Pharmacokinetic assessment of the monepantel plus oxfendazole combined administration in dairy cows

Monepantel (MNP) is a novel anthelmintic compound launched into the veterinary pharmaceutical market. MNP is not licenced for use in dairy animals due to the prolonged elimination of its metabolite monepantel sulphone (MNPSO₂) into milk. The goal of this study was to evaluate the presence of potential in vivo drug‐drug interactions affecting the pattern of milk excretion after the coadministration of the anthelmintics MNP and oxfendazole (OFZ) to lactating dairy cows. The concentrations of both parent drugs and their metabolites were measured in plasma and milk samples by HPLC. MNPSO₂ was the main metabolite recovered from plasma and milk after oral administration of MNP. A high distribution of MNPSO₂ into milk was observed. The milk‐to‐plasma ratio (M/P ratio) for this metabolite was equal to 6.75. Conversely, the M/P ratio of OFZ was 1.26. Plasma concentration profiles of MNP and MNPSO₂ were not modified in the presence of OFZ. The pattern of MNPSO₂ excretion into milk was also unchanged in animals receiving MNP plus OFZ. The percentage of the total administered dose recovered from milk was 0.09 ± 0.04% (MNP) and 2.79 ± 1.54% (MNPSO₂) after the administration of MNP alone and 0.06 ± 0.04% (MNP) and 2.34 ± 1.38% (MNPSO₂) after the combined treatment. The presence of MNP did not alter the plasma and milk disposition kinetics of OFZ. The concentrations of the metabolite fenbendazole sulphone tended to be slightly higher in the coadministered group. Although from a pharmacodynamic point of view the coadministration of MNP and OFZ may be a useful tool, the presence of OFZ did not modify the in vivo pharmacokinetic behaviour of MNP and therefore did not result in reduced milk concentrations of MNPSO₂.     

Effects of the sodium‐glucose cotransporter 2 (SGLT2) inhibitor velagliflozin,a new drug with therapeutic potential to treat diabetes in cats

Sodium‐glucose cotransporter 2 (SGLT2) inhibitors are used in the treatment of human diabetics. They increase glucose excretion and correct hyperglycemia. We examined the investigational SGLT2 inhibitor velagliflozin in two groups of six neutered adult obese cats (equal gender distribution). Placebo (Pl) or drug (D; 1 mg/kg) was administered for 35 days. Routine blood examinations, fructosamine, beta‐hydroxybutyrate (BHB), nonesterified fatty acids (NEFA), glucagon, adiponectin, and leptin were measured before and after treatment, also water intake, and urinary electrolytes, glucose, and volume. Indirect calorimetry, an intravenous glucose tolerance test (IVGTT; 0.8 g/kg) and insulin tolerance test (IVITT) were conducted. All cats tolerated treatment well. Significant changes with D included a decrease in the respiratory exchange ratio, an increase in cholesterol, a small increase in albumin, and a rise in BHB and NEFA. Glucose clearance was unaltered, although less insulin was secreted during the IVGTT (p = .056) suggesting improved insulin sensitivity. IVITT was unchanged. Treatment did not affect glucagon, leptin, or adiponectin. Water intake, urine output, urinary glucose excretion, and the glucose/creatinine ratio but not urinary electrolytes were significantly higher post‐D. We conclude that velagliflozin is a promising drug, which increases urinary glucose excretion in cats and could thereby be beneficial for the treatment of hyperglycemia.     

PK/PD modeling of flunixin meglumine in a kaolin‐induced inflammation model in piglets

Flunixin is marketed in several countries for analgesia in adult swine but little is known about its efficacy in piglets. Thirty‐two piglets (6–8 days old) were randomized to receive placebo saline (n = 11, group CONTROL) or flunixin meglumine intravenously at 2.2 (n = 11, group MEDIUM) or 4.4 (n = 10, group HIGH) mg/kg, 10 hr after subcutaneous injection of kaolin in the left metacarpal area. A hand‐held algometer was used to determine each piglet’s mechanical nociceptive threshold (MNT) from both front feet up to 50 hr after treatment (cut‐off value of 24.5 newton). Serial venous blood samples were obtained to quantify flunixin in plasma using LC‐MS/MS. A PKPD model describing the effect of flunixin on the mechanical nociceptive threshold was obtained based on an inhibitory indirect response model. A two‐compartmental PK model was used. A significant effect of flunixin was observed for both doses compared to control group, with 4.4 mg/kg showing the most relevant (6–10 newton) and long‐lasting effect (34 hr). The median IC50 was 6.78 and 2.63 mg/ml in groups MEDIUM and HIGH, respectively. The ED50 in this model was 6.6 mg/kg. Flunixin exhibited marked antinociceptive effect on kaolin‐induced inflammatory hyperalgesia in piglets.     

Pharmacokinetics of cefquinome in healthy and Pasteurella multocida‐infected rabbits

The pharmacokinetics of cefquinome were studied in healthy and Pasteurella multocida‐infected rabbits after a single intramuscular (IM) injection at 2 mg/kg of its sulfate salt. Twelve female New Zealand white rabbits (2.0–2.5 kg) were used; six of them served as controls, and the other six had been infected with P. multocida; the experiments were conducted 1–2 days after nasal inoculation of P. multocida when rabbits showed the signs of respiratory infection. Plasma concentrations of cefquinome were determined using high‐performance liquid chromatography. The values of elimination half‐life, area under the curve, area under the first moment curve, and mean residence time were significantly lower in infected rabbits (0.48 hr, 4.54 hr*μg/ml, 3.63 hr* hr*μg/ml and 0.8 hr, respectively) than healthy rabbits (0.72 hr, 9.11 hr*μg/ml, 9.85 hr* hr*μg/ml and 1.1 hr, respectively), whereas total body clearance was significantly higher in infected than healthy rabbits. Therefore, P. multocida infection caused significant changes in some of the pharmacokinetic parameters of cefquinome in rabbits. These pharmacokinetic changes may affect dose regimen when used in P. multocida‐infected rabbits.     

Single and multiple dose pharmacokinetics of a novel mirtazapine transdermal ointment in cats

Single and multiple dose pharmacokinetics (PK) of mirtazapine transdermal ointment applied to the inner ear pinna of cats were assessed. Study 1 was a randomized, cross‐over single dose study (n = 8). Cats were treated once with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner ear pinna (treatment) or administered orally (control) and then crossed over after washout. Plasma was collected predose and at specified intervals over 96 hr following dosing. Study 2 was a multiple dose study (n = 8). Cats were treated daily for 14 days with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner pinna. Plasma was collected on Day 13 predose and at specified intervals over 96 hr following the final dose. In Study 1, single transdermal administration of mirtazapine resulted in mean T_max = 15.9 hr, C_max = 21.5 ng/mL, AUC_0‐24 = 100 ng*hr/mL, AUC_0‐∞ = 260 ng*hr/mL and calculated half‐life = 26.8 hr. Single oral administration of mirtazapine resulted in mean T_max = 1.1 hr, C_max = 83.1 ng/mL, AUC_0‐24 = 377 ng*hr/mL, AUC_0‐∞ = 434 ng*hr/mL and calculated half‐life = 10.1 hr. Mean relative bioavailability (F) of transdermal to oral dosing was 64.9%. In Study 2, daily application of mirtazapine for 14 days resulted in mean T_max = 2.1 hr, C_max = 39.6 ng/mL, AUC_0‐24 = 400 ng*hr/mL, AUC_0‐∞ = 647 ng*hr/mL and calculated half‐life = 20.7 hr. Single and repeat topical doses of a novel mirtazapine transdermal ointment achieve measurable plasma concentrations in cats.     

CD117‐ and vimentin‐positive telocytes in the bovine teat sphincter

Mastitis is a common economically relevant problem in dairy farming. As the major entry for pathogens is the papillary duct, one of the first defence mechanisms is the teat sphincter. This sphincter shows a rhythmic contractility of yet unknown origin. Searching for possible modulatory pacemaker cells, teat sphincters of eight cows were stained immunohistochemically with antibodies against CD117 and vimentin and evaluated microscopically for the presence of telocytes. CD117‐ and vimentin‐positive telocytes with telopodes were found in close contact with smooth muscle cells. Our findings present a first evidence of telocytes in the teat of bovines.