine hydrochloride (RAC), an orally active, ß 1-adrenergic agonist (ß1AA), to feedlot steers in the last 42 d of finishing to reduce ammonia (NH3) emissions and improve animal performance. A randomized complete block design was used to allocate 112 Angus and crossbred Angus steers (initial body weight [BW] = 566.0 ± 10.4 kg) to 8 cattle pen enclosures. Pens (n = 4 per treatment, 14 steers per pen, and 56 steers per treatment) were randomly assigned to one of two treatments: 1) CON; finishing ration containing no RAC, 2) RAC; finishing ration containing 27.3 g/907 kg dry matter (DM) basis RAC. Steers were weighed on day -1 and 0 before treatment and day 14, 28, and 42 during treatment. Treatment rations were mixed and delivered daily by masked personnel. Measured emissions included NH3, nitrous oxide (N2O), methane (CH4), hydrogen sulfide (H2S), and carbon dioxide (CO2). The primary response variables assessed were emissions standardized by live weight (LW) and hot carcass weight (HCW). Steers were harvested on day 43 and carcass data were collected on day 43 and 44. Steers fed RAC reduced NH3 emissions by 17.21% from day 0 to 28 (P = 0.032) and tended to reduce NH3 from day 0 to 42 by 11.07% (P = 0.070) vs. CON. When standardized for LW, NH3 was reduced by 23.88% from day 0 to 14 (P = 0.018), 17.80% from day 0 to 28 (P = 0.006), and 12.50% for day 0 to 42 (P = 0.027) in steers fed RAC vs. CON. Steers fed RAC had 14.05% (P = 0.013) lower cumulative NH3 emissions when standardized by HCW vs. CON. Feeding RAC to Steers reduced H2S by 29.49% from day 0 to 14 (P = 0.009) and tended to reduce H2S over day 0 to 28 by 11.14% (P = 0.086) vs. CON. When H2S emissions were standardized for LW, RAC fed steers had a 28.81% reduction from day 0 to 14 (P = 0.008) vs. CON. From day 0 to 42 the RAC fed steers tended to have a 0.24 kg/d greater average daily gain (ADG) (P = 0.066) and tended to eat 4.27% less (P = 0.069) on a DM basis vs. CON. The RAC fed steers had a 19.95% greater gain to feed ratio (G:F) compared to CON (P = 0.012). Steers fed RAC had an average of 12.52 kg greater HCW (P = 0.006) and an increase of 1.93 percentage units in dressing percent (DP) (P = 0.004) vs. CON. Ractopamine is an effective medicated feed additive for reducing NH3 and improving end product performance through HCW yields.

The effects of pretransportation or arrival meloxicam administration to calves entering the feedlot on morbidity, biomarkers, performance, and carcass characteristics.

The objective of this trial was to investigate the effects of using meloxicam as a pretransport or on arrival therapeutic on disease outcomes of bovine respiratory disease (BRD), biomarker outcomes associated with BRD, performance characteristics over the first 42 d on feed, and carcass traits at harvest in cross bred beef cattle. Multisourced, crossbred steer calves (n = 168) consisting of mainly British and British-Continental breeds were purchased from an auction market in central Missouri. Calves were processed prior to transportation and again upon feedlot arrival. Animals were randomized to 3 separate treatments: pretransport meloxicam (PMEL), arrival meloxicam (AMEL), and a control group receiving inactive excipient (CONT). Dosing at 1 mg/kg on weighted averaged administered per os. Animals were weighed and blood was collected pre- and post-transport. Haptoglobin (Hp)-matrix metaloproteinase (MMP)-9 complex, cortisol, and substance P were quantified. Weights were taken again at 42 d and at harvest. Clinical signs of BRD were monitored using indicators of depression, appetite, respiration, and temperature that qualified the animals for treatment. Harvest parameters were collected using a standardized United States Department of Agriculture grading system for quality grade and yield grade. Meloxicam did not have a significant effect on BRD morbidity over the course of the study and there was no significant effect on performance characteristics at 42 d (P > 0.10). Of the calves that did succumb to BRD, no significant differences were found in severity of disease (P > 0.10). Concentrations of substance P and Hp- MMP-9, were increased on arrival (P ≤ 0.05) however no significant treatment effect or interaction were found between AMEL, PMEL, CONT, or across different levels of biomarkers (P > 0.10). Meloxicam use prior to or on arrival does not mitigate disease or improve performance during the feeding period.

The impact of pain on the pharmacokinetics of transdermal flunixin meglumine administered at the time of cautery dehorning in Holstein calves.

OBJECTIVE: To study the influence of pain on the pharmacokinetics and anti-inflammatory actions of transdermal flunixin administered at dehorning. STUDY DESIGN: Prospective, crossover, clinical study. ANIMALS: A total of 16 male Holstein calves, aged 6-8 weeks weighing 61.3 ± 6.6 kg. METHODS: Calves were randomly assigned to one of two treatments: transdermal flunixin and dehorning (PAIN) or transdermal flunixin and sham dehorning (NO PAIN). Flunixin meglumine (3.33 mg kg-1) was administered topically as a pour-on concurrently with hot iron dehorning or sham dehorning. The calves were subjected to the alternative treatment 14 days later. Blood samples were collected at predetermined time points up to 72 hours for measurement of plasma flunixin concentrations. Pharmacokinetics parameters were determined using noncompartmental analysis. Prostaglandin E2 (PGE2) concentration was determined using a commercial enzyme-linked immunosorbent assay. The 80% inhibition concentration (IC80) of PGE2 was determined using nonlinear regression. Pharmacokinetic data were statistically analyzed using paired t tests and Wilcoxon rank sums for nonparametric data. Flunixin and PGE2 concentrations were log transformed and analyzed using repeated measures. RESULTS: A total of 15 calves completed the study. Plasma half-life of flunixin was significantly longer in PAIN (10.09 hours) than NO PAIN (7.16 hours) (p = 0.0202). Bioavailability of transdermal flunixin was 30% and 37% in PAIN and NO PAIN, respectively (p = 0.097). Maximum plasma concentrations of flunixin were 0.95 and 1.16 µg mL-1 in PAIN and NO PAIN, respectively (p = 0.089). However, there was a treatment (PAIN versus NO PAIN) by time interaction (p = 0.0353). PGE2 concentrations were significantly lower in the PAIN treatment at 48 and 72 hours (p = 0.0092 and p = 0.0287, respectively). The IC80 of PGE2 by flunixin was similar in both treatments (p = 0.88). CONCLUSION AND CLINICAL RELEVANCE: Pain alters the pharmacokinetics and anti-inflammatory effects of transdermally administered flunixin.

Pneumatic dart delivery of tulathromycin in calves results in lower antimicrobial concentrations and increased biomarkers of stress and injection site inflammation compared with subcutaneous injection.

Remote drug delivery (RDD) using pneumatic darts has become more prevalent in situations where cattle handling facilities are not available. The objective of this study was to compare the effect of pneumatic dart delivery and subcutaneous injection of tulathromycin on plasma pharmacokinetics and biomarkers of inflammation, stress, and muscle injury in calves. Twenty-three castrated-male Holstein calves, approximately 10 mo of age with an average weight of 378 ± 6.49 kg, were randomly assigned to 1 of 2 groups. Calves in the RDD group (n = 15) received 10 mL of tulathromycin (2.42 to 2.93 mg/kg) delivered into the left neck using a Type U 10.0 mL 1.9-cm 14 G Needle pneumatic dart administered with a breech loading projector. With the exception of 1 light weight calf that received 7 mL (2.53 mg/kg), calves in the injection group (INJ) (n = 8) also received 10 mL of tulathromycin (2.34 to 2.68 mg/kg) administered as a single subcutaneous injection in the left neck using a 14 G, 1.9-cm needle and a 12-mL syringe. Serum tulathromycin, cortisol, creatine kinase (CK), and aspartate aminotransferase (AST) concentrations were determined in combination with other biomarkers of inflammation including mechanical nociceptive threshold (MNT), infrared thermography (IRT), and swelling at the injection site over 432 h after administration. Pneumatic darts failed to deliver the required dose of tulathromycin in 4 of 15 calves evidenced by heavier dart weights post-administration (24 vs. 13.5 g). When these 4 calves were removed from the analysis, calves in the RDD group were found to have a smaller area under the tulathromycin concentration curve (AUC) (P = 0.005) and faster clearance (P = 0.025) compared with the INJ group. Furthermore, the RDD group recorded a greater difference in MNT between the treated and contralateral neck compared with the INJ group at 12 h (P = 0.016), 216 h (P = 0.024), and 288 h (P = 0.0494) after administration. Serum CK was elevated at 24 h (P = 0.03) and AST was greater at 24 h (P = 0.024) and 48 h (P = 0.037) after RDD. Serum cortisol concentrations were also greater at 0.5 h (P = 0.02) after RDD. These findings suggest that RDD is associated with reduced total body exposure to tulathromycin and increased acute stress, muscle damage, and pain at the injection site. Furthermore, the failure of darts to consistently deliver antimicrobial therapy has a negative impact on the welfare of sick animals treated with RDD technologies.

Effect of age on the pharmacokinetics and pharmacodynamics of flunixin meglumine following intravenous and transdermal administration to Holstein calves.

OBJECTIVE To determine the effect of age on the pharmacokinetics and pharmacodynamics of flunixin meglumine following IV and transdermal administration to calves. ANIMALS 8 healthy weaned Holstein bull calves. PROCEDURES At 2 months of age, all calves received an injectable solution of flunixin (2.2 mg/kg, IV); then, after a 10-day washout period, calves received a topical formulation of flunixin (3.33 mg/kg, transdermally). Blood samples were collected at predetermined times before and for 48 and 72 hours, respectively, after IV and transdermal administration. At 8 months of age, the experimental protocol was repeated except calves received flunixin by the transdermal route first. Plasma flunixin concentrations were determined by liquid chromatography-tandem mass spectroscopy. For each administration route, pharmacokinetic parameters were determined by noncompartmental methods and compared between the 2 ages. Plasma prostaglandin (PG) E2 concentration was determined with an ELISA. The effect of age on the percentage change in PGE2 concentration was assessed with repeated-measures analysis. The half maximal inhibitory concentration of flunixin on PGE2 concentration was determined by nonlinear regression. RESULTS Following IV administration, the mean half-life, area under the plasma concentration-time curve, and residence time were lower and the mean clearance was higher for calves at 8 months of age than at 2 months of age. Following transdermal administration, the mean maximum plasma drug concentration was lower and the mean absorption time and residence time were higher for calves at 8 months of age than at 2 months of age. The half maximal inhibitory concentration of flunixin on PGE2 concentration at 8 months of age was significantly higher than at 2 months of age. Age was not associated with the percentage change in PGE2 concentration following IV or transdermal flunixin administration. CONCLUSIONS AND CLINICAL RELEVANCE In calves, the clearance of flunixin at 2 months of age was slower than that at 8 months of age following IV administration. Flunixin administration to calves may require age-related adjustments to the dose and dosing interval and an extended withdrawal interval.

Effect of meloxicam administration on movement, feeding, and drinking behaviors of transported and nontransported cattle.

OBJECTIVE To evaluate the effects of meloxicam on movement, feeding, and drinking behaviors of transported and nontransported cattle. ANIMALS 100 crossbred beef steers. PROCEDURES During experiment 1 of a 2-experiment study, calves from a livestock auction received meloxicam (1 mg/kg, PO; n = 50) or a lactose placebo (1 capsule/calf; 50; control), then calves were transported approximately 1,000 km overnight to a feedlot, where they were instrumented with a real-time location-monitoring ear tag, placed in randomly assigned pens (n = 5 pens/treatment), and monitored for 21 days. During experiment 2, calves in pens were administered the treatment opposite that of experiment 1, returned to their pens without undergoing transportation, and monitored for another 21 days. For each experiment, mean daily distance traveled and percentage time spent near feed (PNF) and water (PNW) were calculated on a pen basis and compared between treatments. RESULTS During experiment 1, mean daily distance traveled, PNF, and PNW did not differ significantly between meloxicam-treated and control calves; however, all 3 behaviors varied significantly by day. During experiment 2, although mean distance traveled was significantly associated with the interaction between day and treatment, it did not differ significantly between meloxicam-treated and control calves within any specific day. Mean PNF and PNW were significantly associated with day only, although no pattern in that effect was evident. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that a single dose of meloxicam prior to transportation did not significantly affect the behaviors of transported and nontransported calves.

Effect of oral administration of meloxicam prior to transport on inflammatory mediators and leukoctye function of cattle at feedlot arrival.

OBJECTIVE To investigate the effects of meloxicam administration before long-distance transport on inflammatory mediators and leukocyte function of cattle at feedlot arrival. ANIMALS 60 healthy yearling beef steers. PROCEDURES Single-source steers were assigned to a transported (n = 40) or nontransported (20) group. Then, half of the steers within each group were assigned to receive meloxicam (1 mg/kg, PO) or a lactose placebo (1 bolus/steer, PO). All steers were transported approximately 1,300 km overnight to a feedlot; however, the nontransported group was moved before treatment (meloxicam or placebo) administration and allowed a 17-day acclimation period, whereas the transported group was moved immediately after treatment administration on day -1. Blood samples for measurement of inflammatory mediators and leukocyte function were collected from all steers on days -1, 0, and 3. RESULTS For steers that received meloxicam, mean plasma meloxicam concentration for the transported group was significantly greater than that for the nontransported group on day 0. For steers that received the placebo, mean haptoglobin-matrix metalloproteinase-9 complex for the transported group was significantly greater than that for the nontransported group on day 0. Mean haptoglobin concentration, neutrophil L-selectin intensity, and polymorphonuclear leukocyte count for the transported group were significantly greater than those for the nontransported group. Mean substance P concentration for nontransported steers that received meloxicam was significantly lower than that for the other 3 treatment groups. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated meloxicam administration to healthy steers immediately before long-distance transport did not significantly mitigate the effects of transport-induced stress on leukocyte function or inflammatory markers.