Evaluation and optimisation of propofol pharmacokinetic parameters in cats for target-controlled infusion.

The aim of this study was to develop and evaluate a pharmacokinetic model-driven infusion of propofol in premedicated cats. In a first step, propofol (10 mg/kg) was administered intravenously over 60 seconds to induce anaesthesia for the elective neutering of seven healthy cats, premedicated intramuscularly with 0.3 mg/kg methadone, 0.01 mg/kg medetomidine and 2 mg/kg ketamine. Venous blood samples were collected over 240 minutes, and propofol concentrations were measured via a validated high-performance liquid chromatography assay. Selected pharmacokinetic parameters, determined by a three-compartment open linear model, were entered into a computer-controlled infusion pump (target-controlled infusion-1 (TCI-1)). In a second step, TCI-1 was used to induce and maintain general anaesthesia in nine cats undergoing neutering. Predicted and measured plasma concentrations of propofol were compared at specific time points. In a third step, the pharmacokinetic parameters were modified according to the results from the use of TCI-1 and were evaluated again in six cats. For this TCI-2 group, the median values of median performance error and median absolute performance error were -1.85 per cent and 29.67 per cent, respectively, indicating that it performed adequately. Neither hypotension nor respiratory depression was observed during TCI-1 and TCI-2. Mean anaesthesia time and time to extubation in the TCI-2 group were 73.90 (±20.29) and 8.04 (±5.46) minutes, respectively.

Pharmacokinetics of intravenous ketorolac in cats undergoing gonadectomy.

AIM: To determine the pharmacokinetics of ketorolac tromethamine (0.5 mg/kg) when administered I/V to cats undergoing gonadectomy. METHODS: Ketorolac was administered to nine female and three male shorthair domestic cats as an I/V bolus of 0.5 mg/kg after intubation, and 20 minutes prior to ovariectomy or orchiectomy. Intra-operative cardiorespiratory variables were monitored and blood samples were collected over 24 hours. Concentrations of ketorolac in serum were determined by high-performance liquid chromatography to establish pharmacokinetic parameters. RESULTS: During surgery, mean end tidal isoflurane concentration was 1.63 (SD 0.24)% and normocapnia and spontaneous ventilation were maintained in all animals. The kinetics of ketorolac was described by a two-compartment model. The distribution and elimination half-lives were 0.09 (SD 0.06) and 4.14 (SD 1.18) hours, respectively. The body clearance was 56.8 (SD 33.1) mL/h/kg. The volume of distribution at steady-state and the mean residence time were 323.9 (SD 115.7) mL/kg and 6.47 (SD 2.86) hours, respectively. CONCLUSION AND CLINICAL RELEVANCE: On the basis of the results, concentrations of ketorolac in serum in cats were above the human effective concentrations for 5-6 hours postoperatively. However, other studies including a control group are advocated to further investigate the ketorolac kinetics and the analgesic efficacy in this species.

Clinical pharmacokinetics of tramadol and main metabolites in horses undergoing orchiectomy.

BACKGROUND: Tramadol is a synthetic codeine analogue used as an analgesic in human and veterinary medicine. It is not approved for use in horses, but could represent a valid tool for pain treatment in this species. OBJECTIVES: The serum pharmacokinetic profile and urinary excretion of tramadol and its metabolites (O-desmethyltramadol [M1], N-desmethyltramadol [M2] and N,O-desmethyltramadol [M5]) was investigated in a multidrug anaesthetic and analgesic approach for orchiectomy in horses. The evaluation of the degree of cardiovascular stability, the intraoperative effect and postoperative analgesia obtained by the visual analogue scale are also reported. Animal and methods: Tramadol (4 mg/kg BW) was administered intravenously to eight male yearlings as a bolus over 60 seconds, 5 min after intubation and 15 min prior to surgery. Drug quantification was performed in serum and urine for tramadol, M1, M2 and M5 by high-performance liquid chromatography with fluorimetric detection. RESULTS: Mean tramadol concentration was 14.87 ± 11.14 µg/mL at 0.08 h, and 0.05 ± 0.06 µg/mL at 10 h. Serum concentrations of M1 and M2 metabolites were quite limited. For M1 and M2, median maximum concentration (Cmax) and time to achieve maximum concentration (Tmax) were 0.05 µg/mL and 0.75 h, and 0.08 µg/mL and 2 h, respectively; M5 was never detected. In urine, tramadol was the most recovered compound, followed by M1, M2 and M5. CONCLUSIONS AND CLINICAL RELEVANCE: Showing no adverse events and based on the kinetic behaviour, pre-operative tramadol IV at a dose of 4 mg/kg BW might be useful and safe as analgesic in horses undergoing surgery.

Pharmacokinetics in foremilk and antimicrobial activity of cephapirin following intramammary administration in healthy and Staphylococcus aureus-infected cows.

AIM: To evaluate the kinetic profile of cephapirin and detect differences in its milk disposition following intramammary administration in healthy, and subclinically Staphylococcus aureus infected, quarters of lactating cows, to assess the minimum inhibitory concentration (MIC) of cephapirin for Staph. aureus field isolates, and to calculate the time during which drug concentrations were above the MIC (T>MIC). METHODS: Five healthy and five Staph. aureus-infected lactating cows received cephapirin at 275 mg/quarter, twice at 12-hour intervals. Foremilk samples were manually collected from individual quarters before treatments and 2, 8, 12 hours after the last drug administration, and then every 12 hours until the tenth milking. Concentrations of cephapirin and desacetyl-cephapirin were measured in milk samples after solid phase extraction and high-performance liquid chromatography analysis. A non-compartmental model was applied to data to obtain pharmacokinetic results. Eleven Staph. aureus isolates from the study-infected quarters and 30 additional isolates from cows in another two farms in the same area were used to determine MIC for cephapirin using the microdilution broth method. RESULTS: Mean maximum drug concentrations were higher in milk from healthy quarters (1334.8 (SD 1322.7) µg/mL) than in the infected ones (234.7 (SD 141.4) µg/mL), but the elimination half-life was longer in the infected (4.8 (SD 1.9) hours) than uninfected (3.3 (SD 0.33) hours) quarters (p<0.05). Mean residence time was comparable in healthy and infected quarters (approximately 8 hours). The amounts of desacetyl-cephapirin recovered in the samples were very low (below 2%). The MIC90 for all field strains of Staph. aureus (n=41) was 0.25 µg/mL. The calculated T>MIC90 was 38 (SD 13), 27 (SD 11) and 35 (SD 8) hours after last treatment in healthy, suspected and infected quarters, respectively. CONCLUSION AND CLINICAL RELEVANCE: The intramammary administration of sodium cephapirin at 275 mg/quarter, twice every 12 hours in lactating cows resulted in higher drug concentrations in milk of quarters with no infection than in the subclinically infected ones. These concentrations were above the MIC90 for 35 hours in infected cows. According to these results intramammary administration of cephapirin at 12-hour intervals during lactation should be potentially effective against Staph. aureus infection, but studies of clinical efficacy are necessary for confirmation.

Pharmacokinetics and perioperative efficacy of intravenous ketorolac in dogs.

Ketorolac (KET) is a nonsteroidal anti-inflammatory drug approved for the use in humans that possesses a potent analgesic activity, comparable to morphine, and could represent a useful tool to control acute pain also in animals. The clinical efficacy and pharmacokinetic profile of intravenous (IV) ketorolac tromethamine (0.5 mg/kg) were studied in 15 dogs undergoing gonadectomy. Intra-operative cardiorespiratory variables were monitored, and post-operative pain was assessed using a subjective pain score (0-24) in all dogs, whereas the pharmacokinetic profile of the drug was determined in 10 animals. During surgery, mean minimal alveolar concentration of isoflurane was 1.69 ± 0.11%, and normocapnia and spontaneous ventilation were maintained in all animals. During pain assessment, no significant differences between males and females were found, and in no case rescue analgesia was necessary. No adverse effects were reported. Serum samples were purified by solid-phase extraction and analysed by HPLC with UV-Vis detection. A large variability was observed in serum concentrations. The kinetics of ketorolac was described by a noncompartmental analysis. The elimination half-life (t½λz ) and ClB were 10.95 ± 7.06 h and 92.66 ± 84.49 mL/h/kg, respectively, and Vdss and Vz were 1030.09 ± 620.50 mL/kg and 1512.25 ± 799.13 mL/kg, respectively. AUC(0→last) and MRT(0→last) were 6.08 ± 3.28 h × µg/mL and 5.59 ± 2.12 h, respectively. The results indicate that ketorolac possess good post-operative analgesic effects until about 6 h after administration in dogs undergoing moderately painful surgery.

Pharmacokinetics of ketamine and propofol combination administered as ketofol via continuous infusion in cats.

The pharmacokinetics of the extemporaneous combination of low doses of ketamine and propofol, known as 'ketofol', frequently used for emergency procedures in humans to achieve safe sedation and analgesia was studied in cats. The study was performed to assess propofol, ketamine and norketamine kinetics in six female cats that received ketamine and propofol (1:1 ratio) as a loading dose (2 mg/kg each, IV) followed by a continuous infusion (10 mg/kg/h each, IV, 25 min of length). Blood samples were collected during the infusion period and up to 24 h afterwards. Drug quantification was achieved by HPLC analysis using UV-visible detection for ketamine and fluorimetric detection for propofol. The pharmacokinetic parameters were deduced by a two-compartment bolus plus infusion model for propofol and ketamine and a monocompartmental model for norketamine. Additional data were derived by a noncompartmental analysis. Propofol and ketamine were quantifiable in most animals until 24 and 8 h after the end of infusion, respectively. Propofol showed a long elimination half-life (t(1/2λ2) 7.55 ± 9.86 h), whereas ketamine was characterized by shorter half-life (t(1/2λ2) 4 ± 3.4 h) owing to its rapid biotransformation into norketamine. The clinical significance of propofol's long elimination half-life and low clearance is negligible when the drug is administered as short-term and low-dosage infusion. The concurrent administration of ketamine and propofol in cats did not produce adverse effects although it was not possible to exclude interference in the metabolism.

Cefquinome sulfate behavior after intramammary administration in healthy and infected cows.

Maintenance of adequate drug concentration at the site of infection is an important problem in mastitis antibiotic therapy, and the efficacy of intramammary ß-lactams can be optimized by maintaining the drug concentration at the site of infection above the minimum inhibitory concentration (MIC) as long as possible. The most important pharmacokinetic and pharmacodynamic parameter for efficacy evaluation is time during which drug concentrations exceed the MIC (t>MIC). In this study, we assessed the pharmacokinetic profile of cefquinome (CFQ) after repeated intramammary administration in healthy cows and cows subclinically infected with Staphylococcus aureus as well as the MIC of Staph. aureus field strains. In addition, the degree of drug passage was investigated from udder to bloodstream by measuring systemic drug absorption in healthy and infected animals. Cefquinome concentrations were quantified by HPLC (UV-visible detection) in milk samples collected from quarters and from blood serum samples. The systemic drug absorption was negligible in healthy and subclinically infected animals (maximum concentration 0.09±0.02 and 0.1±0.01 µg/mL in healthy and subclinically infected animals, respectively). The MIC(90) value for CFQ in Staph. aureus field strains (n=20) was 0.24 µg/mL. The pharmacokinetic and pharmacodynamic evaluation, determined by t>MIC, showed an equal persistence of CFQ in all quarters, indicating an equivalent activity of the drug regardless of the pathological status of the udder. Moreover, with literature data regarding CFQ MIC, the t>MIC has been calculated for other bacterial species.

Pharmacokinetics, intraoperative effect and postoperative analgesia of tramadol in cats.

Tramadol is a synthetic codeine analogue used as an analgesic in human and veterinary medicine, but not approved for use in cats. Tramadol (2 mg/kg) was administered intravenously (IV) as preoperative analgesic in 12 cats (6 males) undergoing surgical gonadectomy. The pharmacokinetic profile of the drug and its O-desmethyl metabolite were determined in 8 animals (4 males), while intraoperative effects and postoperative analgesia, estimated by subjective pain score (0-24), were evaluated in all. Mean intraoperative isoflurane consumption was reduced, but hypoventilation was not observed. Sex-related differences were not observed, particularly in terms of postoperative analgesia: rescue analgesic was never administered. Concentrations of the active O-desmethyl metabolite were persistently high in all the animals. Considering the results obtained in this study, tramadol, at the dose of 2 mg/kg IV, did not produce any evident intraoperative cardiorespiratory side effects and with additional investigation may prove to be an appropriate intraoperative analgesic in cats undergoing gonadectomy.

Cefoperazone sodium preparation behavior after intramammary administration in healthy and infected cows.

Selection of the antimicrobial agent and maintenance of adequate drug concentrations at the site of infection are the most relevant problems in mastitis antibiotic therapy. Intramammary drug efficacy can be maximized by keeping drug concentrations at the site of infection above the minimum inhibitory concentration (MIC) as long as possible; the most important pharmacokinetic and pharmacodynamic (PK/PD) measure for efficacy evaluation is time during which drug concentrations exceed the MIC (t>MIC). To evaluate this measure, the PK profile of cefoperazone (CFP) after single intramammary administration in healthy and subclinical infected Staphylococcus aureus cows and the MIC of Staph. aureus field strains were assessed. In addition, the degree of drug passage from udder to bloodstream was investigated by measuring systemic drug absorption in healthy and infected animals. Cefoperazone concentrations were quantified by HPLC in quarter milk samples and blood serum samples. Systemic drug absorption was negligible in healthy animals (0.020+/-0.006 microg/mL serum at 4 h), whereas it was higher in infected animals (0.102+/-0.079 microg/mL at 4h and 0.025 microg/mL at 24 h), probably due to the damage of epithelial cell junctions caused by subclinical infections. The MIC90 value for CFP in Staph. aureus field strains (n=24) was 0.64 microg/mL. The PK/PD evaluation, determined by t>MIC, showed a longer persistence of CFP in infected quarters than in healthy ones (mean residence time was 8.37+/-1.51 vs. 11.42+/-5.74 h in September and 2.07+/-0.43 vs. 3.31+/-0.91 h in October), with a t>MIC of 45+/-6 h for infected quarters versus 38+/-5 h for healthy quarters different only in October. This could mean a prolonged time in which microorganisms are exposed to drug activity and thus, a greater efficacy of the drug.

Oral and intravenous administration of nimesulide in the horse: rational dosage regimen from pharmacokinetic and pharmacodynamic data.

REASONS FOR PERFORMING STUDY: The selective COX-2-inhibitor nimesulide is used extra-label in equine veterinary practice as an anti-inflammatory agent. However, there are no data on which to base the rational use of the drug in this species. OBJECTIVES: To determine the effective COX selectivity of nimesulide in the horse, and suggest a suitable dosing schedule. METHODS: The pharmacokinetics of nimesulide in the horse after oral administration (1 mg/kg bwt), and oral and i.v. administration (1.5 mg/kg bwt) were investigated, effects of feeding status on bioavailability determined, and plasma protein binding of the drug and its principal metabolites measured. Compartmental and noncompartmental pharmacokinetic analyses were performed. The plasma concentration-time profile was used, together with in vitro literature data on nimesulide inhibition of COX isoforms, to determine the effective COX selectivity of nimesulide in the horse, and suggest a suitable dosing schedule. RESULTS AND CONCLUSIONS: The findings suggest that 1.5 mg/kg bwt may produce adequate clinical effects, and the dosing interval should be 12-24 h depending on condition severity. However, at that dose, the concentration in the animal exceeds the in vitro IC50 for both isoforms, so that COX-1/COX-2 selectivity is lost and side-effects due to COX-1 inhibition are a possibility. Nimesulide should therefore be used with caution in equine clinical practice.

Early transoesophageal echocardiography in cryptogenic and lacunar stroke and transient ischaemic attack.

OBJECTIVES: To test the hypothesis that transoesophageal echocardiography (TOE) carried out within three days of a first stroke or transient ischaemic attack of cryptogenic or lacunar type may disclose more thrombi or spontaneous echo contrast (SEC) than previously reported. This finding may help early treatment decisions. METHODS: Patients aged between 40 and 80 years, admitted for transient ischaemic attack or ischaemic stroke during a 40 month period, were prospectively considered. TOE was carried out within 72 hours of symptom onset with a 5 MHz biplanar transducer. Subjects with recurring events, very severe strokes, large artery obstructions, or obvious cardiac sources of embolism were excluded. RESULTS: Sixty five patients were studied, 43 with a cryptogenic stroke or transient ischaemic attack (66.2%), and 22 with a lacunar stroke (33.8%). The mean (SD) interval between symptom onset and TOE was 43.4 (17.2) hours for cryptogenic, and 48.5 (19.5) hours for lacunar patients. Atrial thrombi were found in one patient with a cryptogenic stroke (2.32% of cryptogenic events; 95% confidence interval 0.06-12.29), whereas SEC was found in five patients (7.7% overall), two with a lacunar and three with a cryptogenic stroke. CONCLUSIONS: An early TOE does not seem to increase substantially the detection of atrial thrombi or SEC in patients with a first stroke or transient ischaemic attack of cryptogenic or lacunar nature. Therefore, this examination can be carried out when the patients' conditions are stable, and without overloading the cardiovascular laboratory daily schedule.

[Situs ambiguus and atrial isomerism. Angiographic analysis of associated congenital heart diseases]. / Situs ambiguus e isomerismo atriale. Analisi angiografica delle cardiopatie congenite associate.

Forty-seven cases of situs ambiguus have been analyzed angiographically: 24 had right atrial isomerism and 23 left atrial isomerism. The following criteria were considered for identification: auricular morphology; inferior vena cava: azygos continuation or connection in median position to the atrial cavity; bronchial anatomy; anatomy of the pulmonary arteries and their relation to the bronchi. In the group with right atrial isomerism we observed levocardia in 15 cases, dextrocardia in 7 and mesocardia in 2. Bilateral superior vena cava was identified in 13 cases. Inferior vena cava drained in most cases (21) in the middle portion of the atrial cavity; it was on the same side of the abdominal aorta in 20 cases. Pulmonary venous drainage was visualized in 19 patients: in 8 cases it followed the usual pattern of the total anomalous drainage, supracardiac (7) or infracardiac (1); in 2 cases mixed forms were found; in 9 cases the pulmonary veins entered directly the common atrial cavity. Common atrium was seen in 80% of the cases; in the remaining a huge atrial septal defect was present. The atrioventricular connection was double inlet in the 16 cases of univentricular heart; in all of them, and in additional 7 biventricular hearts, the mode was via a common atrio-ventricular valve; only in one case the atria connected to the ventricles through two distinct atrioventricular valves. The univentricular hearts in most cases (22) were, angiographically, of indeterminate type. The interventricular relationship was normal (left ventricle posterior and to the left) in 6 of the 8 biventricular hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Double outlet right ventricle with atrioventricular discordance. Report on cases having situs solitus, dextrocardia, pulmonary stenosis and levomalposition of the aorta.

We describe six patients with situs solitus of viscera and atria, dextrocardia, atrioventricular discordance, ventricular septal defect, double outlet from the morphological right ventricle, pulmonic stenosis and levomalposition of the aorta. Four patients were male and two female; their age ranged from 3.5 to 31 years (mean 13.8 years). All had various degrees of disability, and presented with cyanosis, clubbing and high hematocrit levels. One patient had an atrio-ventricular block that varied from first to third degree; another patient showed intermittent junctional rhythm. At angiography the ventricular septum appeared to be almost perpendicular to the frontal plane in most cases, so that the anteroposterior projection resulted in a true axial view. One overriding left atrioventricular valve and one straddling right atrio-ventricular valve were demonstrated; no significant incompetence of either valve was observed. The ventricular septal defect was always single and related to the subpulmonary outflow. Pulmonic stenosis was valvular in every patient; an additional infundibular obstruction was present in one case. In two cases an additional stenosis was discovered at the supravalvular level. The left pulmonary branch was stenotic in one case; it was hypoplastic, with controlateral dilatation, in two cases; both pulmonary arteries were dilated in one case. The aorta was always to the left of the pulmonary artery, either anterior or side by side. Three patients were operated on in different Institutions: one had a pulmonic valvotomy at the age of six years; one, aged twenty, had a right Blalock-Taussig shunt; the third, with overriding left atrioventricular valve, underwent a modified Fontan operation at the age of thirty years with success.(ABSTRACT TRUNCATED AT 250 WORDS)

Non invasive evaluation of left ventricular performance in 294 diabetic patients without clinical heart disease.

The authors studied the modification of systolic time intervals (STI), pre-ejection period (PEP) and left ventricular ejection time (LVETc), before and after isometric exercise, in 294 diabetic patients without clinical evidence of cardiomyopathy and in good metabolic control compared to 132 normal subjects. The study was aimed at detecting preclinical alterations of left ventricular function. Diabetic patients considered together did not show any difference in STI in basal conditions or after isometric exercise compared to normal subjects. When diabetic patients were divided into sub-groups according to their treatment, the insulin-treated diabetics showed modification of STI after isometric exercise, which indicated an alteration of left ventricular function. Also subjects treated with oral hypoglycemic agents showed similar but less evident changes. In diabetic patients on diet only and in those with duration of diabetes of 6 months or less, STI was identical to that of normal subjects. These data do not explain the pathogenesis of myocardial involvement, although they are in accordance with studies which have laid emphasis on the alteration of compliance of the diabetic heart.