The pharmacokinetics of oclacitinib maleate, a Janus kinase inhibitor, in the dog.

The pharmacokinetics of oclacitinib maleate was evaluated in four separate studies. The absolute bioavailability study used a crossover design with 10 dogs. The effect of food on bioavailability was investigated in a crossover study with 18 dogs. The breed effect on pharmacokinetics was assessed in a crossover study in beagles and mongrels dogs. Dose proportionality and multiple dose pharmacokinetics were evaluated in a parallel design study with eight dogs per group. In all four studies, serial blood samples for plasma were collected. Oclacitinib maleate was rapidly and well absorbed following oral administration, with a time to peak plasma concentration of <1 h and an absolute bioavailability of 89%. The prandial state of dogs did not significantly affect the rate or extent of absorption of oclacitinib maleate when dosed orally, as demonstrated by the lack of significant differences in pharmacokinetic parameters between the oral fasted and oral fed treatment groups. The pharmacokinetics of oclacitinib in laboratory populations of beagles and mixed breed dogs also appeared similar. Following oral administration, the exposure of oclacitinib maleate increased dose proportionally from 0.6 to 3.0 mg/kg. Additionally, across the pharmacokinetic studies, there were no apparent differences in oclacitinib pharmacokinetics attributable to sex.

The pharmacokinetics of maropitant citrate dosed orally to dogs at 2 mg/kg and 8 mg/kg once daily for 14 days consecutive days.

The pharmacokinetics of maropitant were evaluated in beagle dogs dosed orally with Cerenia® tablets (Pfizer Animal Health) once daily for 14 consecutive days at either 2 mg/kg or 8 mg/kg bodyweight. Noncompartmental pharmacokinetic analysis was performed on the plasma concentration data to measure the AUC(0-24) (after first and last doses), Ct (trough concentration-measured 24 h after each dose), Cmax (after first and last doses), tmax (after first and last doses), λz (terminal disposition rate constant; after last dose), t(1/2) (after last dose), and CL/F (oral clearance; after last dose). Maropitant accumulation in plasma was substantially greater after fourteen daily 8 mg/kg doses than after fourteen daily 2 mg/kg doses as reflected in the AUC(0-24) accumulation ratio of 4.81 at 8 mg/kg and 2.46 at 2 mg/kg. This is most likely due to previously identified nonlinear pharmacokinetics of maropitant in which high doses (8 mg/kg) saturate the metabolic clearance mechanisms and delay drug elimination. To determine the time to reach steady-state maropitant plasma levels, a nonlinear model was fit to the least squares (LS) means maropitant Ct values for each treatment group. Based on this model, 90% of steady-state was determined to occur at approximately four doses for daily 2 mg/kg oral dosing and eight doses for daily 8 mg/kg oral dosing.

Pharmacokinetics of ceftiofur crystalline-free acid sterile suspension in the equine.

Absolute bioavailability and dose proportionality studies were performed with ceftiofur in horses. In the absolute bioavailability study, thirty animals received either an intravenous dose of ceftiofur sodium at 1.0 mg/kg or an intramuscular (i.m.) dose of ceftiofur crystalline-free acid (CCFA) at 6.6 mg/kg. In the dose proportionality study, 48 animals received daily i.m. ceftiofur sodium injections at 1.0 mg/kg for ten doses or two doses of CCFA separated by 96 h, with CCFA doses of 3.3, 6.6, or 13.2 mg/kg. Noncompartmental and mixed-effect modeling procedures were used to assess pharmacokinetics (PK). CCFA was well absorbed with a bioavailability of 100%. AUC(0-∞) and C(max) increased in a dose-related manner following administration of the two doses of CCFA at 3.3, 6.6, and 13.2 mg/kg. The least-squares mean terminal half-life (t(½) ) following the tenth daily i.m. injection of ceftiofur sodium at 2.2 mg/kg was 40.8 h, but the least-squares mean t(½) following the second i.m. injection of CCFA at 6.6 mg/kg was 100 h. The time that plasma ceftiofur equivalent concentrations remain above a threshold concentration of 0.2 µg/mL has been associated with efficacy, and following administration of two 6.6 mg/kg doses of CCFA, the mean time above 0.2 µg/mL was 262 h. Simulations with the nonlinear mixed-effect PK model predicted that more than 97.5% of horses will have plasma ceftiofur equivalent concentrations >0.2 µg/mL for 96 h after the second 6.6 mg/kg dose of CCFA.

The pharmacokinetics of mavacoxib, a long-acting COX-2 inhibitor, in young adult laboratory dogs.

The pharmacokinetics of mavacoxib were evaluated in an absolute bioavailability study, a dose-proportionality study and a multi-dose study in young healthy adult laboratory Beagle dogs and in a multi-dose safety study in Beagle-sized laboratory Mongrel dogs. When administered as the commercial tablet formulation at 4 mg/kg body weight (bw) to fasted dogs, the absolute bioavailability (F) of mavacoxib was 46.1%; F increased to 87.4% when mavacoxib was administered with food. Following intravenous administration, the total body plasma clearance of mavacoxib was 2.7 mL·h/kg, and the apparent volume of distribution at steady-state was 1.6 L/kg. The plasma protein binding of mavacoxib was approximately 98% in various in vitro and ex vivo studies. The dose-normalized area under the plasma concentration-time curve was similar in Beagle and Beagle-sized Mongrel dogs when mavacoxib was administered with food. Mavacoxib exhibited dose-proportional pharmacokinetics for single oral doses of 2-12 mg/kg in Beagle dogs and for multiple oral doses of 5-25 mg/kg in Beagle-sized Mongrel dogs. Only minor accumulation occurred when mavacoxib was administered at doses of 2-25 mg/kg bw orally to laboratory dogs with a 2-week interval between the 1st two doses but with a monthly interval thereafter. Across all three Beagle studies (n = 63) the median terminal elimination half-life (t(½) ) was 16.6 days, with individual values ranging 7.9-38.8 days. The prolonged t(½) for mavacoxib supports the approved regimen in which doses are separated by 2-4 weeks.

Pharmacokinetic properties of toceranib phosphate (Palladia, SU11654), a novel tyrosine kinase inhibitor, in laboratory dogs and dogs with mast cell tumors.

Toceranib phosphate (Palladia, SU11654), an oral tyrosine-kinase inhibitor, is under investigation for the treatment of mast cell tumors in dogs. The pharmacokinetics of toceranib phosphate has been characterized in dogs. Means of the following pharmacokinetic parameters were estimated following a 1.0 mg/kg i.v. dose to laboratory beagles: plasma clearance of 1.45 L/kg/h, volume of distribution of 29.7 L/kg, and terminal half-life of 17.7 h. Following single oral doses of 3.25 mg/kg administered to laboratory beagles, mean C(max) estimates ranged from 68.6 ng/mL to 112 ng/mL with t(max) ranging from 5.3 h and 9.3 h postdose. Terminal half-life was estimated at 31 h. Oral bioavailability was 76.9%. There were no statistically significant (P > 0.05) differences with any pharmacokinetic parameter due to fed/fasted state or with time during 13 weeks of every-other-day dosing at 3.25 mg/kg. Toceranib concentrations were proportional with dose over the range of 2.0 to 6.0 mg/kg. The pharmacokinetics of toceranib in client-owned dogs of a variety of pure and mixed breeds with mast cell tumors was similar to that in healthy laboratory dogs. In summary, toceranib phosphate exhibited moderate clearance, a high volume of distribution, and a moderate elimination half-life. After a single oral dose at 3.25 mg/kg, the concentration vs. time curve showed broad, sustained exposure with measurable concentrations for more than 48 h. These pharmacokinetic parameters support every-other-day administration of toceranib phosphate at an initial dose of 3.25 mg/kg for the treatment of mast cell tumors in dogs.

Efficacy and safety of maropitant, a selective neurokinin 1 receptor antagonist, in two randomized clinical trials for prevention of vomiting due to motion sickness in dogs.

Maropitant (Cerenia), a selective neurokinin(1) receptor antagonist, was evaluated for efficacy and safety in prevention of vomiting due to motion sickness in dogs in two randomized clinical trials. One-hundred eighty-nine dogs with a history of motion sickness were enrolled at 26 veterinary clinics (across 12 US states) across the two trials; of these, 163 were fully evaluable, 19 were evaluable only for safety, and seven were not evaluable. Each trial used a two-period crossover design. Each dog was treated orally with placebo or maropitant (minimum dose of 8 mg/kg body weight using unit dosing) tablets at approximately 2 h (Trial 1) or 10 h (Trial 2) before an automobile ride of approximately 60 min, during which dogs were observed for signs of motion sickness. Following a 10-14-day washout period, each dog was administered the opposite treatment and taken for another journey (same route, driver and vehicle). Maropitant reduced the occurrence of vomiting compared to placebo by 86.1% or 76.5% when given approximately 2 or 10 h prior to travel, respectively. No significant clinical signs were observed after maropitant treatment. Maropitant was safe and effective in preventing vomiting due to motion sickness in dogs when administered at a minimum dose of 8 mg/kg body weight as oral tablets 2 or 10 h prior to travel.

Comparative efficacy of maropitant and selected drugs in preventing emesis induced by centrally or peripherally acting emetogens in dogs.

Maropitant (Cerenia; a novel, selective neurokinin(1) receptor antagonist), chlorpromazine, metoclopramide and ondansetron were compared in two randomized, placebo-controlled studies for efficacy in preventing emesis induced by emetogens acting centrally (apomorphine; Study 1) or peripherally (syrup of ipecac; Study 2) in dogs. In each study, ten male and ten female beagles were treated in a five-treatment, five-period crossover design. The five treatments were 0.9% saline (0.1 mL/kg), maropitant (1 mg/kg), metoclopramide (0.5 mg/kg), or chlorpromazine (0.5 mg/kg) all administered subcutaneously, or ondansetron (0.5 mg/kg) administered intravenously. One hour posttreatment dogs were challenged with apomorphine at 0.1 mg/kg intravenously (Study 1) or syrup of ipecac at 0.5 mL/kg orally (Study 2). Following emetogen challenge, dogs were observed for 30 min (Study 1) or 1 h (Study 2) for emesis. No clinical signs, other than those related to emesis, were observed. Efficacy of maropitant in preventing emesis induced centrally by apomorphine was not different (P > 0.05) from metoclopramide or chlorpromazine but was superior (P < 0.0001) to ondansetron. Efficacy of maropitant in preventing emesis induced by syrup of ipecac was not different (P > 0.05) from ondansetron but was superior (P

Safety and efficacy of injectable and oral maropitant, a selective neurokinin 1 receptor antagonist, in a randomized clinical trial for treatment of vomiting in dogs.

Maropitant (Cerenia), a selective neurokinin(1) receptor antagonist, was evaluated for safety and efficacy in treatment and prevention of acute vomiting due to various etiologies in dogs in a randomized clinical trial. Two-hundred seventy-eight dogs were enrolled from 29 veterinary hospitals. Two-hundred fifty-two were evaluable for efficacy, while 275 were evaluable for safety. A randomized block design was utilized (three maropitant- and one placebo-treated dog per block). Initial treatment was maropitant at 1 mg/kg body weight (0.45 mg/lb) or an equivalent volume of saline (placebo) administered subcutaneously. On the subsequent 1 to 4 days, maropitant or placebo (dependent on allocation) was administered subcutaneously or orally at approximate 24-h intervals as needed. Oral doses were administered as maropitant tablets using unit dosing to deliver a minimum dose of 2 mg/kg body weight (0.9 mg/lb) or equivalent numbers of similar placebo tablets. Dogs and housing were observed twice daily for evidence of vomiting. Emesis was significantly (P

Influence of dirlotapide, a microsomal triglyceride transfer protein inhibitor, on the digestibility of a dry expanded diet in adult dogs.

The objectives of this study were to evaluate the effects of dirlotapide, a microsomal triglyceride transfer protein inhibitor, on apparent nutrient digestibility of an expanded dry dog food, on defecation frequency and fecal consistency. Eighteen beagles were randomized to either placebo (n = 6) or dirlotapide (n = 12). Testing was divided into a 21-day adaptation phase (days -21 to -1) and a 35-day treatment (digestibility testing) phase (days 0-35). During the treatment phase, dogs were administered oral dirlotapide (0.3 mg/kg) or placebo (0.06 mL/kg) once daily. For digestibility testing, feces were collected over two periods for 7 days each starting on days -9 and 28. All dogs were fed a commercial adult dog food throughout the study. Food intake was adjusted to maintain body weight during adaptation, followed by pair-feeding placebo dogs the amount of food ingested by the dirlotapide dogs during the treatment period. Dogs in both groups had reduced food intake and lost similar amounts of body weight during treatment. Dogs receiving 0.3 mg dirlotapide/kg once daily had a small but significant (P = 0.018) decrease (6.16 +/- 2.22%, mean +/- SD) in crude fat digestibility compared with the placebo-treated food-restricted dogs, but no difference in crude protein, dry matter, or energy digestibility was observed. Fecal consistency and volume and defecation frequency were similar between groups. Dirlotapide effectively reduced appetite and energy intake without affecting nutrient digestibility, except for a minimal decrease in fat digestibility.

The comparative plasma pharmacokinetics of intravenous cefpodoxime sodium and oral cefpodoxime proxetil in beagle dogs.

The pharmacokinetic properties of cefpodoxime, and its prodrug, cefpodoxime proxetil, were evaluated in two separate studies, one following intravenous (i.v.) administration of cefpodoxime sodium and the second after oral (p.o.) administration of cefpodoxime proxetil to healthy dogs. After cefpodoxime administration, serial blood samples were collected and plasma concentrations were determined by high performance liquid chromatography (HPLC). A single i.v. administration of cefpodoxime sodium at a dose of 10 mg cefpodoxime/kg body weight resulted in a cefpodoxime average maximum plasma concentration (Cmax) of 91 (+/-17.7) microg/mL, measured at 0.5 h after drug administration, an average half-life (t1/2) of 4.67 (+/-0.680) h, an average AUC(0-infinity) of 454 (+/-83.1) h.microg/mL, an average V(d(ss)) of 151 (+/-27) mL/kg, an average Cl(B) of 22.7 (+/-4.2) mL/h/kg and an average MRT(0-infinity) of 5.97 (+/-0.573) h. When dose normalized to 10 mg cefpodoxime/kg body weight, cefpodoxime proxetil administered orally resulted in Cmax of 17.8 +/- 11.4 microg/mL for the tablet formulation and 20.1 +/- 6.20 microg/mL for the suspension formulation and an average AUC(0-LOQ) of 156 (+/-76.1) h.microg/mL for the tablet formulation and 162 (+/-48.6) h.microg/mL for the suspension formulation. Relative bioavailability of the two oral formulations was 1.04 (suspension compared with tablet), whereas the absolute bioavailability of both oral formulations was estimated to be approximately 35-36% in the cross-study comparison with the i.v. pharmacokinetics. Combined with previous studies, these results suggest that a single daily oral dose of 5-10 mg cefpodoxime/kg body weight as cefpodoxime proxetil maintains plasma concentrations effective for treatment of specified skin infections in dogs.

The pharmacokinetics of maropitant, a novel neurokinin type-1 receptor antagonist, in dogs.

Maropitant is the first NK1 receptor antagonist developed to treat and prevent emesis in dogs; it is administered by subcutaneous (s.c.) injection at 1 mg/kg, or orally (p.o.), in tablet form, at either 2 or 8 mg/kg depending on indication. The absolute bioavailability of maropitant was markedly higher (90.7%) following s.c. injection than after oral administration (23.7% at the 2 mg/kg dose and 37.0% at the 8 mg/kg dose). First-pass metabolism contributes to the low bioavailability of maropitant following oral administration. The difference in bioavailability between the two oral doses reflects the nonlinear kinetics characterizing the disposition of maropitant within the 2-8 mg/kg dose range. Systemic clearance of maropitant following intravenous (i.v.) administration was 970, 995 and 533 mL/h.kg at doses of 1, 2 and 8 mg/kg, respectively. Nonproportional kinetics were observed for p.o. administered maropitant at doses ranging from 2 to 16 mg/kg but dose proportionality was demonstrated at higher doses (20-50 mg/kg). Linearity was also demonstrated following s.c. administration at 0.5, 1 and 2 mg/kg. Maximum plasma drug concentration (Cmax) occurred 0.75 h (tmax) after s.c. administration at 1 mg/kg, and at 1.7 and 1.9 h after oral administration of 8 and 2 mg/kg doses, respectively. The apparent terminal half-life of maropitant was 7.75, 4.03 and 5.46 h after dosing at 1 mg/kg (s.c.), 2 mg/kg (p.o.) and 8 mg/kg (p.o.), respectively. Feeding status had no effect on oral bioavailability. Limited accumulation occurred following once-daily administration of maropitant for five consecutive days at 1 mg/kg (s.c.) or 2 mg/kg (p.o.). At the dose of 8 mg/kg (p.o.) once daily for two consecutive days, the mean AUC(0-24h) (second dose) was 218% that of the first dose value. Urinary recovery of maropitant and its main metabolite was minimal (<1%), thus supporting the evidence that maropitant clearance is primarily hepatic.

Efficacy of injectable maropitant (Cerenia) in a randomized clinical trial for prevention and treatment of cisplatin-induced emesis in dogs presented as veterinary patients.

Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of cisplatin therapy. Maropitant (Cerenia), a novel neurokinin-1 receptor antagonist, was evaluated for prevention and treatment of cisplatin-induced emesis in tumour-bearing dogs. Dogs (n = 122) were randomly allocated to three treatment groups: T01, placebo before and after cisplatin; T02, placebo before and maropitant after cisplatin; or T03, maropitant before and placebo after cisplatin. Maropitant treatment (T02) following a cisplatin-induced-emetic event resulted in significantly fewer subsequent emetic events (P = 0.0005) than in placebo-treated dogs (T01). In placebo-treated (T01) dogs, 56.4% were withdrawn from the study because of treatment failure compared with 5.3% in group T02. When maropitant was administered prior to cisplatin treatment (T03) in a prevention regime, 94.9% did not vomit compared with only 4.9% of placebo-treated dogs, and significantly fewer emetic events (P < 0.0001) were observed in those dogs that did vomit. In summary, maropitant was safe and highly effective in reducing or completely preventing cisplatin-induced emesis.

Factors affecting cure and somatic cell count after pirlimycin treatment of subclinical mastitis in lactating cows.

This study investigated the associations of both bacteriological cure and quarter somatic cell count (SCC) after intramammary antibiotic treatment with treatment duration, cow characteristics, and pretreatment bacteriology and SCC. For the purpose of this paper, data from 2 treatment groups in each of 2 multi-location studies were selected. These studies were conducted to evaluate the efficacy of daily intramammary infusions with 50 mg of pirlimycin hydrochloride for the treatment of subclinical mastitis. Data from study 1 allowed for comparison of a group of cows that received pirlimycin intramammarily for 2 d with a group that received no treatment, and study 2 provided data for comparison of pirlimycin for 2 d with pirlimycin for 8 d. Quarter milk samples from cows with a high monthly SCC were tested for bacteriology and SCC. If one or more quarters had both a positive bacteriology and an SCC >/=300,000 cells/mL, the cow was enrolled and randomly allocated to a treatment group. Enrolled cows were monitored for clinical mastitis and other disease for 4 wk after treatment initiation. At 3 and 4 wk after treatment initiation, milk samples were taken from each enrolled quarter to determine the SCC and conduct a bacteriological culture. Bacteriological culture results were interpreted such that quarters where the same bacterial species was cultured before treatment and found in at least 1 of the 2 posttreatment samples were considered a failure. The analysis of SCC used a mixed linear model (SAS proc mixed) and the analysis of bacteriological cure used a mixed logistic model (SAS glimmix macro). Bacteriological cure rate was significantly higher for lower parity, lower number of colonies in the pretreatment culture, longer treatment duration, and for streptococci compared with Staphylococcus aureus. However, treatment regimen affected bacteriological cure differently in major than in minor pathogens and there was a significant interaction of treatment regimen with stage of lactation. Posttreatment SCC was significantly higher with increasing parity, in rear quarters, and with shorter duration of treatment. In the group of second and third parity animals, post-treatment SCC was more reduced in front quarters than in rear quarters. Also, the difference in posttreatment SCC between younger and older cows increased with higher pretreatment SCC. In conclusion, when predicting bacteriological cure following treatment of subclinical mastitis during lactation both treatment regimen and other risk factors need to be considered. The other risk factors may vary with treatment regimen. Posttreatment SCC was associated with treatment regimen, other risk factors, and interactions among the other risk factors; but these other risk factors did not vary significantly with treatment regimen.

A dose-response study of melengestrol acetate on feedlot performance and carcass characteristics of beef steers.

The dose response of melengestrol acetate (MGA) on ADG (kg/d) and gain efficiency (gain/DMI, g/kg) was estimated in beef steers fed a finishing diet under commercial feedlot conditions. Melengestrol acetate is not approved for use in steers as a feed additive. The study design was five blocks of four pens (each pen was assigned a dose of MGA) with 166 to 200 steers per pen. Melengestrol acetate was fed to steers at 0 (n = 899, five pens), 0.1 (n = 900, five pens), 0.2 (n = 899, five pens), and 0.4 (n = 900, five pens) mg of MGA/steer daily. Pens within a block were slaughtered on the same day. Blocks 1 through 5 were fed MGA for 123, 122, 116, 124, and 138 d, respectively. The experimental unit was a pen of steers, and blocking was based on source of steers. The ADG was 1.81, 1.85, 1.80, and 1.83 kg/d for steers fed 0, 0.1, 0.2, and 0.4 mg MGA per day, respectively. For ADG, the dose was significant, but neither linear nor quadratic effects were significant. Compared with steers of the control group, ADG was greater for steers fed 0.1 mg MGA (P < 0.01). Feed efficiencies were 170, 173, 171, and 172 g/kg for steers fed 0, 0.1, 0.2, and 0.4 mg MGA/d, respectively; however, no effects of dose (P = 0.19) or linear (P = 0.21) or quadratic (P > 0.60) effects were observed. There was no evidence for either positive or negative effects of MGA on DMI, hot carcass weight, dressing percent, quality grade, yield grade, back fat thickness, marbling score, longissimus muscle area, and incidence of dark cutter carcasses in response to feeding MGA to steers at doses of 0.1, 0.2, and 0.4 mg daily. The incidence of buller behavior (0.43 to 1.11%) was low and did not permit an accurate test of the clinical observations that feeding MGA to steers decreases the occurrence of buller steers. Melengestrol acetate fed to finishing beef steers produced small improvements in growth performance (ADG, 2.2%) at the 0.1 mg MGA dose, but none of the doses examined produced improvement in carcass quality or yield grade measurements.

Concentrations of progesterone in milk of cows administered an intravaginal progesterone insert.

Milk from pregnant cows contains concentrations of progesterone (P4) considered safe for human consumption. The objective of this study was to determine if concentrations of P4 in milk during administration of an intravaginal progesterone insert (CIDR insert) are less than concentrations of P4 in milk associated with pregnancy. Results have implications for human use of milk from cows receiving CIDR inserts. Holstein cows (N = 64; > 40 and < 150 d after calving) were administered 25 mg of PGF2alpha i.m. (study d 0) and 20 cows detected in estrus from 2 to 4 d later were assigned randomly to either control (N = 10; no further treatment) or CIDR insert (N = 10; 1.38 g of P4) inserted on study d 17 (14 +/- 1 d after estrus) and removed 7 d later. Composite milk samples were collected contemporaneously from each of the 20 estrous cycling cows and from 10 pregnant cows (> or = 60 and < or = 220 d of gestation) twice daily from study d 17 to 27. Concentrations of P4 in defatted milk samples were quantified using a validated radioimmunoassay. Mean logs of areas under the curve of concentrations of P4 from the afternoon on study d 17 through the afternoon on study d 27 were 3.05 ng day/ml for control, 3.33 ng day/ml for CIDR insert, and 3.81 ng day/ml for pregnant cows. Therefore, increased P4 due to pregnancy was 0.76 ng day/ml (3.81-3.05), whereas the increase in P4 due to CIDR insert was only 0.28 ng day/ml (3.33-3.05). Applying a 95% confidence interval to 0.28 ng day/ml provided an upper value of 0.70 ng day/ml, lower than the increase due to pregnancy. Because milk from pregnant cows is considered safe for human consumption, it follows that milk from cows administered CIDR inserts should also be considered safe, based on concentrations of P4.

Intravaginal progesterone insert to synchronize return to estrus of previously inseminated dairy cows.

An intravaginal progesterone insert (CIDR insert; 1.38 g of progesterone) was evaluated for synchronization of returns to estrus (SR), conception rate (CR), and pregnancy rate (PR) in dairy cows previously artificially inseminated (AI). Healthy, nonpregnant, lactating Holstein cows, > or = 40 and < or = 150 d postpartum at eight commercial farms were used. Cows detected in estrus and receiving AI 2, 3, or 4 d after one injection of PGF2alpha (25 mg) were assigned as either controls (n = 945), or to receive a CIDR insert (n = 948) for 7 d (14 to 21 +/- 1 d after AI). Cows were observed for returns to estrus from 18 to 26 +/- 1 d after initial AI (resynchrony period) and were reinseminated if in estrus. Vaginal mucus on CIDR inserts (97.3% retention) at removal was scored: 1 = no mucus; 2 = clear; 3 = cloudy; 4 = yellow; and 5 = red or brown. Percentage of cows in estrus (SR) during the 3 d after CIDR insert removal was contrasted to the highest 3-d cumulative percentage in estrus for controls. Cows conceiving to initial AI were omitted in calculations of SR, CR, and PR during resynchrony. Mucous scores of 3 or 4 (mild irritation) were observed in 65% of cows and a score of 5 (more severe irritation) was observed in 2%; otherwise, health was unaffected. The PR to initial AI was lower for cows subsequently receiving CIDR inserts than for controls (32.7 vs. 36.7%). The CIDR insert increased SR (34.1 vs. 19.3% in 3 d) and overall estrus detection (43% in 4 d vs. 36% in 9 d) compared with controls. For the 9-d resynchrony period, CR and PR for CIDR-treated (26.7, 12.2%) and control (30.9, 11.1%) cows did not differ significantly. The CIDR inserts improved synchrony of returns to estrus, slightly reduced PR to initial AI, but did not affect CR or PR to AI during the resynchrony period.

Dose determination and confirmation of a long-acting formulation of ceftiofur (ceftiofur crystalline free acid) administered subcutaneously for the treatment of bovine respiratory disease.

The objective of this work was to determine and confirm an effective dose of ceftiofur crystalline free acid sterile oil suspension (CCFA-SS, 100 mg ceftiofur equivalents (CE)/mL], a long-acting single-administration ceftiofur formulation, for the treatment of the bacterial component of bovine respiratory disease (BRD). Study 1 was a dose determination study that used an intratracheal Mannheimia haemolytica (Pasteurella haemolytica) challenge model to evaluate single-administration doses of CCFA-SS at 0.0, 1.1, 2.2, 3.3, 4.4 or 5.5 mg CE/kg body weight (BW) for the treatment of BRD. Data from this study were used to select doses for field testing in three multi-location clinical studies. In Study 2, the efficacy of a single administration dose of CCFA-SS at 4.4 mg CE/kg BW was compared with a negative control for the treatment of naturally occurring BRD in feedlot cattle. Treatments were administered when uniform clinical signs of BRD were present. Study 3 used a design similar to Study 2, and compared single-administration doses of CCFA-SS at 3.0 or 4.4 mg CE/kg BW with the positive-control tilmicosin (Micotil(R) 300 Injection, Elanco Animal Health) at 10 mg/kg BW. Study 4 compared the efficacy of single doses of CCFA-SS of 1.1-8.8 mg CE/kg BW with tilmicosin at 10 mg/kg BW. A total of 1176 cattle were included in these clinical studies. In Study 1, a dose of 4.55 mg CE/kg BW was determined to be effective. This was rounded to 4.4 mg CE/kg for field testing. In Study 2, a single dose of CCFA-SS at 4.4 mg CE/kg BW had a higher treatment success rate on day 14 (61%) than negative controls (26%, P < 0.01). However, in Study 3 this dose was judged to be at the beginning of an efficacious dose range for the treatment of BRD when compared with tilmicosin. In Study 4, day 28 treatment success rates were higher for CCFA-SS at 4.4-8.8 CE/kg BW than for tilmicosin (P=0.002) or the noneffective CCFA-SS dose of 1.1 mg CE/kg BW (P < 0.001). Based on decision criteria for Study 4, the effective dose was determined to be 4.4-5.5 mg CE/kg BW. These clinical studies demonstrated that a single dose of CCFA-SS (100 mg CE/mL) administered subcutaneously (s.c.) in the neck at 4.4-5.5 mg CE/kg BW is an effective treatment for BRD in feedlot cattle. However, this route of administration is no longer being considered for this formulation because of the ceftiofur residues that are present at the injection site for extended periods of time.

Multilocation trial of ceftiofur for treatment of postpartum cows with fever.

OBJECTIVE: To evaluate the effect of ceftiofur for treatment of postpartum cows with fever. DESIGN: Multilocation randomized complete block design trial. ANIMALS: 330 cows. PROCEDURE: Cows with rectal temperature > or = 39.5 C (103.1 F) during the first 10 postpartum days were randomly assigned to a treatment (ceftiofur; 1 mg/kg [0.45 mg/lb] of body weight daily for 3 days) or untreated control group. Cure (no additional or alternative antimicrobial treatment used, rectal temperature < 39.5 C, and no other concurrent clinical signs of disease when evaluated at 9 or 10 days after enrollment), milk production, and rectal temperature were evaluated. RESULTS: Ceftiofur-treated cows were significantly more likely to be cured than control cows (56.0 vs 28.9%, respectively), with an odds ratio of 3.14 when vaginal discharge (a factor with moderate interaction with treatment) was present at enrollment. Among cows that had an abnormal calving (a significant interaction factor), treated cows had first milking yield 2.27 kg (5 lb) greater than control cows. Treated cows had a significantly greater reduction in rectal temperature (1.19 C [2.14 Fl), compared with control cows (1.04 C [1.87 F]). CONCLUSIONS AND CLINICAL RELEVANCE: Parenteral administration of ceftiofur significantly improved cure rate, milk yield, and rectal temperature in postpartum cows with fever and vaginal discharge or dystocia. These findings provide information to determine appropriate treatment for postpartum cows, which for years has been debated in the dairy industry.

The effect of daily slaframine injection of salivary score, feed intake, ruminal pH, and circulating concentrations of somatotropin and insulin-like growth factor I.

In a randomized complete block design with repeated measures, ruminally cannulated crossbred beef steers (n = 24; 279 +/- 3.2 kg) had ad libitum access to a 90% concentrate diet and were injected daily with slaframine dichloride (SF) at doses of 0, 30, or 60 micrograms SF free-base/kg BW. On d 1, 2, 7, 14, and 21, salivary scores were determined hourly from -2 to 8 h relative to injection (0 h), and ruminal pH was measured at 0, 4, and 8 h. Feed intake was measured daily. Serum concentrations of somatotropin (ST) were measured in samples collected at 20-min intervals from -40 min to 8 h on d 2, 7, 14, and 21, and IGF-I was measured at 8 h. Mean salivary score increased with SF injection (P < .01; .4, 3.3, and 3.7 for 0, 30, and 60 micrograms of SF/kg BW, respectively), although there was a dose x day interaction (P < .01). Injection of SF reduced DMI (P < or = .01; 6.39, 4.95, and 2.64 kg of DM/d for 0, 30, and 60 micrograms of SF/kg BW, respectively). Mean ruminal pH was increased (P < .01); 6.03, 6.42, and 6.72 for 0, 30, and 60 micrograms of SF/kg BW, respectively). Steers administered 60 micrograms of SF/kg BW lost weight (P = .02; 15.1 and -20.3 kg for 0 and 60 micrograms of SF/kg BW, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)