A. Di Salvo

The disposition of enrofloxacin in seabream (Sparus aurata L.) after single intravenous injection or from medicated feed administration

Serum concentrations of enrofloxacin (EF) after intravenous (i.v.) or oral administration of single doses (2.5 and 10 mg/kg b.w., respectively) were investigated in seabream (Sparus aurata L.) kept in seawater at 25–27 °C. The tissue disposition of the drug was studied after oral administration. At prefixed time points, from 1 h to 5 days after administration, blood and edible tissues (muscle plus adherent skin) from 10 individuals in each group were collected and stored at −20 °C. Each serum and tissue sample was essayed for EF by HPLC after liquid–liquid extraction. Serum was also checked for the presence of the metabolite ciprofloxacin (CF). The quantification limits for EF were 0.010 μg/ml in serum and 0.015 μg/g in tissues. Following intravenous administration, considerably high serum concentrations of EF (range 2.605–3.810 μg/ml) were detected during the first 4 h. The concentrations decreased subsequently, indicating a first rapid distribution, followed by a slow phase of elimination. At the last time point of the experiment (120 h), there were still detectable amounts of EF in serum samples (range 0.040–0.087 μg/ml). Enrofloxacin levels of 0.335–1.138 μg/ml were reached in serum within 1 h after in feed administration. The maximum values were measured at 8 h (1.709–2.846 μg/ml), then slowly declined and were measurable (0.048–0.149 μg/ml) for up to 120 h. Compared to serum, lower concentrations of EF were determined in muscle plus skin: 0.156–0.398 μg/g after 1 h, 0.102–2.002 μg/g at 8 h and 0.015–0.031 μg/g at the last sample point. No CF was found in serum.

Seabream (Sparus aurata L.): disposition of amoxicillin after single intravenous or oral administration and multiple dose depletion studies

Abstract Single dose administration (trial 1): Serum and tissue concentrations of amoxicillin (AMX) were investigated in seabream ( Sparus aurata L.) kept in seawater at 22 °C and 32‰ of salinity. Amoxicillin was given intravenously (i.v.) at 40 mg/kg b.w. or orally (p.o.) at 80 mg/kg b.w. The serum concentrations were examined by using both radioimmunoassay-microbial receptor technology (Charm II test for β-lactams) and microbiological assay (spores of Bacillus stearothermophilus ATCC 10149); the tissue levels were determined by Charm II test. A slow clearance of AMX from serum was observed after i.v. administration, the concentrations at 72 h ranging from 0.94 to 0.66 μg/ml. Despite using the trihydrate form of amoxicillin, the apparent oral bioavailability was only 0.33%. Low levels were determined in muscle, skin and liver. Multiple dose administration (trial 2): A depletion kinetic study was conducted at water temperature of 22–26 °C after in feed administration (10 days) of AMX at the dose of 80 mg/kg b.w./day. AMX was only occasionally detected at very low concentrations in muscle, liver, skin, and vertebrae both during and after treatment cessation. Different formulations (conventional, micronized and microencapsulated AMX) were assayed in seabream at 24–26 °C after a 5-day period on medicated diet at the dose of 80 mg/kg b.w./day (trial 3) to verify if the nonconventional forms could improve the tissue distribution of AMX after in-feed administration. The results achieved in muscle and adherent skin were below the LOQ at each scheduled sampling time regardless of the formulation administered.

Evaluation of pharmacokinetic and pharmacodynamic properties of cimicoxib in fasted and fed horses

Abstract AIMS: To determine the pharmacokinetics of cimicoxib and to assess the inhibition of cyclooxygenase (COX) after a 5 mg/kg, single oral administration in horses that were fasted or fed. METHODS: The study was conducted using an open, single dose (5 mg/kg), two treatment (fasted and fed), two-period, crossover design with a 2-week interval between dosages. Six healthy mares received 5 mg/kg of cimicoxib via nasogastric tube after fasting for 12 hours, or 2 hours after feeding. After administration, blood samples were collected for up to 24 hours and plasma used for pharmacokinetic analysis. Additional serum and plasma samples were used to measure concentrations of thromboxane B2 (TXB2) and prostaglandin E2 (PGE2), to assess COX-1 and -2 inhibition, respectively. RESULTS: Following cimicoxib administration, the mean maximum plasma concentration was 0.16 (SD 0.01) µg/mL and 0.14 (SD 0.03) µg/mL in fasted and fed groups, respectively. The mean time taken to reach maximum plasma concentration was longer in the fed group (5.91 (SD 3.23) hours) compared with the fasted group (3.25 (SD 1.17) hours), but this difference was not significant (p=0.12). The mean maximal inhibition of TXB2 was 62.4 (SD 13.8)% and 54.6 (SD 15.4)%, and of PGE2 was 72.1 (SD 43.3)% and 68.5 (SD 24.4)%, in fasted and fed horses, respectively. CONCLUSION: In the present study, although the COX-2 selective action of cimicoxib was not apparent, a relatively low concentration of cimicoxib resulted in both COX-1 and -2 inhibition in horses. Further investigations are required to establish an optimal dosage regimen and safety profile before clinical trials are initiated.

Treatment of Chronic Atrial Fibrillation in the Horse with Flecainide: Personal Observation

Birettoni, F., Porciello, F., Rishniw, M., della Rocca, G., Di Salvo, A. and Sgorbini, M., 2007. Treatment of chronic atrial fibrillation in the horse with flecainide: Personal observation. Veterinary Research Communications, 31(Suppl. 1), 273–275

Pharmacokinetics and residue depletion of erythromycin in rainbow trout Oncorhynchus mykiss (Walbaum)

Erythromycin (ERY) is a drug active against Gram-positive bacteria such as Lactococcus garvieae, a pathogen responsible for an important disease that may cause a substantial decrease in rainbow trout Oncorhynchus mykiss (Walbaum) production, the species of fish most commonly produced in Italy. In the literature, studies on the kinetics behaviour of ERY in fish are limited. Therefore, the aim of the present study was to evaluate the pharmacokinetics of ERY in rainbow trout after a single oral treatment with 75 mg kg⁻¹ body weight (b.w.) of ERY and the residue depletion after multiple oral administration of 75 mg kg⁻¹ b.w. day⁻¹ of ERY for 10 days. Blood concentrations of ERY increased up to 20.24 ± 13.32 μg mL⁻¹ at 6 h, then decreased to 5.97 ± 3.89 μg mL⁻¹ at 24 h. The time during which the antibiotic remains in the bloodstream at concentrations exceeding the MIC (T > MIC) and the area under the serum concentration-time curve (AUC)/MIC are both pharmacokinetic-pharmacodynamic (PK/PD) predictors of ERY efficacy, and the data obtained allowed us to hypothesize that a dosage of 75 mg kg⁻¹ b.w. day⁻¹ of ERY could treat the lactococcosis in trout. Regarding the study of ERY depletion, rapid elimination was observed in tissue (muscle plus adherent skin); in fact the concentrations were below the limit of quantification in all samples (except two) by day 10 post-treatment. ERY is not licensed in Europe for use in aquaculture, and its use is possible only by off-label prescription with a precautionary withdrawal time of 500 degree-days, as established by Directive 2004/28/EC. From the data obtained in this study, a withdrawal time of 8.90 days was calculated, corresponding, in our experimental conditions, to 117.5 degree-days, a value significantly lower than that established by the European directive.

Pharmacokinetic profiles of meloxicam in turtles (Trachemys scripta scripta) after single oral, intracoelomic and intramuscular administrations

Meloxicam is an anti-inflammatory and analgesic drug used to treat many pathological conditions in turtles. With the aim to fill the lack of data about its pharmacokinetic in this species, eighteen turtles (Trachemys scripta scripta) were divided in three groups and treated with a single dose of meloxicam (0.2 mg/kg) by intramuscular, intracoelomic and oral route, respectively. At scheduled time points, blood samples were collected and meloxicam concentrations were determined by HPLC. Pharmacokinetic parameters were calculated from the obtained concentration-time curves. After intramuscular treatment, a plasma peak of meloxicam equal to 1590.03 ± 1845.32 ng/mL (mean ± SD) and a Tmax of 1.17 ± 0.45 h were reached, indicating a quick absorption of the drug. The intracoelomic administration brought to the largest AUC (12621.04 ± 6203.79 h*ng/mL) and to a Cmax and a Tmax equal to 1154.52 ± 662.78 ng/mL and 2.82 ± 1.39 h, respectively. Following oral treatment, the plasma concentrations of meloxicam were very low indicating a scarce absorption. Further studies are warranted to determine the effective plasma concentration of meloxicam in turtles and, consequently, the dosage regimen.

Intra-articular administration of lidocaine plus adrenaline in dogs: Pharmacokinetic profile and evaluation of toxicity in vivo and in vitro

The aim of this study was to evaluate the safety of intra-articular (IA) lidocaine plus adrenaline for improving peri-operative analgesia in anaesthetized dogs undergoing arthroscopy of the elbow. A solution of lidocaine (L) 1.98% plus adrenaline 1:100.000 was administered via the IA route and its safety evaluated in terms of cardio-, neuro-, and chondro-toxicity. No bradycardia or hypotension was recorded from induction to the last observational time point. Signs of toxicity of the nervous system could have been masked by the general anaesthesia but lidocaine concentrations detected in the blood were lower than those thought to be capable of producing toxicity. The assessment of in vitro chondrotoxicity showed a dose- and time-dependent effect of lidocaine on the viability of articular cells. Adrenaline appeared to reduce the chondrotoxicity of 1% lidocaine, following an exposure of up to 30 min.

Pharmacokinetics and antinociceptive effects of tramadol and its metabolite O-desmethyltramadol following intravenous administration in sheep

Although sheep are widely used as an experimental model for various surgical procedures there is a paucity of data on the pharmacokinetics and efficacy of analgesic drugs in this species. The aims of this study were to investigate the pharmacokinetics of intravenously (IV) administered tramadol and its active metabolite O-desmethyltramadol (M1) and to assess the mechanical antinociceptive effects in sheep. In a prospective, randomized, blinded study, six healthy adult sheep were given 4 and 6 mg/kg tramadol and saline IV in a cross-over design with a 2-week wash-out period. At predetermined time points blood samples were collected and physiological parameters and mechanical nociceptive threshold (MNT) values were recorded. The analytical determination of tramadol and M1 was performed using high performance liquid chromatography. Pharmacokinetic parameters fitted a two- and a non-compartmental model for tramadol and M1, respectively. Normally distributed data were analysed by a repeated mixed linear model. Plasma concentration vs. time profiles of tramadol and M1 were similar after the two doses. Tramadol and M1 plasma levels decreased rapidly in the systemic circulation, with both undetectable after 6 h following drug administration. Physiological parameters did not differ between groups; MNT values were not statistically significant between groups at any time point. It was concluded that although tramadol and M1 concentrations in plasma were above the human minimum analgesic concentration after both treatments, no mechanical antinociceptive effects of tramadol were reported. Further studies are warranted to assess the analgesic efficacy of tramadol in sheep.

Intra-articular administration of lidocaine in anaesthetized dogs: pharmacokinetic profile and safety on cardiovascular and nervous systems

The intra-articular administration of lidocaine is a frequent practice in human orthopaedic surgical procedures, but an eventual absorption of the drug into the bloodstream can lead to toxicity, mainly concerning the central nervous system and the cardiovascular systems. The purpose of this study was to determine the pharmacokinetic profile and the safety, in terms of cardiovascular and CNS toxicity, of lidocaine after intra-articular administration to anesthetized dogs undergoing arthroscopy. Lidocaine 2% was administered to eight dogs before surgery in differing amounts, depending on the volume of the joints involved, and blood samples were taken at predetermined time points. The maximum serum concentration of lidocaine ranged from 0.50 to 3.01 μg/mL (mean ± SD: 2.18 ± 0.91 μg/mL), and the time to reach it was 28.75 ± 15.74 min. No signs of cardiac toxicity were detected during the entire procedure, and possible signs of CNS toxicity were masked by the anaesthesia. However, concentrations reported in literature as responsible for neurotoxicity in dog were achieved in three of eight investigated subjects. Pending further studies, veterinarians should consider the possibility of side effects occurring following the intra-articular administration of local anaesthetics.

Naproxen in the horse: pharmacokinetics and side effects in the elderly.

It is well-known that old animals show physiologic and/or pathologic variation that could modify the pharmacokinetics of drugs and the related pharmacodynamic response. In order to define the most appropriate therapeutic protocol in old horses, pharmacokinetic profile and safety of naproxen were investigated in horses aged over 18 years after oral administration for 5 days at the dose of 10 mg/kg b.w./day. After the first administration, the maximum concentration (Cmax 44.21 ± 9.21 μg/mL) was reached at 2.5 ± 0.58 h post-treatment, the harmonic mean terminal half-life was 6.96 ± 1.73 h, AUC0-24h was 459.71 ± 69.95 h μg/mL, MRT was 7.44 ± 0.74 h and protein binding was 98.47 ± 2.72%. No drug accumulation occurred with repeated administrations. No clinical and laboratory changes were detected after administration of naproxen. Gastric endoscopies performed after the treatment did not show pathological changes of the gastric mucosa.