Pharmacokinetics of intranasal and intramuscular flunixin in healthy grower pigs.

Flunixin meglumine is a nonsteroidal anti-inflammatory drug approved to manage pyrexia associated with swine respiratory disease. In the United States, no analgesic drugs are approved for use in swine by the FDA, although they are needed to manage painful conditions. This study evaluated the pharmacokinetics and relative bioavailability of intranasal versus intramuscular flunixin in grower pigs. Six pigs received 2.2 mg/kg flunixin either intranasally via atomizer or intramuscularly before receiving flunixin via the opposite route following a 5-day washout period. Plasma samples were collected over 60 h and analysed using ultra-performance liquid chromatography and tandem mass spectrometry to detect flunixin plasma concentrations. A non-compartmental pharmacokinetic analysis was performed. The median Cmax was 4.0 µg/mL and 2.7 µg/mL for intramuscular and intranasal administration, respectively, while the median AUCinf was 6.9 h µg/mL for intramuscular administration and 4.9 h µg/mL for intranasal administration. For both routes, the median Tmax was 0.2 h, and flunixin was detectable in some samples up to 60 h post-administration. Intranasal delivery had a relative bioavailability of 88.5%. These results suggest that intranasal flunixin has similar, although variable, pharmacokinetic parameters to the intramuscular route, making it a viable route of administration for use in grower swine.

Effect of a single intravenous injection of branched chain amino acids on body temperature of cats undergoing general anesthesia.

OBJECTIVE: To evaluate the effect of a single intravenous injection of branched chain amino acids (BCAAs) on body temperature in cats undergoing general anesthesia. STUDY DESIGN: Prospective, blinded, randomized, crossover, experimental study. ANIMALS: A total of 10 healthy adult cats (five female and five male). METHODS: Cats were anesthetized three times with three different treatments in a random order: 3 mL kg-1 lactated Ringer's solution (LRS), 100 mg kg-1 BCAAs (B100) or 200 mg kg-1 BCAAs (B200) solution immediately before induction of anesthesia. After induction, rectal temperature was measured every 5 minutes. Blood samples were collected for the measurement of blood glucose (BG) just before induction, at the end of the 90 minute period of anesthesia, and 24 hours after anesthesia induction. The differences between baseline and each subsequent rectal temperature, and BG measurements were analyzed. Areas under the curve (AUCs) for temperature differences were calculated for each animal for the anesthetic period (AUCT0-90). Parametric or nonparametric data were analyzed by one-way repeated measures anova or Friedman test. A value of p < 0.05 was considered significant. RESULTS: There were no significant differences in AUCT0-90 between groups: 41.6 ± 7.7 for LRS, 43.4 ± 6.9 for B100 and 42.9 ± 7.5 for B200 (p = 0.368). No significant differences were observed in BG between groups at 90 minutes and 24 hours after anesthesia induction (p = 0.283 and p = 0.089, respectively). The incidence of hypoglycemia [BG ≤ 3.17 mmol L-1 (57 mg dL-1)] after anesthesia tended to be higher in both B100 (4/10 cats) and B200 groups (3/10 cats) than in LRS group (1/10 cats). CONCLUSIONS AND CLINICAL RELEVANCE: A single, preanesthetic intravenous injection of BCAAs did not attenuate heat loss during anesthesia. More cats were hypoglycemic in the BCAA groups than in the LRS group.

Plasma pharmacokinetics of clorsulon following administration of a single subcutaneous or intravenous injection to cattle.

The benzenedisulfonamide derivative clorsulon is a potent fasciolicide which is marketed in fixed combination injectables, typically combined with the macrocyclic lactone ivermectin. In the presented pharmacokinetic study, the plasma profile of clorsulon in 32 healthy, young Brown Swiss cattle was administered a single intravenous dose at 3 mg/kg body weight or subcutaneously at 3, 6 or 12 mg/kg body weight (4 intact male and 4 female animals per treatment) as a 30% w/v clorsulon injection formulation. Serial blood samples were collected up to 24 days after administration to establish the pharmacokinetics, bioavailability and dose proportionality of clorsulon. Following a single intravenous injection of clorsulon at 3 mg/kg body weight, the area under the concentration versus time curve from the start of dose administration to the time of the last quantifiable concentration (AUClast ) was 4830 ± 941 day*ng/mL, and half-live was 2.37 ± 0.98 days. The back extrapolated concentration at time 0 was 38,500 ± 6070 ng/mL. The volume of distribution at steady state and clearance were 685 ± 107 mL/kg and 664 ± 127 mL/day/kg, respectively. In the groups dosed at 3, 6 or 12 mg/kg body weight by subcutaneous injection, clorsulon plasma concentrations rose to maximum within 0.5 day and decreased to the last sample point. For these groups, the maximum plasma clorsulon concentrations were 3100 ± 838, 5250 ± 1220 and 10,800 ± 1730 ng/mL, respectively, and the AUClast was 5330 ± 925, 9630 ± 1300 and 21,500 ± 3320 day*ng/mL, respectively. Half-lives, 2.01 ± 0.62, 3.84 ± 1.42 and 5.36 ± 0.60 days, respectively, increased significantly with dose, likely related to increasing dose volume. Clorsulon was well absorbed and fully bioavailable (103%-114%) after subcutaneous injection. No gender-related difference in systemic exposure was observed. Assessment of Cmax and AUClast demonstrated a proportional increase in systemic exposure to the clorsulon subcutaneous doses over the range of 3-12 mg/kg body weight.

Pharmacokinetics of hydrorphone hydrochloride after intravenous and subcutaneous administration in ferrets (Mustela putorius furo).

OBJECTIVE: To determine the pharmacokinetic profile of hydromorphone 0.2 mg kg-1 administered by the intravenous (IV) and subcutaneous (SC) route in ferrets. STUDY DESIGN: Randomized, crossover study. ANIMALS: A group of eight adult ferrets weighting (mean ± standard deviation) 1.02 ± 0.22 kg. METHODS: Hydromorphone hydrochloride 0.2 mg kg-1 was administered IV or SC with a washout period of 7 days. Blood samples were collected from a jugular catheter before administration of hydromorphone and at 5, 10, 15, 20, 30, 45, 60, 90, 120, 240, 360, 480 and 720 minutes after hydromorphone administration. Plasma hydromorphone concentrations were determined by liquid chromatography/tandem mass spectrometry. Data were analyzed using a non-linear mixed effects model. RESULTS: The hydromorphone effective half-life was (t1/2) 45 min-1. Systemic clearance (Cls) and the volume of distribution (Vdss) following IV administration were 84.8 mL kg-1 min-1 and 5.59 L kg-1, respectively. The maximum observed plasma concentration was 59.53 ± 14.02 ng mL-1 within 10 minutes following SC administration. The SC bioavailability was 102.0%. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of IV and SC hydromorphone (0.2 mg kg-1) was characterized by a high clearance, short terminal half-life and large volume of distribution. Hydromorphone plasma concentrations remained greater than 2 ng mL-1 for 2 hours in most ferrets, a threshold reported to provide antinociceptive effects in other species. Hydromorphone was well absorbed following SC injection, providing an alternative administration route for clinical use in ferrets.

Characterisation of the pruritus responses and pruritic behaviours in an interleukin 31-induced canine model of pruritus.

BACKGROUND: Intravenous administration of interleukin (IL)-31 in healthy dogs has been used as a model to assess antipruritic drugs. However, there is no known in-depth characterisation of pruritic behaviours, and the repeatability of the IL-31-induced pruritus in the individual dogs is currently unknown. OBJECTIVES: To evaluate the immediate/delayed pruritus responses and the pruritic behaviours observed in the IL-31-induced pruritic model in healthy dogs after repeated IL-31 injections. ANIMALS: Fifteen healthy laboratory beagles. METHODS: All dogs were video-recorded for 270 min after two intravenous recombinant IL-31 injections (1.75 µg/kg) and vehicle (phosphate-buffered saline, control) injections, respectively; interventions were randomised and performed with a 2 week wash-out period. Two blinded investigators reviewed the pruritic behaviours of all video recordings. RESULTS: Both canine IL-31 (IL-31_01, IL-31_02) injections significantly increased pruritic seconds and categorical minutes ('YES'/'NO' behaviour per discrete 1 min interval) in healthy dogs compared with both vehicle groups (Vehicle_01, Vehicle_02). The second intravenous canine IL-31 (IL-31_02) administered 14 days after the first IL-31 injection induced a significant increase in pruritic seconds (p = 0.021) and not pruritic categorical minutes (p = 0.231). An increase in pruritic seconds was observed in both IL-31 groups in the first 30 min post-administration, while there was no significant difference between IL-31 and vehicle groups. CONCLUSIONS AND CLINICAL RELEVANCE: In conclusion, intravenous IL-31 reproducibly induces itch responses in dogs. Future evaluations of the canine IL-31 pruritic model should assess total pruritic behaviours in seconds rather than using a biased 'YES/NO' behaviour per 1 min scoring system.

Population pharmacokinetic analysis of enrofloxacin and its active metabolite ciprofloxacin after intravenous injection to cats with reduced kidney function.

BACKGROUND: It is unknown if enrofloxacin accumulates in plasma of cats with reduced kidney function. HYPOTHESIS: To determine if enrofloxacin and its active metabolite ciprofloxacin have reduced clearance in azotemic cats. ANIMALS: Thirty-four cats hospitalized for clinical illness with variable degree of kidney function. METHODS: Prospective study. After enrofloxacin (dose 5 mg/kg) administration to cats, sparse blood sampling was used to obtain 2 compartment population pharmacokinetic results using nonlinear mixed-effects modeling. Plasma enrofloxacin and ciprofloxacin concentrations were measured and summed to obtain the total fluoroquinolone concentration. A model of ciprofloxacin metabolism from enrofloxacin was created and evaluated for covariate effects on clearance, volume of distribution, and the metabolic rate of ciprofloxacin generation from enrofloxacin. RESULTS: Body weight was the only covariate found to affect total fluoroquinolone volume of distribution (effect 1.63, SE 0.19, P < .01) and clearance (effect 1.63, SE 0.27, P < .01). Kidney function did not have a significant effect on total fluoroquinolone clearance (median 440.8 mL/kg/h (range 191.4-538.0 mL/kg/h) in cats with normal kidney function, 365.8 mL/kg/h (range 89.49-1092.0 mL/kg/h) in cats with moderate kidney dysfunction, and 308.5 mL/kg/h (range 140.20-480.0 mL/kg/h) in cats with severe kidney dysfunction (P = .64). Blood urea nitrogen concentration influenced the metabolic generation of ciprofloxacin from enrofloxacin (effect 0.51, SE 0.08, P < .01), but other markers of kidney function did not. CONCLUSIONS AND CLINICAL IMPORTANCE: Adjustment of enrofloxacin dosage is not indicated for azotemic cats.

Pharmacokinetics and bioavailability of meloxicam in Pekin ducks following intravenous, intramuscular and oral administration.

OBJECTIVE: To determine the pharmacokinetics and bioavailability of meloxicam following intravenous (IV), intramuscular (IM), and oral administrations at a dose of 1.0 mg kg-1 in Pekin ducks. STUDY DESIGN: Randomized experimental trial. ANIMALS: A total of 18 clinically healthy male Pekin ducks. METHODS: Pekin ducks were randomly assigned to three groups of six ducks: IV, IM and oral. Meloxicam (1.0 mg kg-1) was administered to each Pekin duck. A non-compartmental analysis was used to evaluate pharmacokinetic parameters. RESULTS: No local or systemic adverse effects were observed in any bird. Meloxicam was detected in the plasma up to 120 hours following IV, IM or oral administration. The elimination half-life of the IV route was slightly shorter than that of the IM and oral routes (p < 0.05). Following IV administration, volume of distribution at steady state and total clearance were 133.17 mL kg-1 and 6.68 mL kg-1 hour-1, respectively. The mean absorption time was 2.29 hours for IM and 1.13 hours for oral route. There were significant differences between IM and oral administration for the peak plasma concentration (Cmax), time to reach Cmax and bioavailability (p < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: Meloxicam showed long elimination half-life and high bioavailability following IM and oral administration. Meloxicam in Pekin ducks provided the effective therapeutic concentration indicated in other species for up to 48 hours. However, there is a need to determine the clinical efficacy of meloxicam in Pekin ducks.

Biliary excretion and pharmacokinetics of several fluoroquinolones after intravenous injection in rabbits.

The aim of this study was to measure the concentrations of enrofloxacin (ERFX) and other fluoroquinolones; orbifloxacin (OBFX), marbofloxacin (MBFX), and ofloxacin (OFLX) in the plasma and bile of rabbits after a single intravenous (IV) injection. Twenty male rabbits were divided into four groups and given each drug by IV injection into the ear vein at a dose of 5.0 mg/kg BW. The concentration of ERFX, ciprofloxacin (CPFX), OBFX, MBFX and OFLX in plasma and bile were determined by HPLC. CPFX, metabolite of ERFX, was also measured by HPLC in plasma and bile of rabbits receiving ERFX. Several pharmacokinetic parameters in plasma were calculated and biliary clearance (CLbile) was calculated from extent of biliary excretion and accumulation of AUC of each drug. After IV injection, elimination half-life (t1/2ß) was 4.13, 3.68, 6.60, 5.14 hr; volume of distribution at a steady state (Vdss) was 1.24, 0.503, 0.771, 1.02 L/kg; and total body clearance (CLtot) was 1.05, 0.418, 0.271, 0.453 L/kg/hr, respectively. The values for CLbile for ERFX, OBFX, MBFX, and OFLX were 0.0048, 0.0050, 0.0057, and 0.0094 L/kg/hr, respectively. These values represent 0.48%, 1.2%, 2.1%, and 2.3% of the total body clearance (CLtot) of each drug, respectively. The biliary clearance of CPFX was also measured and found to be 0.0199 L/kg/hr with ERFX administration. The results showed that ERFX, OBFX, MBFX, and OFLX were not excreted into the bile to a significant extent, making them safe drugs to use in rabbits.

Age-related changes in the pharmacokinetics of meloxicam after intravenous administration in sheep.

The pharmacokinetics of meloxicam was studied in 1-, 6-, and 12-month-old sheep following a single intravenous (i.v.) dose of 1 mg/kg. The experiments were carried out when the Romanov sheep were 1 month old (7.93 ± 0.91 kg), 6 months old (27.47 ± 4.91 kg), and 12 months old (37.10 ± 3.64 kg). Meloxicam concentration in plasma was determined by high-performance liquid chromatography and the data collected were evaluated by non-compartmental kinetic analysis. Meloxicam was detected in the plasma up to 72 h following i.v. administration in all age groups. The volume of distribution at steady state (Vdss ) and total body clearance (ClT ) were significantly higher in 1-month-old (304.87 mL/kg and 16.57 mL/h/kg) than in 12-month-old (193.43 mL/kg and 10.50 mL/h/kg) sheep. The area under the concentration-time curve from 0 to 72 h value of meloxicam was lower in 1-month-old (58.51 h*µg/mL) compared to 12-month-old (92.59 h*µg/mL) sheep. There was no difference in t1/2ʎz value in different age groups. The body extraction ratio values for meloxicam ranged from 0.0186 to 0.0719 after i.v. administration in all age groups. Meloxicam showed an increase in plasma concentration and a decrease in Vdss and ClT in 12-month-old compared to 1-month-old sheep. Compared to 1-month-old and 12-month-old sheep, there was no difference in these parameters in 6-month-old sheep. Because the age of sheep has an influence on the pharmacokinetics of meloxicam, dosage apparently may need to be adjusted for age.

Pharmacokinetics of meloxicam in pigeons after single intravenous, oral, and intramuscular administration.

This study aimed to determine the pharmacokinetics of meloxicam in pigeons. Twenty-four 7-wk-old meat pigeons (Columba livia) were randomly divided into 3 groups (PO, IM, and IV) and given a single dose of 1 mg/kg body weight of meloxicam. Plasma samples were taken at predetermined times, which were then analyzed using a validated high-performance liquid chromatography (HPLC) method and subjected to noncompartmental analysis using Phoenix software. Results indicated that meloxicam was absorbed effectively and quickly after PO and IM dosing. Peak concentrations (0.83 ± 0.21 and 1.59 ± 0.49 µg/mL) were achieved at 2 and 0.26 h, respectively, with mean absorption times of 2.56 ± 1.50 and 1.47 ± 0.89 h. Bioavailability was high at 86.31 ± 43.45% and 81.57 ± 52.58%, respectively, and the area under the concentration-time curve (AUC0-∞) was 5.33 ± 2.68 and 5.03 ± 3.26 h·µg/mL. After IV administration, the elimination was faster with a total body clearance (CL) of 188.75 ± 83.23 mL/h/kg, an elimination half-life (t1/2λz) of 1.76 ± 0.56 h, and a volume of distribution at steady-state (VSS) of 427.50 ± 188.43 mL/kg. Considering the lack of a precise analgesic threshold of meloxicam in pigeons and the notable differences in its analgesic threshold among various animal species, formulating a dosing regimen in pigeons presented a significant challenge. Based on the previous analgesic threshold (3.5 µg/mL) in parrots, a higher dose (e.g., 2 mg/kg) or shorter dosing interval (e.g., every 6 h) is recommended for treating pain in pigeons. Nonetheless, further pharmacodynamic research is required to verify these recommendations.

Disposition kinetics of robenacoxib following intravenous and oral administration in geese (Anser anser domesticus).

Robenacoxib (RX) is a veterinary cyclooxygenase-2 selective inhibitor drug. It has never been tested on birds and is only labelled for use in cats and dogs. The purpose of this study was to assess its pharmacokinetics in geese after single intravenous (IV) and oral (PO) administrations. Four-month healthy female geese (n = 8) were used. Geese were subjected to a two-phase, single-dose (2 mg/kg IV, 4 mg/kg PO), open, longitudinal study design with a four-month washout period between the IV and the PO phases. Blood was collected from the left wing vein to heparinized tubes at 0, 0.085 (for IV only), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, and 24 h. Plasma RX concentrations were measured using HPLC coupled to an UV detector, and the data were pharmacokinetically analysed using ThothPro™ 4.3 software in a non-compartmental approach. Following IV administration, terminal elimination half-life, volume of distribution, and total clearance were 0.35 h, 0.34 L/kg, and 0.68 L/h/kg, respectively. For the PO route, the mean peak plasma concentration was 6.78 µg/mL at 0.50 h. The t1/2λz was very short and significantly different between the IV and PO administrations (0.35 h IV vs. 0.99 h PO), suggesting the occurrence of a flip-flop phenomenon. The Cl values corrected for the F% were significantly different between IV and PO administrations. It might have been a consequence of the longitudinal study design and the altered physiological and environmental conditions after a 4-month washout period. The absolute oral F% computed with the AUC method surpassed 150%, but after normalizing it to t1/2λz, it was 46%. In conclusion, the administration of RX might not be suitable for geese, due to its short t1/2λz.

High bioavailability, short half-life, and metabolism into hydromorphone-3-glucuronide following single intramuscular and intravenous administration of hydromorphone hydrochloride to great horned owls (Bubo virginianus).

OBJECTIVE: To determine the pharmacokinetic parameters of hydromorphone hydrochloride and its metabolite, hydromorphone-3-glucuronide (H3G), after a single IV and IM dose in great horned owls (Bubo virginianus). ANIMALS: 6 healthy adult great horned owls (3 females and 3 males). PROCEDURES: A single dose of hydromorphone (0.6 mg/kg) was administered once IM (pectoral muscles) and IV (left jugular) with a 6-week washout period between experiments. Blood samples were collected at 5 minutes and 0.5, 1.5, 2, 3, 6, 9, and 12 hours after drug administration. Plasma hydromorphone and H3G concentrations were determined with liquid chromatography-tandem mass spectrometry, and a noncompartmental analysis was used for the determination of pharmacokinetic parameters. RESULTS: Hydromorphone had a high bioavailability of 170.8 ± 37.6% and rapid elimination after IM administration and rapid plasma clearance and a large volume of distribution after IV administration. Mean Cmax was 225.46 ± 0.2 ng/mL at 13 minutes after IM injection. Mean volume of distribution and plasma drug clearance was 4.29 ± 0.5 L/kg and 62.11 ± 14.6 mL/min/kg, respectively, after IV administration. Mean t1/2 was 1.62 ± 0.36 and 1.35 ± 0.59 hours after IM and IV administration, respectively. The metabolite H3G was readily measured shortly after administration by both routes. CLINICAL RELEVANCE: A single dose of 0.6 mg/kg was well tolerated in all birds. Hydromorphone rapidly attained plasma concentrations following IM administration and had high bioavailability and short t1/2. This study is the first to document the presence of the metabolite H3G in avian species, which suggests similar hydromorphone metabolism as in mammals.

Comparative pharmacokinetics of florfenicol in heifers after intramuscular and subcutaneous administration.

Florfenicol was administered to five heifers intramuscularly at a dose rate of 20 mg/kg bwt and following wash-out period, subcutaneously at a dose rate of 40 mg/kg bwt. Blood plasma samples were collected from heifers before injection of florfenicol and up to 120 h after intramuscular (IM) injection and up to 264 h after subcutaneous (SC) injection. Florfenicol concentrations in plasma were measured by high-performance liquid chromatography with mass-spectrometric detection. Pharmacokinetics of florfenicol was estimated using non-compartment analysis. Mean maximum plasma concentration, area under the concentration-time curve and elimination half-life for florfenicol were 3.2 µg/ml, 101.5 µg × h/ml and 24.5 h, respectively, after IM injection at 20 mg/kg bwt, and 2.7 µg/ml, 194.5 µg × h/ml and 103.8 h, respectively, after SC injection at 40 mg/kg bwt. The obtained results indicated that both administration routes provided comparable bioavailability, whereas SC route was attributed with lower peak levels and markedly slower absorption of florfenicol from injection site. Both administration routes provided plasma florfenicol levels which are expected to be effective against prevalent infectious agents of cattle.

Pharmacokinetic profiles of the two major active metabolites of metamizole, 4-methylaminoantipyrine (MAA) and 4-aminoantipyrine (AA), after intravenous injection in cats.

This study aimed to determine the pharmacokinetic profile of two active metabolites of metamizole (dipyrone), N-methyl-4-aminoanthypyrine (MAA) and 4-aminoanthypyrine (AA), after intravenous administration in cats. Eight healthy mixed-breed cats were intravenously administered metamizole (25 mg/kg). Blood samples were collected at predetermined time points for up to 48 h after administration. Information on behavioral changes in the animals and adverse effects was collected. Plasma aliquots were processed and analyzed using the ultra-performance liquid chromatography tandem mass spectrometry technique. A validated UPLC-MS/MS method was used to characterize the pharmacokinetics of MAA and AA. Salivation was identified as an adverse clinical sign. The mean maximal plasma concentrations of MAA and AA were 29.31 ± 24.57 µg/mL and 1.69 ± 0.36 µg/mL, with half-lives of around 4.98 and 14 h, respectively. The area under the plasma concentration curve values were 28.54 ± 11.33 and 49.54 ± 11.38 h*µg/mL for MAA and AA, respectively. The plasma concentration of MAA was detectable for up to 24 h and was smaller than AA. AA was detectable for >48 h. Results suggest that metamizole is converted into active metabolites in cats. Further PK/PD and safety studies should be performed before defining the dose or administration intervals for clinical use.

Pharmacokinetics of danofloxacin after single oral and intravenous administration in non-laying hens.

The current study aimed to explore the pharmacokinetics of danofloxacin in non-laying hens after a single oral (PO) and intravenous (IV) dose, both at 5 mg/kg body weight (BW). Eighteen 13-week-old healthy hens were equally and randomly divided into two groups. After both doses, blood samples (approximately 1 ml) were collected at different time points. Danofloxacin concentrations were quantified by a validated high-performance liquid chromatography (HPLC) method followed by a non-compartmental analysis using the software of WinNonLin. The elimination half-lives (t1/2λz s) after PO and IV routes were determined as 8.15 ± 3.37 and 7.69 ± 3.40 h, respectively. After IV administration, danofloxacin had an initial concentration (C0 ) of 3.62 µg/ml, a volume of distribution at steady state (VSS ) of 3579.72 ± 454.29 ml/kg, and a total body clearance (Cl) of 0.49 ml/h/g. After PO administration, the absolute bioavailability and absorption half-life (t1/2ka ) were calculated as 100.99% ± 23.10% and 0.82 ± 0.58 h, respectively. Based on the calculated ratio values of AUC/MIC and Cmax /MIC, an oral dose of 5 mg/kg danofloxacin would be expected to successfully treat hens infected with strains with MIC values ≤0.1 µg/ml.

Comparing the effects of intravenous injection and intranasal atomisation of detomidine in sheep.

BACKGROUND: Detomidine is an α-2 agonist sedative drug which reduces the release of norepinephrine in nerves. Administering this drug through intranasal (IN) route could cause direct transmission to the central nervous system. Therefore, IN administration of detomidine would decrease the side effects and the onset of sedation. OBJECTIVES: In this study, IN administration of detomidine in sheep through an atomiser was compared to its IV administration. METHODS: Fifteen mature female sheep with an approximate weight of 49.53 ± 1.72 kg were used. They were randomly divided into three groups: (1) atomising 10 µg/kg (IND10 ); (2) IV 10 µg/kg (IVD) and (3) atomising 30 µg/kg (IND30 ). Following administration, vital signs, electrocardiographic components, sedative score and biochemistry profile were measured after 15, 30 and 60 min, which were compared with the baseline measures. RESULTS: Bradycardia and the percentage of reduction from the baseline value in the respiratory rate were lower in the IND10 group compared to those in the IVD group. There was no significant difference in terms of the temperature and blood oxygen saturation (SpO2 ) among all the groups (p > 0.05). The level of cortisol declined in all the groups, and in the IND30 (60 min), it was significantly different with the baseline value. The level of glucose increased in all the groups compared to the baseline, which was not significant. Insulin concentration was reduced in all the groups, and in the IND30 group, it changed significantly 60 min after the drug administration. Sedation onset time was faster in the IV group. However, sedation scores between the two administration methods were not different, and only a dose-dependent increase was found in the sedation score in the atomisation group. CONCLUSIONS: Our findings revealed that IN atomisation of detomidine triggers similar sedation as its IV administration, which could be used as an alternative method.

Dosing protocols to increase the efficacy of butorphanol in dogs.

The purpose of this study was to improve butorphanol dosing in dogs. Twelve Beagles (6 males, 6 females) were enrolled. Six were randomly allocated to each butorphanol treatment: IV (0.4 mg/kg), IV loading dose (0.2 mg/kg) with IV CRI (0.2 mg/kg/h for 8 h), SC (0.4 mg/kg), SC (0.8 mg/kg) with an equal volume sodium bicarbonate (SC-bicarbonate), and IV after CYP inhibitors. We hypothesized that the CRI would produce longer durations than IV bolus, and SC-bicarbonate suspension would produce longer durations than SC. Hypothermia, an opioid effect paralleling antinociception in dogs, and sedation were evaluated. Pharmacokinetics and CYP inhibitor effects on butorphanol pharmacokinetics were determined. Rectal temperatures were significantly lower than baseline from 1.5-4 h (IV), 1-5 h (CRI), and 2-7 h (SC-bicarbonate), but not after SC. Dogs in all treatments had sedation. Butorphanol's half-life was ~1.5 h. SC-bicarbonate had lower bioavailability (61%) relative to SC, with no sustained release, and the CRI mean steady-state plasma concentration was 43.1 ng/ml. CYP inhibitors had minor pharmacokinetic effects on butorphanol. Butorphanol 0.4 mg/kg IV and 0.2 mg/kg loading dose with 0.2 mg/kg/h CRI decreased rectal temperature, but 0.4 mg/kg SC did not. Further studies are required to determine clinical analgesia of butorphanol.

Pharmacokinetics and bioavailability of danofloxacin in swan geese (Anser cygnoides) following intravenous, intramuscular, subcutaneous, and oral administrations.

The aim of this study was to determine the pharmacokinetics and bioavailability of danofloxacin in swan geese (Anser cygnoides) after intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) administrations at 10 mg/kg dose. In this study, eight clinically healthy swan geese were used. The study was performed in four periods according to a crossover design with a 15 days washout period between two administrations. The plasma concentrations of danofloxacin were analyzed using high-performance liquid chromatograph-ultraviolet detection, and pharmacokinetic parameters were estimated by non-compartmental analysis. Following IV administration, terminal elimination half-life (t1/2ʎz ), total clearance, and volume of distribution at steady state were 6.03 h, 0.34 L/h/kg, and 2.71 L/h/kg, respectively. After IM, SC, and PO administration, t1/2ʎz was longer than that after IV administration. The Cmax of danofloxacin following IM, SC, and PO administrations was 3.65, 2.76, and 1.98 µg/mL at 0.63, 1, and 2 h, respectively. The bioavailability following IM, SC, and PO administrations was 87.99, 72.77, and 57.68%, respectively. This information may help in the use of danofloxacin in geese, yet the determination of optimal dosage regimen and pharmacodynamic studies are needed.

Pharmacokinetics of tildipirosin in horses after intravenous and intramuscular administration and its potential muscle damage.

Tildipirosin is a novel semisynthetic macrolide antibiotic exclusively used in veterinary practice to treat respiratory infections. There are no pharmacokinetic or safety information available regarding the use of tildipirosin after intramuscular administration in horses. Thus, the objective of this work was to determine the disposition kinetics of tildipirosin after intravenous (IV) and intramuscular (IM) administration in horses and its potential muscle damage and cardiotoxicity. Six mature, Spanish-breed horses were used in a crossover study with a washout period of 30 days. Tildipirosin (18%) was administered at single doses by IV (2 mg/kg) and IM (4 mg/kg) routes. Tildipirosin plasma concentrations were determined by HPLC assay with ultraviolet detection. Muscle damage and inflammation were assessed by creatine kinase (CK) and haptoglobin (Hp), respectively. Creatine kinase myocardial band (CK-MB) and troponin (Tn) were used to evaluate cardiotoxicity. Tildipirosin in horses reached peak concentrations (Cmax = 1.13 µg/mL) at 0.60 h (tmax) after IM administration with an absolute bioavailability of 109.2%. Steady-state volume of distribution and clearance were 3.31 ± 0.57 L/kg and 0.22 ± 0.02 L/h/kg, respectively. Tildipirosin did not cause cardiotoxicity since CK-MB and Tn basal levels were not significantly different from those obtained after several days post-administration. Mild local reactions were observed after IM administration. This local inflammation was associated with mild myolysis (CK 239-837 UI/L), which was detectable for 48 h. In brief, tildipirosin could help to treat respiratory infections in horses because it showed extensive distribution, high bioavailability and did not provoke general adverse reactions.

Pharmacokinetics and bioavailability of carprofen in sheep.

The aim of this study was to determine the pharmacokinetics and bioavailability of carprofen in sheep following single intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) administrations of a parenteral formulation at a dose of 4 mg/kg. A total of eight sheep were used for the investigation. The study comprised four periods, according to a crossover design with a 21-day washout period between treatments. Plasma concentrations of carprofen were measured using HPLC-UV. Pharmacokinetic parameters were estimated by non-compartmental model analysis. Following IV administration, t1/2ʎz , ClT , and Vdss were 43.36 h, 1.98 ml/h/kg, and 121.36 ml/kg, respectively. The Cmax(obs) was 26.57 mg/ml for the IM, 23.76 mg/ml for the SC, and 15.90 mg/ml for the PO. The bioavailability following IM, SC, and PO administrations was 75.47%, 82.00%, and 62.51%, respectively. Plasma creatine kinase activity increased significantly at 3, 6, and 12 h following IM administration of carprofen. Despite differences in plasma concentrations and bioavailability among administration routes, carprofen at 4 mg/kg dose may provide the plasma concentration (>1.5 µg/ml) needed for analgesic effect during 144 h in all routes. However, because of the slow absorption rate after SC and PO routes, the IV route may be preferred primarily for the rapid onset in the analgesic and anti-inflammatory effect of carprofen in sheep. Despite the favorable kinetics, the muscle damage caused by IM injection limits use of carprofen via IM route.