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.     

Pharmacodynamics and pharmacokinetics of cefoperazone and cefamandole in dogs following single dose intravenous and intramuscular administration

The pharmacokinetics and intramuscular (i.m.) bioavailability of cefoperazone and cefamandole (20mg/kg) were investigated in dogs and the findings related to minimal inhibitory concentrations (MICs) for 90 bacterial strains isolated clinically from dogs. The MICs of cefamandole for Staphylococcus intermedius (MIC(90) 0.125 microg/mL) were lower than those of cefoperazone (MIC(90) 0.5 micro/mL) although the latter was more effective against Escherichia coli strains (MIC(90) 2.0 microg/mL vs. 4.0 microg/mL). The pharmacokinetics of the drugs after intravenous administrations were similar: a rapid distribution phase was followed by a slower elimination phase (t((1/2)lambda2) 84.0+/-21.3 min for cefoperazone and 81.4+/-9.7 min for cefamandole). The apparent volume of distribution and body clearance were 0.233 L/kg and 1.96 mL/kg/min for cefoperazone, 0.190 L/kg and 1.76 mL/kg/min for cefamandole. After i.m. administration the bioavailability and peak serum concentration of cefamandole (85.1+/-13.5% and 35.9+/-5.4 microg/mL) were significantly higher than cefoperazone (41.4+/-7.1% and 24.5+/-3.0 micog/mL), but not the serum half-lives (t(1/2el) 134.3+/-12.6 min for cefoperazone and 145.4+/-12.3 min for cefamandole). The time above MIC(90) indicated that cefamandole can be administered once daily to dogs for the treatment of staphylococcal infections (T>MIC for S. intermedius 23.8+/-0.3 and for Staphylococcus aureus 21.6+/-0.6h).     

Forecasting Infections of the Leaf Curl Disease on Peaches Caused by Taphrina deformans

An Israeli model forecasting leaf curl disease on peaches caused by Taphrina deformans was validated in the Emilia-Romagna region of northern Italy, during a three-year period (1996–1998), in 13 cases (year × location × cultivar). When the peach trees are susceptible to infection, the model uses mathematical functions to calculate the risk of infection on the basis of weather conditions (daily rainfall greater than 10mm, and maximum air temperature greater than 5°C), and it forecasts periods of possible symptom appearance based on the length of incubation. Peach trees became susceptible to infection between the end of January and mid March, when the first leaf buds attained phenological stage C, i.e. appearance of leaf apex. The trees remained susceptible for at least 9 weeks: the last infection occurred in mid-May.Since most of the leaf curl onsets observed in the orchards fell within the range of model forecasts, the model proved to be accurate in signalling both the first seasonal infection and repeated infections during the primary inoculum season. Few errors occurred, caused either by conditions of rainfall and temperature lower than the thresholds fixed in the model, or by discrepancies between forecast and actual length of incubation. Infection occurred also at 3.1–3.5°C, and with 9.6mm rainfall. Thus, thresholds should not be accepted too rigorously, and perhaps temperature should not be considered as a limiting factor for infection under the conditions of the present work. The length of incubation showed high variability: it was 23 days long on average, with a 95% confidence interval ranging from 20 to 27 days, and extreme values of 9 and 33 days.     

Superficial digital flexor tendonitis in Thoroughbred race horses: outcome following non-surgical treatment and superior check desmotomy

Objective This study documents the results of non-surgical treatment and treatment by superior check desmotomy in Thoroughbred racehorses with superficial digital flexor (SDF) tendonitis. Design A prospective study was made of 124 thoroughbred racehorses with unilateral or bilateral SDF tendonitis. Procedure The flexor tendons were assessed by physical and ultrasonographic examination before treatment, and the lesions detected in affected tendons were characterised according to lesion type, length and cross-sectional area. Ninety three horses were managed non-surgically and 31 by superior check desmotomy. Recurrent or new injuries were defined as injuries affecting a previously injured superficial digital flexor tendon, the contralateral SDF tendon, or the suspensory ligament (interosseous muscle) in either forelimb. Results No statistically significant difference was found in ultrasonographic lesion severity between treatment groups. Horses managed by superior check desmotomy were 1.3 times more likely to complete five or more races than horses managed non-surgically (95% confidence limits 0.93–1.82). Horses treated surgically were 1.2 times more likely to develop recurrent or new injuries after returning to training than horses managed non-surgically (95% CL 0.95–1.55). Horses under-going superior check desmotomy were 5.5 times more likely to develop suspensory desmitis than horses treated non-surgically (95% CL 1.13–26.4). There was no difference in the time to recurrent or new injury between treatment groups. Conclusion There was no statistically significant difference between treatment groups in the proportions of horses able to complete five or more races after an episode of superficial digital flexor tendonitis. Superior check desmotomy did not appear to offer an advantage over non-surgical treatment in preventing recurrent or new injuries in Thoroughbred racehorses. Horses undergoing superior check desmotomy appeared to be at greater risk of developing suspensery ligament injuries than horses managed non-surgically.     

Development of a methodology to forecast the nutritional value of new tomato hybrids

Tomato is a food of great relevance both due to its large-scale consumption and its richness in bioactive components. It is an important component of the traditional Mediterranean diet as well as of other diets. Nowadays, concerns about human health and environment preservation have changed the objectives of tomato breeding. In this study, eight tomato F₁ hybrids and their parental lines were analyzed for nutritional properties and agronomic traits using a new selection method that combines biochemical and agronomic evaluation. Eight traits contributing to the nutritional quality of tomato (lycopene, β-carotene, other carotenoids, flavonoids, phenolic acids, vitamins C and E, dry residue) and average yield were assessed in fifteen tomato genotypes. Furthermore the pathogen resistances possessed from these genotypes were, also, considered. In order to select valuable tomato hybrids, a nutritional index (I_QUAN) and an agronomic index (AI) were calculated. Our results suggested that the I_QUAN nutritional index may be very useful to forecast the nutritional value of F₁ hybrids based on parental performance. Combining the use of the I_QUAN and AI indexes, we were able to select two hybrids (MR 48 and MR 47) that contain considerable amounts of antioxidants and acceptable parameters for commercial production.     

Tritrichomonas foetus: a scanning electron microscopy study of erythrocyte adhesion associated with hemolytic activity

The in vitro hemolytic activity of Tritrichomonas foetus was investigated. The parasite was tested against human erythrocytes of groups A, B, AB, and O, and against erythrocytes of nine adult animals of different species (the rabbit, rat, chicken, cat, dog, swine, horse, bovine, and sheep). The results showed that T. foetus strains (ATCC KV1, K, PAL, 5022, RJ, 90) did not present any hemolytic activity against any human erythrocyte group nor against rabbit, rat, chicken, cat, dog and swine erythrocytes. T. foetus strains, however, lysed horse, bovine, and sheep erythrocytes. No hemolysin released by the parasites could be identified. Hemolysis did not occur with trichomonad culture supernatants, with sonicated extracts of T. foetus, nor with killed organisms. Scanning electron microscopy (SEM) showed that human erythrocytes did not adhere to the trophozoites, in contrast horse erythrocytes adhered to the surface of the parasites and were phagocytosed for up to 90 min. The parasites are able to exert their cytopathic effects through: (a) physical contact established between the two cell surfaces, (b) toxins released from parasites into the interaction media, or (c) the association of both mechanisms. Further studies are necessary to clarify the importance of the hemolytic activity in the biology of T. foetus.     

Pharmacokinetics of amoxicillin/clavulanic acid combination after intravenous and oral administration in goats

Summary

The intravenous and oral pharmacokinetics of an amoxicillin and clavulanic acid combination (20 mg/kg of sodium amoxicillin and 5 mg/kg of potassium clavulanate) were studied in six goats. After intravenous administration the pharmacokinetics of both drugs could be described by an open two‐compartment model. Amoxicillin had a greater distribution volume (0.19 ± 0.01 l/kg) than clavulanic acid (0.15 ± 0.01 l/kg), whereas the distribution and elimination constants were higher for the latter, which was eliminated more quickly than amoxicillin. After oral administration of both drugs their pharmacokinetic behaviour was best described by an open one‐compartment model with first‐order absorption. Elimination half‐lives were twice as long after oral (2.15 ± 0.20 h and 1.94 ± 0.16 h for amoxicillin and clavulanic acid respectively) than after intravenous administration (1.20 ± 0.16 h and 0.86 ± 0.09, respectively). An apparent ‘flip‐flop’ situation was evident in this study. Bioavailability was 27% for amoxicillin and 50% for clavulanic acid.     

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.     

Artifactual changes in canine blood following storage, detected using the ADVIA 120 hematology analyzer

BACKGROUND: Artifactual changes in blood may occur as a consequence of delayed analysis and may complicate interpretation of CBC data. OBJECTIVE: The aim of this study was to characterize artifactual changes in canine blood, due to storage, using the ADVIA 120 hematology analyzer. METHODS: Blood samples were collected into EDTA from 5 clinically healthy dogs. Within 1 hour after blood sample collection and at 12, 24, 36 and 48 hours after storage of the samples at either 4 degrees C or room temperature (approximately 24 degrees C), a CBC was done using the ADVIA 120 and multispecies software. A linear mixed model was used to statistically evaluate significant differences in values over time, compared with initial values. RESULTS: The HCT and MCV were increased significantly after 12 hours of collection at both 4 degrees C and 24 degrees C, and continued to increase through 48 hours. The MCHC initially decreased significantly at 12-24 hours and then continued to decrease through 48 hours at both temperatures. Changes in HCT, MCV, and MCHC were greater at 24 degrees C than at 4 degrees C at all time points. A significant increase in MPV and a decrease in mean platelet component concentration were observed at all time points at 24 degrees C. Samples stored at 24 degrees C for 48 hours had significantly higher percentages of normocytic-hypochromic RBCs, and macrocytic-normochromic RBCs, and lower platelet and total WBC counts. CONCLUSIONS: Delayed analysis of canine blood samples produces artifactual changes in CBC results, mainly in RBC morphology and platelet parameters, that are readily detected using the ADVIA 120. Refrigeration of specimens, even after 24 hours of storage at room temperature, is recommended to improve the accuracy of CBC results for canine blood samples.