C. Kowalski

Pharmacokinetic evaluation of tramadol and its major metabolites after single oral sustained tablet administration in the dog: a pilot study.

The study evaluated the pharmacokinetics of tramadol and its major metabolites O-desmethyltramadol (M1), N-desmethyltramadol (M2) and N-O didesmethyltramadol (M5) following a single oral administration of a sustained release (SR) 100mg tablet to dogs. Plasma tramadol concentration was greater than the limit of quantification (LOQ) in three dogs, M1 was quantified only in one dog while M2 and M5 were quantified in all of the dogs. The median values of C(max) (maximum plasma concentration), T(max) (time to maximum plasma concentration) and T(1/2) (half-life) for tramadol were 0.04 (0.17-0.02)mirog mL(-1), 3 (4-2) and 1.88 (2.211-1.435)h, respectively. M5 showed median values of C(max), T(max) and T(1/2) of 0.1 (0.19-0.09)microg mL(-1), 2 (3-1) and 4.230 (6.583-1.847)h, respectively. M2 showed median values of C(max), T(max) and T(1/2) of 0.22 (0.330-0.080)microg mL(-1), 4 (7-3) and 4.487 (6.395-1.563)h, respectively. The findings suggest that the SR formulation of tramadol may not have suitable pharmacokinetic characteristics to be administered once-a-day as an effective and safe treatment for pain in the dog.

Biopharmaceutical profile of tramadol in the dog

Biopharmaceutical profile of tramadol in the dog M. Giorgi & S. Del Carlo & G. Saccomanni & B. Łebkowska-Wieruszewska & V. Turini & C. Kowalski Published online: 8 July 2009 # Springer Science + Business Media B.V. 2009

Pharmacokinetic profiles of the novel COX-2 selective inhibitor cimicoxib in dogs

Cimicoxib (CX) is a novel imidazole derivative that is a cyclo-oxygenase (COX)-2 selective non-steroidal anti-inflammatory drug and the latest COX-2 selective inhibitor to be released for veterinary use. Currently there is limited information available on the pharmacokinetic (PK) properties of CX. The aim of the current study was to evaluate the PK features of CX after administration of the recommended dose and after administration of a more variable dose rate in the form of the commercially available tablet. In addition, the effects of food intake on the PK properties were also evaluated. In the first study, five healthy Beagle dogs received 2mg/kg CX via the oral route following a period of fasting. The second study was conducted using six healthy Labrador retriever dogs which each received an 80 mg tablet (approximate dose 1.95-2.5mg/kg) using a crossover design, both in the fasted and fed condition. The plasma concentrations of CX were detected by a validated HPLC method. No adverse effects were observed in any dogs during the experiment. The results from the PK analysis were similar between the studies, regardless of precision of dose and fasted and fed conditions. The mean peak concentration of CX was 0.49 and 0.43 μg/mL under fasted and fed conditions, respectively. The mean half-life was about 3h after all treatments. In addition, simulated multiple dosing data revealed that time over minimal effective concentration was similar after 1.95, 2.0 and 2.5mg/kg dose administrations. These findings suggest that slight variation from the recommended dose should not alter the therapeutic outcome. In addition, CX can be administered to fed dogs without significantly affecting blood levels.

Pharmacokinetic profiles of the analgesic drug flupirtine in cats

Flupirtine (FLU) is a non-opioid analgesic drug with no antipyretic or antiphlogistic effects, used in the treatment of a wide range of pain states in human beings. There is a substantial body of evidence on the efficacy of FLU in humans but this is inadequate to recommend its off-label use in veterinary clinical practice. The aim of this study was to evaluate the pharmacokinetic profiles of FLU after IV and PO administration in healthy cats. Six mixed breed adult cats were randomly assigned to two treatment groups using an open, single-dose, two-treatment, two-phase, paired, cross-over design (2 × 2 Latin-square). Group 1 (n  =  3) received a single dose of 5 mg/kg of FLU injected IV into the jugular vein. Group 2 (n  =  3) received the same dose via PO route. The wash out period was 1 week. Blood samples (1 mL) were collected at assigned times and plasma was then analysed by a validated HPLC method. No adverse effects at the point of injection and no behavioural changes or alterations in health parameters were observed in the animals during or after the study (up to 7 days after the full study). After IV administration, FLU was detectable in plasma up to 36 h. After PO administration, FLU plasma concentrations were lower than those following IV administration, but they were detectable over the same time range. The terminal part of both mean pharmacokinetic curves showed a similar trend of elimination. The oral bioavailability was approximately 40%. This is the first study of FLU in an animal species of veterinary interest and it could pave the way for the use of this active ingredient in the veterinary field.

Withdrawal of amoxicillin and penicillin G procaine from milk after intramammary administration in dairy cows with mastitis

Abstract Introduction: There are many veterinary products containing β-lactam antibiotics which are used for mastitis treatment in cows. The aim of the study was to determine whether mastitis could have any effect on amoxicillin (AMX) or penicillin G procaine (PEN) withdrawal period from milk, in the context of current maximum residue limits established by the European Commission. Material and Methods: The study was conducted on 17 dairy Black and White cows with clinical mastitis during the lactation period. The first group (n = 8) received 200 mg of amoxicillin (AMX), whereas the second group (n = 9) received 200,000 IU/mg of penicillin G procaine (PEN) by intramammary administration. For the measurement of AMX and PEN concentrations in milk, the liquid chromatography tandem mass spectrometry method was applied. Pharmacokinetic calculations were performed using Phoenix WinNonlin 6.4 software. Results: The determined AMX and PEN half-life values in the mammary gland suggest that the drug withdrawal is at a level of 99.9% within 81 h (≈3.5 days) and 116 h (≈5 days) after administration of AMX and PEN, respectively. The present research indicates that, at 60 h after administration, the average PEN concentration in the milk from cows with clinical signs of mastitis may still reach 4.96 g/kg and that of AMX can even be 6.92 g/kg. Conclusion: The results obtained confirm that, in mastitis cases, a 72-h withdrawal period is sufficient for elimination of AMX to a lower level than the established maximum residue limit (MRL) values. However, in the case of PEN, at 69 h after administration, the drug concentration may be close to that of the determined MRL.

Pharmacokinetic - pharmacodynamic model and ampicillin residue depletion after intramammary administration in cows

Abstract Introduction: The objective of this study was to describe a pharmacokinetic–pharmacodynamic (PK/PD) approach for determination of a rational dosage of ampicillin (AMP) and depletion of the antibiotic residues in milk after intramammary administration to cows. Material and Methods: The cows came from different farms from the Lublin Province area. They (n = 9) received 5 g of the drug, containing 75 mg of AMP sodium in physiological solution, through a syringe tube by intramammary administration. Following single intramammary administration, the milk samples (5 mL) were collected after 2, 4, 6, 8, 10, 24, 36, 48, and 60 h. The liquid chromatography-mass spectrometry analysis was performed on the Agilent 1200 system connected to an AB Sciex API 4000™ mass spectrometer. The pharmacokinetic analysis of the concentrations of the antibiotic in milk was performed using software Phoenix® WinNonlin® 6.4. Calculations were made in non-compartmental (slopes, highest, amounts, and moments) and compartmental analysis. Results: The pharmacokinetic characteristics of AMP after intramammary administration indicate rapid elimination of the drug from milk. The mean residence time had a several-fold lower value than the designated elimination half-life and amounts to only 3.4 h. The concentration of the drug in the milk dropped relatively quickly and the process was very dynamic. Conclusion: The conducted research confirms the rationale of using the PK/PD model in order to verify the dosing regimen for other antibiotic groups and various indicators of the applied PK/PD model.

Quercetin decrease somatic cells count in mastitis of dairy cows

Quercetin is a dietary flavonoid which has an effect on inflammation, angiogenesis and vascular inflammation. In several other flavonoids (e.g. kaempferol, astragalin, alpinetin, baicalein, indirubin), anti-inflammatory mechanism was proven by using mice mastitis model. The aim of the current study was pilot analysis of quercetin tolerability and its impact on somatic cells count (SCC) after multiple intramammary treatment on dairy cows with clinical mastitis. Based on SCC and clinical investigation, 9 dairy cows with clinical mastitis of one quarter were selected for the pilot study. Baseline analysis (hematology, TNFα, SCC) was performed every 24h among all cows three days before the first dose (B1-B3). After the baseline monitoring (B1-B3) eight days treatment (D1-D8) was performed with a high and low dose. Selected blood parameters were analyzed. Starting from D1 to D8, a decrease of SCC in relation to baseline was characterized by declining trend. The presented results allowed the confirmation of the significant influence of quercetin on the reduction of SCC in mastitis in dairy cows after 8days of therapy.

Withdrawal of cefoperazone with milk after intramammary administration in dairy cows – prospective and retrospective analysis

The aim of the study was to carry out retrospective and prospective comparative analyses of the pharmacokinetics of CEF after single intramammary (IMM) administration in cows. The prospective study (study A) was conducted on 9 dairy cows of the Polish Black-White race with clinical mastitis during the lactation period. Milk samples were collected at 2, 4, 6, 8, 10, 24, 36, 48, 72 and 84 h after single IMM administration of 250 mg of CEF to one quarter. Drug concentrations in milk samples were determined by HPLC-MS/MS technique and the results of the pharmacokinetic analysis were compared to those obtained in previous studies based on the microbiological (study B) and HPLC-UV methods (study C and D). Pharmacokinetic parameters were calculated based on adapted two-compartment model of drug distribution. One of the findings of the comparison of the analysed investigations is that the CEF kinetics determined with the microbiological method is consistent with the results obtained by the authors of this paper. Both studies yielded similar results of the key pharmacokinetic parameters related to the level of the drug distribution to tissues and elimination half-life. In the pharmacodynamic analysis, the observations in all four studies were entirely consistent and have shown lower values of T>MIC90 in healthy animals and significantly higher values in infected dairy cows. The comparison of studies A, B, C, and D revealed that the time of complete CEF wash-out of 90.90% varied and amounted to 5.7, 8.0, 2.2, and 2.2 days after administration of the drug, respectively. It was confirmed that not only the type of the analytical method but also correct sampling have a significant impact on determination of the correct value of the drug half-life after IMM administration. The comparative analysis of studies in which the milk yield was high and low allows a conclusion that this parameter in the case of CEF has no significant effect on T>MIC90.

Activity of β-lactam antibiotics against certain microorganisms which cause mastitis in cows

Abstract Introduction: The objective of this study was to determine the current profile of bacteria responsible for the infection of the mammary gland and to assess their sensitivity to selected β-lactam antibiotics. Material and Methods: The study was conducted on 119 (n = 119) dairy cows of the Polish Black-White breed aged 4 to 10 years with inflammation of the mammary gland. The cows came from different farms: smallholder farms and large dairy cattle farms in the Lublin and Bialystok Provinces. Before the process of collection of milk samples, the teats were cleaned and immersed in a liquid disinfectant. The first streams were collected into containers which were subsequently utilised. Afterwards, 2-4 mL of milk or secretions was milked into sterile disposable tubes. The milk samples were collected into plastic bottles and kept in a cooler with ice until transportation to the laboratory. Tests of resistance to β-lactam antibiotics were performed by disc diffusion. Results: Contagious and environmental bacteria were isolated from all dairy barns. In the group of contagious bacteria, the presence of typical pathogens responsible for the mammary gland infections, i.e. Staph. aureus, Str. agalactiae, and C. bovis, was detected. A relatively broad group of the isolates was formed by environmental bacteria responsible for inflammation of the mammary gland: Str. dysgalactiae, Str. uberis, Staph. chromogenes, Staph. hyicus, Staph. warneri, and E. coli. Among the environmental organisms, streptococci constituted the largest percentage (23%), followed by staphylococci (13.2%), and E. coli (8.8%). The largest group of infectious pathogens comprised Str. agalactiae (29.6%) and Staph. aureus (20.8%). Conclusion: Our investigation of the current profile of the isolates responsible for mastitis in the Lublin and Bialystok Provinces showed that environmental bacteria are the major cause of the disease. In view of the substantially varying degrees of sensitivity of the microorganisms isolated from cases of mastitis to β-lactam antibiotics, each therapeutic treatment should be preceded by susceptibility testing.