FATAL ACUTE HEMOLYSIS FOLLOWING TRIAZOLE THERAPY IN AFRICAN PENGUINS (SPHENISCUS DEMERSUS).

Aspergillosis is a major cause of morbidity and mortality in penguins, with triazole antifungal drugs being commonly used for prophylaxis and treatment. This report describes 15 cases of fatal hemolysis associated with liquid itraconazole and voriconazole formulations administered to African penguins (Spheniscus demersus) from four institutions. All penguins underwent stressful events (e.g. relocation, induced molt) and were administered commercial liquid itraconazole formulations or compounded voriconazole liquid suspension. Observed clinical signs in affected penguins prior to death included hyporexia, weight loss, lethargy, dyspnea, red-tinged droppings, and obtunded mentation. Intra- and extravascular hemolysis and hemoglobinuric nephrosis were the primary pathologic manifestations on postmortem examination. The concentration-dependent hemolytic potentials of itraconazole, voriconazole, and commercial and compounded vehicle suspensions were evaluated in vitro by exposing chicken whole blood as a surrogate for penguin blood. Hemoglobin content in blood plasma was then measured by spectrophotometry. Neither itraconazole nor voriconazole alone induced hemolysis in vitro. The vehicle ingredients sorbitol and hydromellose induced hemolysis, but not at predicted plasma levels in chicken erythrocytes, suggesting neither the azole antifungals nor their major vehicles alone were likely to contribute to hemolysis in vivo in these penguins. Potential mechanisms of toxicosis include generation of an unmeasured reactive metabolite causing hemolysis, preexisting erythrocyte fragility, or species-specific differences in hemolytic thresholds that were not assessed in the chicken erythrocyte model. More research is needed on the potential for toxicosis of azole antifungal drugs and carrier molecules in this and other avian species.

Pharmacokinetics of a Single Intramuscular Injection of Ceftiofur Crystalline Free Acid in Bald Eagles (Haliaeetus leucocephalus).

The objective of this study was to evaluate the pharmacokinetic properties of ceftiofur crystalline free acid (CCFA) administered intramuscularly at dosages of 10 and 20 mg/kg in bald eagles (BAEAs) (Haliaeetus leucocephalus). Ceftiofur crystalline free acid is a long-acting, injectable, third-generation cephalosporin antibiotic drug. A prospective, randomized, complete crossover design was used for this pharmacokinetic investigation. CCFA (10 or 20 mg/kg) was administered intramuscularly, and blood samples were obtained from 6 adult, nonreleasable, healthy BAEAs at predetermined sampling times. After a 4-week washout period, the protocol was repeated with each bird receiving the dose not given during the initial sample collection according to the randomized crossover design. Plasma ceftiofur free acid equivalents were quantified and data were analyzed by a noncompartmental pharmacokinetic approach. The mean observed peak plasma concentrations were 9.23 µg/mL and 15.08 µg/mL for 10 and 20 mg/kg CCFA IM administration, respectively. The mean observed time to maximum plasma concentration was 18 and 17.6 hours, and the mean terminal elimination half-life was 32.38 and 38.08 hours for intramuscular administration of 10 and 20 mg/kg CCFA, respectively, in the BAEAs. Reported minimum inhibitory concentrations of raptor bacterial isolates from a prior study was used to determine the target minimum inhibitory concentration of 1 µg/mL selected for this investigation. From the previously published information, a target plasma concentration of 4 µg/mL was determined for the CCFA in the BAEAs. From the results of this study, CCFA may be dosed every 60 and 110 hours at 10 mg/kg IM, and every 80 and 160 hours at 20 mg/kg IM in BAEAs.

Tear film concentrations of topically applied 0.5% oxytetracycline ointment in normal canine eyes.

OBJECTIVE: To determine the tear film levels of oxytetracycline in normal canine eyes after application of the ophthalmic ointment, Terramycin™ (0.5% oxytetracycline, polymyxin B sulfate), to guide appropriate treatment frequency. ANIMALS STUDIED: Ten research beagles. PROCEDURES: Ten research beagles with confirmed normal eyes were administered 0.02 mL of Terramycin™ ophthalmic ointment onto the dorsal bulbar conjunctival surface of the right eye. Tear samples were collected via dye-less Schirmer tear strips at 2, 4, 6, 8, and 12 hours post-administration. The sample for each timepoint was collected on a separate day, and concentrations of oxytetracycline were determined using high-performance liquid chromatography (HPLC). RESULTS: There was a semi-logarithmic decline in the median tear concentration of oxytetracycline. The median (2.5th and 97.5th percentiles) tear concentrations of oxytetracycline at 2, 4, 6, 8, and 12 hours were 43.5 µg/mL (11.1-302.2 µg/mL), 28.7 µg/mL (8.04-113.7 µg/mL), 16.1 µg/mL (4.96-37.7 µg/mL), 9.2 µg/mL (4.52-28.1 µg/mL), and 6.11 µg/mL (4.36-26.7 µg/mL), respectively. Mean (±SD) drug recovery via HPLC was 88% (±7.5%). CONCLUSIONS: Ophthalmic Terramycin™ achieves a substantially higher tear level than the MIC for common bacterial corneal pathogens up to 12 hours post-administration in normal eyes. Anti-collagenolytic tear levels were not achieved at the timepoints evaluated or with the manufacturer-prescribed dosing frequency. HPLC can be used to analyze tear concentrations of ophthalmic ointment formulations.

Pharmacokinetics of midazolam in sevoflurane-anesthetized cats.

OBJECTIVE: To estimate the pharmacokinetics of midazolam and 1-hydroxymidazolam after midazolam administration as an intravenous bolus in sevoflurane-anesthetized cats. STUDY DESIGN: Prospective pharmacokinetic study. ANIMALS: A group of six healthy adult, female domestic cats. METHODS: Anesthesia was induced and maintained with sevoflurane. After 30 minutes of anesthetic equilibration, cats were administered midazolam (0.3 mg kg-1) over 15 seconds. Venous blood was collected at 0, 1, 2, 4, 8, 15, 30, 45, 90, 180 and 360 minutes after administration. Plasma concentrations for midazolam and 1-hydroxymidazolam were measured using high-pressure liquid chromatography. The heart rate (HR), respiratory rate (fR), rectal temperature, noninvasive mean arterial pressure (MAP) and end-tidal carbon dioxide (Pe'CO2) were recorded at 5 minute intervals. Population compartment models were fitted to the time-plasma midazolam and 1-hydroxymidazolam concentrations using nonlinear mixed effect modeling. RESULTS: The pharmacokinetic model was fitted to the data from five cats, as 1-hydroxymidazolam was not detected in one cat. A five-compartment model best fitted the data. Typical values (% interindividual variability where estimated) for the volumes of distribution for midazolam (three compartments) and hydroxymidazolam (two compartments) were 117 (14), 286 (10), 705 (14), 53 (36) and 334 mL kg-1, respectively. Midazolam clearance to 1-hydroxymidazolam, midazolam fast and slow intercompartmental clearances, 1-hydroxymidazolam clearance and 1-hydroxymidazolam intercompartment clearance were 18.3, 63.5 (15), 22.1 (8), 1.7 (67) and 3.8 mL minute-1 kg-1, respectively. No significant changes in HR, MAP, fR or Pe'CO2 were observed following midazolam administration. CONCLUSION AND CLINICAL RELEVANCE: In sevoflurane-anesthetized cats, a five-compartment model best fitted the midazolam pharamacokinetic profile. There was a high interindividual variability in the plasma 1-hydroxymidazolam concentrations, and this metabolite had a low clearance and persisted in the plasma for longer than the parent drug. Midazolam administration did not result in clinically significant changes in physiologic variables.

Pharmacokinetics and Drug Residue in Eggs After Multiple-Day Oral Dosing of Amoxicillin-Clavulanic Acid in Domestic Chickens.

This study examined the pharmacokinetics of orally administered amoxicillin and clavulanic acid tablets (Clavamox, 125 mg/kg PO q12h for 9 doses) in domestic hens and examined both amoxicillin and clavulanic acid concentrations in eggs. Therapeutic plasma concentrations (0.5 µg/mL) of amoxicillin were not reached at any time point, and no amoxicillin was detected in plasma after 2 hours. Pharmacokinetic parameters could not be calculated. The clavulanic acid half-life was 1.1 hours and it was detected up to 8 hours after dosing. No amoxicillin was detected in eggs 4 days postdosing, nor was clavulanic acid detected in any eggs during the same time period. On the basis of these results, orally dosing hens with amoxicillin and clavulanic acid tablets at 125 mg/kg PO q12h does not reach therapeutic plasma concentrations. Additional studies are needed to examine different doses and formulations of medication to determine better dosing and withdrawal recommendations for domestic chickens.

Evaluation of the sedative effects and pharmacokinetics of detomidine gel administered intravaginally to horses.

OBJECTIVES: To determine the sedative effects and pharmacokinetic profile of detomidine when administered intravaginally as a gel formulation to horses. STUDY DESIGN: Randomized, crossover, masked experimental design. ANIMALS: A group of six healthy adult mares (494 ± 56 kg). METHODS: Mares were studied on two occasions and were administered either detomidine hydrochloride (10 µg kg-1) intravenously (treatment IV) or detomidine gel (40 µg kg-1) intravaginally (treatment IVG), separated by 1 week. Sedation, ataxia, muzzle-floor distance and heart rate (HR) were evaluated every 15 minutes for 240 minutes. Venous blood samples were collected at 15, 30, 45, 60, 90, 120, 150, 180, 240, 300 and 360 minutes postadministration and were analyzed for detomidine and metabolites using liquid chromatography-tandem mass spectrometry. Measured variables were compared over time and between treatments using mixed model analysis. Correlation between drug plasma concentrations and muzzle-floor distance, and sedation and ataxia scores was determined using the Spearman correlation coefficient. Data are presented as mean ± standard error of the mean and p value was set at <0.05. RESULTS: Sedation was shorter with IV (119 ± 16 minutes) than with IVG (188 ± 22 minutes). Ataxia scores remained greater than baseline for 90 and 135 minutes for treatments IV and IVG, respectively. HR was lower than baseline for 45 and 30 minutes for IV and IVG, respectively, but did not differ between treatments. The mean maximum plasma concentration of detomidine, time to maximum concentration and bioavailability for treatment IVG was 8.57 ng mL-1, 0.37 hour and 25%, respectively. There was a significant correlation (r = 0.68) between plasma detomidine concentrations and sedation score. CONCLUSIONS AND CLINICAL RELEVANCE: Detomidine gel administered intravaginally resulted in clinically important sedation and is a viable method for detomidine gel delivery in mares.

Effect of fentanyl on the induction dose and minimum infusion rate of alfaxalone preventing movement in dogs.

OBJECTIVE: To determine the effect of fentanyl on the induction dose and minimum infusion rate of alfaxalone required to prevent movement in response to a noxious stimulus (MIRNM) in dogs. STUDY DESIGN: Experimental crossover design. ANIMALS: A group of six healthy, adult, intact female mixed-breed dogs, weighing 19.7 ± 1.3 kg. METHODS: Dogs were randomly administered one of three treatments at weekly intervals: premedication with 0.9% saline (treatment A), fentanyl 5 µg kg-1 (treatment ALF) or fentanyl 10 µg kg-1 (treatment AHF), administered intravenously over 5 minutes. Anesthesia was induced 5 minutes later with incremental doses of alfaxalone to achieve intubation and was maintained for 90 minutes in A with alfaxalone (0.12 mg kg-1 minute-1), in ALF with alfaxalone (0.09 mg kg-1 minute-1) and fentanyl (0.1 µg kg-1 minute-1) and in AHF with alfaxalone (0.06 mg kg-1 minute-1) and fentanyl (0.2 µg kg-1 minute-1). The alfaxalone infusion was increased or decreased by 0.006 mg kg-1 minute-1 based on positive or negative response to antebrachium stimulation (50 V, 50 Hz, 10 ms). Data were analyzed using a mixed-model anova and presented as least squares means ± standard error. RESULTS: Alfaxalone induction doses were 3.50 ± 0.13 (A), 2.17 ± 0.10 (ALF) and 1.67 ± 0.10 mg kg-1 (AHF) and differed among treatments (p < 0.05). Alfaxalone MIRNM was 0.17 ± 0.01 (A), 0.10 ± 0.01 (ALF) and 0.07 ± 0.01 mg kg-1 minute-1 (AHF) and differed among treatments. ALF and AHF decreased the MIRNM by 44 ± 8% and 62 ± 5%, respectively (p < 0.05). Plasma alfaxalone concentrations at MIRNM were 5.82 ± 0.48 (A), 4.40 ± 0.34 (ALF) and 2.28 ± 0.09 µg mL-1 (AHF). CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl, at the doses studied, significantly decreased the alfaxalone induction dose and MIRNM.

PHARMACOKINETICS OF A SUSTAINED-RELEASE FORMULATION OF MELOXICAM AFTER SUBCUTANEOUS ADMINISTRATION TO AMERICAN FLAMINGOS ( PHOENICOPTERUS RUBER).

Meloxicam is commonly used in avian medicine to relieve pain and inflammation, but the recommended dosing frequency can be multiple times per day, which can contribute to stress during convalescence. In this study, the pharmacokinetics of a sustained-release formulation of meloxicam were determined after subcutaneous administration of a single 3-mg/kg dose to eight healthy adult American flamingos ( Phoenicopterus ruber). Blood samples were collected before (time 0) and at 0.5, 1, 4, 8, 12, 24, 48, 96, and 120 hr after drug administration. Analysis of meloxicam in plasma samples was conducted with the use of reversed-phase high-performance liquid chromatography, and pharmacokinetic parameters were calculated by noncompartmental analysis. Plasma concentrations reached a mean maximum (±standard deviation) of 7.65 (±2.39) µg/ml at 0.56 (±0.18) hr with a terminal half-life of 1.76 (±1.41) hr. Based on these findings, this sustained-release formulation of meloxicam does not extend the interval between treatments as compared to the regular formulation, so it is not recommended in American flamingos at this time.

Pharmacokinetics and Egg Residues of Meloxicam After Multiple Day Oral Dosing in Domestic Chickens.

With increased ownership of backyard poultry, veterinarians must treat these birds appropriately and take into consideration drug withdrawal times for eggs meant for consumption. Few studies have examined the pharmacokinetics or egg residues for medications commonly used in avian medicine. This study determined the pharmacokinetics of meloxicam in domestic chickens (n = 8) after oral dosing at 1 mg/kg q12h for a total of 9 doses (5 days). Additionally, the presence of meloxicam residues in eggs was determined. The terminal half-life, maximum concentration, and time to maximum concentration were 3.02 ± 1.15 hours, 7.14 ± 1.54 µg/mL, and 1.6 ± 0.52 hours, respectively. No drug was detected in yolks and whites after 8 days and 3 days, respectively. On the basis of these results, a 2-week withdrawal time should be adequate to avoid drug residues in eggs meant for consumption.

Effect of dexmedetomidine on the minimum infusion rate of propofol preventing movement in dogs.

OBJECTIVE: To determine the effect of dexmedetomidine on induction dose and minimum infusion rate of propofol preventing movement (MIRNM). STUDY DESIGN: Randomized crossover, unmasked, experimental design. ANIMALS: Three male and three female healthy Beagle dogs weighing 10.2 ± 2.8 kg. METHODS: Dogs were studied on three occasions at weekly intervals. Premedications were 0.9% saline (treatment P) or dexmedetomidine (1 µg kg-1, treatment PLD; 2 µg kg-1, treatment PHD) intravenously. Anesthesia was induced with propofol (2 mg kg-1 and then 1 mg kg-1 every 15 seconds) until intubation. Anesthesia was maintained for 90 minutes in P with propofol (0.5 mg kg-1 minute-1) and saline, in PLD with propofol (0.35 mg kg-1 minute-1) and dexmedetomidine (1 µg kg-1 hour-1), and in PHD with propofol (0.3 mg kg-1 minute-1) and dexmedetomidine (2 µg kg-1 hour-1). The stimulus (50 V, 50 Hz, 10 ms) was applied to the antebrachium, and propofol infusion was increased or decreased by 0.025 mg kg-1 minute-1 based on a positive or negative response, respectively. Data were analyzed using a mixed-model anova and presented as mean ± standard error. RESULTS: Propofol induction doses were 8.68 ± 0.57 (P), 6.13 ± 0.67 (PLD) and 4.78 ± 0.39 (PHD) mg kg-1 and differed among treatments (p < 0.05). Propofol MIRNM values were 0.68 ± 0.13, 0.49 ± 0.16 and 0.26 ± 0.05 mg kg-1 minute-1 for P, PLD and PHD, respectively. Propofol MIRNM decreased 59% in PHD (p < 0.05). Plasma propofol concentrations were 14.04 ± 2.30 (P), 11.30 ± 4.30 (PLD) and 7.96 ± 0.72 (PHD) µg mL-1 and dexmedetomidine concentrations were 0.68 ± 0.12 (PLD) and 0.89 ± 0.08 (PHD) ng mL-1 at MIRNM determination. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine (1 and 2 µg kg-1) decreased propofol induction dose. Dexmedetomidine (2 µg kg-1 hour-1) resulted in a significant decrease in propofol MIRNM.

Effect of fentanyl on the induction dose and minimum infusion rate of propofol preventing movement in dogs.

OBJECTIVE: To determine the effect of fentanyl on the induction dose of propofol and minimum infusion rate required to prevent movement in response to noxious stimulation (MIRNM) in dogs. STUDY DESIGN: Crossover experimental design. ANIMALS: Six healthy, adult intact male Beagle dogs, mean±standard deviation 12.6±0.4 kg. METHODS: Dogs were administered 0.9% saline (treatment P), fentanyl (5 µg kg-1) (treatment PLDF) or fentanyl (10 µg kg-1) (treatment PHDF) intravenously over 5 minutes. Five minutes later, anesthesia was induced with propofol (2 mg kg-1, followed by 1 mg kg-1 every 15 seconds to achieve intubation) and maintained for 90 minutes by constant rate infusions (CRIs) of propofol alone or with fentanyl: P, propofol (0.5 mg kg-1 minute-1); PLDF, propofol (0.35 mg kg-1 minute-1) and fentanyl (0.1 µg kg-1 minute-1); PHDF, propofol (0.3 mg kg-1 minute-1) and fentanyl (0.2 µg kg-1 minute-1). Propofol CRI was increased or decreased based on the response to stimulation (50 V, 50 Hz, 10 mA), with 20 minutes between adjustments. Data were analyzed using a mixed-model anova and presented as mean±standard error. RESULTS: ropofol induction doses were 6.16±0.31, 3.67±0.21 and 3.33±0.42 mg kg-1 for P, PLDF and PHDF, respectively. Doses for PLDF and PHDF were significantly decreased from P (p<0.05) but not different between treatments. Propofol MIRNM was 0.60±0.04, 0.29±0.02 and 0.22±0.02 mg kg-1 minute-1 for P, PLDF and PHDF, respectively. MIRNM in PLDF and PHDF was significantly decreased from P. MIRNM in PLDF and PHDF were not different, but their respective percent decreases of 51±3 and 63±2% differed (p=0.035). CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl, at the doses studied, caused statistically significant and clinically important decreases in the propofol induction dose and MIRNM.

PHARMACOKINETICS OF PIROXICAM IN CRANES (FAMILY GRUIDAE).

To investigate the pharmacokinetics of the nonsteroidal anti-inflammatory drug (NSAID) piroxicam in cranes, three brolgas (Antigone rubicunda) were administered piroxicam as a single oral dose at 0.5 mg/kg and 1.0 mg/kg during separate trials. Serial blood samples were collected for quantification of piroxicam in plasma. Piroxicam was readily absorbed at both dosages, and no adverse effects were observed. Plasma concentrations peaked at 3.67 hr with a concentration of 4.00 µg/ml for the lower dosage, and at 0.83 hr at 8.77 µg/ml for the higher dosage. Piroxicam may exhibit linear kinetics and dose proportionality in brolgas, but will require further study. Mean peak plasma concentrations in brolgas were comparable to concentrations demonstrated to be analgesic in humans. To the authors' knowledge, this study represents the first pharmacokinetic investigation of piroxicam in an avian species.

Pharmacokinetics of a Single Intramuscular Injection of Long-Acting Ceftiofur Crystalline-Free Acid in Cattle Egrets ( Bubulcus ibis).

We determined the pharmacokinetic properties of ceftiofur crystalline-free acid (CCFA), a long-acting antibiotic, after a single intramuscular injection in cattle egrets ( Bubulcus ibis). A dose of 20 mg/kg was administered intramuscularly to 18 birds and blood samples were collected via jugular venipuncture at 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours after CCFA administration. Plasma concentrations of ceftiofur free acid equivalents (CFAEs) were measured via high-performance liquid chromatography. The minimum inhibitory concentration (MIC) of 1 µg/mL was reached by 1 hour after administration and remained higher than the MIC for at least 72 hours in all birds. This target concentration is effective for many bacterial infections in avian species. The area under the plasma concentration versus time curve was 451.3 h*µg/mL, maximum plasma concentration was 16.22 µg/mL, time to maximum plasma concentration was 3.2 hours, mean harmonic half-life was 37.92 hours, and time that the concentrations of CFAEs were higher than the target MIC was a minimum of 72 hours.

Plasma Concentrations of Itraconazole, Voriconazole, and Terbinafine When Delivered by an Impregnated, Subcutaneous Implant in Japanese Quail ( Coturnix japonica ).

Aspergillosis is a common fungal infection in both wild and pet birds. Although effective antifungal medications are available, treatment of aspergillosis can require months of medication administration, which entails stressful handling one or more times per day. This study examined the delivery of the antifungal drugs itraconazole, voriconazole, and terbinafine to Japanese quail ( Coturnix japonica ) via an impregnated implant. Implants contained 0.5, 3, 8, or 24 mg of itraconazole, voriconazole, or terbinafine. The implants were administered subcutaneously over the dorsum and between the scapulae. Blood was collected from birds before and 2, 7, 21, 42, and 56 days after implant placement. Plasma was analyzed by high-performance liquid chromatography for concentrations of itraconazole, voriconazole, or terbinafine, as appropriate. During the course of the study, targeted terbinafine concentrations were achieved in some birds at various time points, but concentrations were inconsistent. Itraconazole and voriconazole concentrations were also inconsistent and did not reach targeted concentrations. Currently, the implant examined in this study cannot be recommended for treatment of aspergillosis in avian species.

PHARMACOKINETICS OF CEFTIOFUR CRYSTALLINE FREE ACID, A LONG-ACTING CEPHALOSPORIN, IN AMERICAN FLAMINGOS (PHOENICOPTERUS RUBER).

Antibiotic usage is a vital component of veterinary medicine but the unique anatomy of some species can make administration difficult. The objective of this study was to determine the pharmacokinetic parameters of ceftiofur crystalline free acid (CCFA), a long-acting cephalosporin antibiotic, after parenteral administration in American flamingos ( Phoenicopterus ruber ). A dose of 10 mg/kg of CCFA was administered intramuscularly to 11 birds and blood was collected at various time points from 0 to 192 hr. Pharmacokinetic parameters for ceftiofur equivalents were determined and reached levels above minimum inhibitory concentrations of various bacterial organisms in other avian species through 96 hr in 9/11 birds. Based on these findings and comparison to other avian studies, ceftiofur crystalline free acid appears to be a long-acting antibiotic option for American flamingos. Administration of this antibiotic should be utilized in conjunction with culture and sensitivity of suspected pathogens.

CLINICAL INFECTION OF CAPTIVE ASIAN ELEPHANTS (ELEPHAS MAXIMUS) WITH ELEPHANT ENDOTHELIOTROPIC HERPESVIRUS 4.

Elephant endotheliotropic herpesvirus (EEHV) can cause lethal hemorrhagic disease in juvenile Asian elephants. A number of EEHV types and subtypes exist, where most deaths have been caused by EEHV1A and EEHV1B. EEHV4 has been attributed to two deaths, but as both diagnoses were made postmortem, EEHV4 disease has not yet been observed and recorded clinically. In this brief communication, two cases of EEHV4 infection in juvenile elephants at the Houston Zoo are described, where both cases were resolved following intensive treatment and administration of famciclovir. A quantitative real-time polymerase chain reaction detected EEHV4 viremia that correlated with clinical signs. High levels of EEHV4 shedding from trunk wash secretions of the first viremic elephant correlated with subsequent infection of the second elephant with EEHV4. It is hoped that the observations made in these cases--and the successful treatment regimen used--will help other institutions identify and treat EEHV4 infection in the future.

PHARMACOKINETICS OF TRAMADOL HYDROCHLORIDE AND ITS METABOLITE O-DESMETHYLTRAMADOL FOLLOWING A SINGLE, ORALLY ADMINISTERED DOSE IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

Tramadol is a synthetic, centrally acting, opiate-like analgesic that is structurally related to codeine and morphine. The objective of this study was to determine the pharmacokinetics of tramadol hydrochloride and its major active metabolite O-desmethyltramadol (M1) in the California sea lion (Zalophus californianus). A single dose of tramadol was administered orally in fish at 2 mg/kg to a total of 15 wild California sea lions admitted for rehabilitation. Twenty-four total blood samples were collected post drug administration at 10, 20, 30, and 45 min and at 1, 3, 5, 6, 8, 12, and 24 hr. Blood plasma was separated and stored at -80°C until analysis with high-performance liquid chromatography was performed to determine levels of tramadol and M1, the major active metabolite. The results indicate that the plasma levels of parent tramadol are low or negligible during the first 30-45 min and then reach the predicted mean maximum plasma concentration of 358 ng/ml at 1.52 hr. The M1 metabolite was not detectable in 21 of 24 plasma samples, below the level of quantification of 5 ng/ml in one sample, and detectable at 11 and 17 ng/ml in two of the samples. This study suggests that a 2 mg/kg dose would need to be administered every 6-8 hr to maintain concentrations of tramadol above the minimum human analgesic level for mild to moderate pain. Based on dosing simulations, a dose of 4 mg/kg q8 hr or q12 hr, on average, may represent an adequate compromise, but further studies are needed using a larger sample size. Pharmacodynamic studies are warranted to determine if tramadol provides analgesic effects in this species. The potential for tramadol toxicosis at any dose also has not been determined in this species.

Pharmacokinetics of tramadol and its primary metabolite O-desmethyltramadol in African penguins (Spheniscus demersus).

Analgesia is an important part of veterinary medicine, but until recently there have been limited studies on analgesic drugs in avian species. Tramadol represents an orally administered opioid drug that has shown analgesic potential in numerous species, including mammals, birds, and reptiles. The objective of this study was to determine the pharmacokinetic parameters of tramadol and its primary metabolite, O-desmethyltramadol (M1), after oral administration of tramadol hydrochloride (HCl) in African penguins (Spheniscus demersus). A dose of 10 mg/kg of tramadol HCl was administered orally to 15 birds, and blood was collected at various time points from 0 to 36 hr. Tramadol and M1 concentrations were determined and were consistent with therapeutic concentrations in humans through 12 hr in 9/15 birds for tramadol and 36 hr in 14/15 birds for M1. Based on these findings and a comparison with other avian studies, an oral dose of 10 mg/kg of tramadol once daily appears to be a promising analgesic option for African penguins.

Pharmacokinetics of nebulized terbinafine in Hispaniolan Amazon parrots (Amazona ventralis).

Aspergillosis is one of the most difficult diseases to treat successfully in avian species. Terbinafine hydrochloride offers numerous potential benefits over traditionally used antifungals for treatment of this disease. Adding nebulized antifungals to treatment strategies is thought to improve clinical outcomes in lung diseases. To determine plasma concentrations of terbinafine after nebulization, 6 adult Hispaniolan Amazon parrots were randomly divided into 2 groups of 3. Each bird was nebulized for 15 minutes with 1 of 2 terbinafine solutions, one made with a crushed tablet and the second with raw drug powder. Blood samples were collected at baseline and at multiple time points up to 720 minutes after completing nebulization. Plasma and nebulization solutions were analyzed by high-performance liquid chromatography. The terbinafine concentration of the solution made with a crushed tablet (0.87 +/- 0.05 mg/mL) was significantly lower than was that made with raw powder (1.02 +/- 0.09 mg/mL). Plasma concentrations of terbinafine did not differ significantly between birds in the 2 groups. Plasma terbinafine concentrations in birds were maintained above in vitro minimum inhibitory concentrations for approximately 1 hour in birds nebulized with the crushed tablet solution and 4 hours in birds nebulized with the raw powder solution. Higher concentrations of solution, longer nebulization periods, or more frequent administration are likely needed to reach therapeutic plasma concentrations of terbinafine for clinically relevant periods in Hispaniolan Amazon parrots.

The pharmacokinetics and pharmacodynamics of midazolam after intravenous administration to donkeys (Equus africanus asinus).

The pharmacokinetics and pharmacodynamics of midazolam were studied in eight 1-to-3-year-old healthy gelded donkeys. Blood samples were obtained. Heart rate, respiratory rate, rectal temperature, sedation/excitement, ataxia, and response to tactile and auditory stimuli were recorded at baseline until 48 hours after intravenous (IV) midazolam (0.1 mg/kg) administration. Plasma midazolam and 1-hydroxymidazolam were measured using reversed-phase high-performance liquid chromatography. Pharmacokinetic variables were calculated using non-compartmental analysis. Physiologic data were analyzed using a mixed-effects model followed by Dunnett's test and behavioral data were analyzed using a Friedman test then a Dunn's test; P < 0.05 was considered significant. Midazolam was detectable for up to 60 minutes post-treatment in 7 donkeys. The median total body clearance, volume of distribution at steady state, elimination half-life, and area under concentration-time profile were 1210 mL/kg/h, 359 mL/kg, 0.27 hours, and 82.7 h × ng/mL, respectively. 1-hydroxymidazolam was detected (29 to 105 ng/mL) between 5 to 15 minutes post-treatment in 4 donkeys. Compared to baseline, rectal temperature and ataxia increased from 90 to 720 minutes (P ≤ 0.038) and 3 to 15 minutes (P ≤ 0.024) post-treatment, respectively. No other parameters showed statistically significant differences. Healthy donkeys cleared midazolam rapidly from plasma after IV administration. Transient ataxia and recumbency without sedation were observed.

La pharmacocinétique et la pharmacodynamique du midazolam ont été étudiées chez huit ânes hongres en bonne santé âgés de 1 à 3 ans. Des échantillons de sang ont été obtenus. La fréquence cardiaque, la fréquence respiratoire, la température rectale, la sédation/excitation, l'ataxie et la réponse aux stimuli tactiles et auditifs ont été enregistrées au départ jusqu'à 48 heures après l'administration intraveineuse (IV) de midazolam (0,1 mg/kg). Le midazolam plasmatique et le 1-hydroxymidazolam ont été mesurés par chromatographie liquide haute performance en phase inversée. Les variables pharmacocinétiques ont été calculées à l'aide d'une analyse non compartimentale. Les données physiologiques ont été analysées à l'aide d'un modèle à effets mixtes suivi du test de Dunnett et les données comportementales ont été analysées à l'aide d'un test de Friedman puis d'un test de Dunn; P < 0,05 était considéré comme significatif. Le midazolam était détectable jusqu'à 60 minutes après le traitement chez sept ânes. La clairance corporelle totale médiane, le volume de distribution à l'état d'équilibre, la demi-vie d'élimination et l'aire sous le profil concentration-temps étaient respectivement de 1210 mL/kg par heure, 359 mL/kg, 0,27 heure et 82,7 heures × ng/mL. Le 1-hydroxymidazolam a été détecté (29 à 105 ng/mL) entre 5 et 15 minutes après le traitement chez quatre ânes. Par rapport au départ, la température rectale et l'ataxie ont augmenté de 90 à 720 minutes (P ≤ 0,038) et de 3 à 15 minutes (P ≤ 0,024) après le traitement, respectivement. Aucun autre paramètre n'a montré de différences statistiquement significatives. Des ânes en bonne santé ont rapidement éliminé le midazolam du plasma après administration IV. Une ataxie transitoire et un décubitus sans sédation ont été observés.(Traduit par Docteur Serge Messier).