Tetracycline, Sulfonamide, and Erythromycin Residues in Beef, Eggs, and Honey Sold as "Antibiotic-Free" Products in East Tennessee (USA) Farmers' Markets.

Foods that contain antibiotic residues have potential adverse health effects on consumers and provide selective pressure for the threat of antimicrobial resistance (AMR). This study's objective was to measure tetracycline, sulfonamide, and erythromycin residues in beef, eggs, and honey sold as "antibiotic-free" at farmers' markets in East Tennessee (East TN) in the United States (U.S.). Between July and September 2020, 36 "antibiotic-free" food products (9 beef, 18 egg, and 9 honey products) were purchased from East TN farmers' markets and tested for tetracycline, sulfonamide, and erythromycin residues using competitive enzyme-linked immunosorbent assays (cELISA). All beef, egg, and honey products had tetracycline residue; the median concentrations were 51.75, 30.25, and 77.86 µg/kg, respectively. Sulfonamide residue was present in every sample of beef. Of 18 eggs, 11 eggs had detectable sulfonamide residue; the median concentrations were 3.50 and 1.22 µg/kg in beef and eggs, respectively. Each sample of beef and honey contained erythromycin residue; the median concentrations were 3.67 and 0.68 µg/kg, respectively. Overall, the median concentrations of tetracycline, sulfonamide, and erythromycin residues were below the maximum residue levels (MRLs) set in the U.S. for beef and eggs. Thus, the beef and eggs sold as "antibiotic-free" in East TN farmers' markets can be considered safe for consumption. Safety determination for honey could not be made because MRLs have not been set for honey in the U.S. Because these residues should not be expected in "antibiotic-free" food products, it is important to further investigate the potential sources of these residues in these products.

Application of pharmacokinetic/pharmacodynamic concepts to the development of treatment regimens for sporadic canine urinary tract infections: Challenges and paths forward.

Antimicrobial efficacy can be predicted based on infection site exposure to the antimicrobial agent relative to the in vitro susceptibility of the pathogen to that agent. When infections occur in soft tissues (e.g., muscle, blood, and ligaments), exposure at the infection site is generally assumed to reflect an equilibrium between the unbound concentrations in plasma and that in the interstitial fluids. In contrast, for sporadic urinary tract infections (UTIs) in dogs and uncomplicated UTIs in humans, the primary site of infection is the bladder wall. Infection develops when bacteria invade the host bladder urothelium (specifically, the umbrella cells that form the urine-contacting layer of the stratified uroepithelium) within which these bacteria can avoid exposure to host defenses and antimicrobial agents. Traditionally, pathogen susceptibility has been estimated using standardized in vitro tests that measure the minimal concentration that will inhibit pathogen growth (MIC). When using exposure-response relationships during drug development to explore dose optimization, these relationships can either be based upon an assessment of a correlation between clinical outcome, drug exposure at the infection site, and pathogen MIC, or upon benchmark exposure-response relationships (i.e., pharmacokinetic/pharmacodynamic indices) typically used for the various drug classes. When using the latter approach, it is essential that the unbound concentrations at the infection site be considered relative to the MIC within the biological matrix to which the pathogen will be exposed. For soft tissue infections, this typically is the unbound plasma concentrations versus MICs determined in standardized media such as cation-adjusted Mueller Hinton broth, which is how many indices were originally established. However, for UTIs, it is the unbound drug concentrations within the urine versus the MICs in the actual urine biophase that needs to be considered. The importance of these relationships and how they are influenced by drug resistance, resilience, and inoculum are discussed in this review using fluoroquinolones and beta-lactams as examples.

Pharmacokinetic characterization of fluorocoxib D, a cyclooxygenase-2-targeted optical imaging agent for detection of cancer.

SIGNIFICANCE: Fluorocoxib D, N-[(rhodamin-X-yl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, is a water-soluble optical imaging agent to detect cyclooxygenase-2 (COX-2)-expressing cancer cells. AIM: We evaluated the pharmacokinetic and safety properties of fluorocoxib D and its ability to detect cancer cells in vitro and in vivo. APPROACH: Pharmacokinetic parameters of fluorocoxib D were assessed from plasma collected at designated time points after intravenous administration of 1 mg / kg fluorocoxib D in six research dogs using a high-performance liquid chromatography analysis. Safety of fluorocoxib D was assessed for 3 days after its administration using physical assessment, complete blood count, serum chemistry profile, and complete urinalysis in six research dogs. The ability of fluorocoxib D to detect COX-2-expressing cancer cells was performed using human 5637 cells in vitro and during rhinoscopy evaluation of specific fluorocoxib D uptake by canine cancer cells in vivo. RESULTS: No evidence of toxicity and no clinically relevant adverse events were noted in dogs. Peak concentration of fluorocoxib D (114.8 ± 50.5 ng / ml) was detected in plasma collected at 0.5 h after its administration. Pretreatment of celecoxib blocked specific uptake of fluorocoxib D in COX-2-expressing human 5637 cancer cells. Fluorocoxib D uptake was detected in histology-confirmed COX-2-expressing head and neck cancer during rhinoscopy in a client-owned dog in vivo. Specific tumor-to-normal tissue ratio of detected fluorocoxib D signal was in an average of 3.7 ± 0.9 using Image J analysis. CONCLUSIONS: Our results suggest that fluorocoxib D is a safe optical imaging agent used for detection of COX-2-expressing cancers and their margins during image-guided minimally invasive biopsy and surgical procedures.

Determination of plasma-chlortetracycline (CTC) concentrations in grazing beef cattle fed one of four FDA approved free-choice CTC-medicated minerals.

Control of active bovine anaplasmosis in the United States is predicated on the use of chlortetracycline (CTC)-medicated feed throughout the vector season. However, data describing population pharmacokinetics of chlortetracycline in cows, on pasture, having free-choice access to CTC-medicated mineral for consecutive months is lacking. This study documented plasma-CTC concentrations in grazing cows during peak vector season in an anaplasmosis endemic herd. Each pasture was administered one of the four Food and Drug Administration approved CTC-medicated mineral formulations and were assigned as follows: 0.77 g/kg, Aureo Anaplaz C700 Pressed (Sweetlix Livestock Supplements, Mankato, MN); 5.5 g/kg, Purina Anaplasmosis Block (Purina Animal Nutrition, Gray Summit, MO); 6.6 g/kg, Stockmaster Aureo FC C6000 Mineral (Hubbard Feeds, Mankato, MN); 8.8 g/kg, MoorMan's Special Range Minerals AU 168XFE (ADM Animal Nutrition, Quincy, IL). Blood samples were collected monthly for determining plasma drug concentration by Ultra performance liquid chromatography (UPLC) and mass spectrometry. Continued plasma-CTC monitoring allowed for characterization of trends between treatment groups (pastures), age groups (<3 yr or >4 yr), and sampling times (June to October). Results indicate formulation (pasture) and time were significant factors affecting concentrations of CTC in plasma. Cows exposed to 5.5 g/kg block formulation recorded higher CTC plasma concentrations compared with other pasture groups (P = 0.037). Plasma-CTC concentrations increased over time (month of measurement; P = 0.0005). Specifically, concentrations measured after 5 months of continuous CTC treatment were higher than those measured in earlier months.

Pharmacokinetics of a Single Dose of Oral and Intramuscular Meloxicam in African Penguins ( Spheniscus demersus).

Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that has been used orally and intramuscularly in numerous avian species, but not studied to date, in African penguins ( Spheniscus demersus). The study describes the pharmacokinetic parameters of meloxicam after oral and intramuscular administration to African penguins. Several pilot studies were conducted initially where meloxicam (1, 0.5, and 0.25 mg/kg) was given intramuscularly to 4 birds, and orally (1 mg/kg) to 2 birds. Based on pilot study results, one group of 8 penguins was given meloxicam 0.5 mg/kg intramuscularly and one group of 8 penguins was given 1 mg/kg orally. Blood samples were collected at baseline and at 11 time intervals per group after administration of meloxicam. Meloxicam time to maximum plasma concentration (Tmax), maximum concentration (Cmax), and half-life (t1/2) after intramuscular administration were 1.00 hour, 8.03 µg/mL, and 31.87 hours, respectively, while oral administration produced a Tmax, Cmax, and t1/2 of 12.00 hours, 10.84 µg/mL, and 28.59 hours, respectively. Based on plasma meloxicam concentrations found to be therapeutic in other bird species and humans, the recommended dosage and frequency for African penguins is 1 mg/kg orally every 48 hours and 0.5 mg/kg intramuscularly every 24 hours. Further studies are needed to determine the multiple-dose pharmacokinetics of meloxicam in African penguins.

Pharmacokinetics of meloxicam after intramuscular and oral administration of a single dose to American flamingos (Phoenicopertus ruber).

OBJECTIVE To determine pharmacokinetics after IM and oral administration of a single dose of meloxicam to American flamingos (Phoenicopertus ruber). ANIMALS 14 adult flamingos. PROCEDURES Flamingos were allocated to 2 groups. Each group received a dose of meloxicam (1 mg/kg) by the IM or oral route. After a 4-week washout period, groups received meloxicam via the other route of administration. Plasma meloxicam concentrations were measured with high-performance liquid chromatography. Data for each bird were analyzed. Estimated values of selected pharmacokinetic parameters were compared by use of a linear mixed-effects ANOVA. Pooled concentration-time profiles for each route of administration were analyzed to examine the influence of body weight on pharmacokinetics. RESULTS Mean ± SD maximum plasma concentration was 1.00 ± 0.88 µg/mL after oral administration. This was approximately 15% of the mean maximum plasma concentration of 5.50 ± 2.86 µg/mL after IM administration. Mean time to maximum plasma concentration was 1.33 ± 1.32 hours after oral administration and 0.28 ± 0.17 hours after IM administration. Mean half-life of the terminal phase after oral administration (3.83 ± 2.64 hours) was approximately twice that after IM administration (1.83 ± 1.22 hours). CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the extent and rate of meloxicam absorption were less after oral administration than after IM administration. Intramuscular administration resulted in a short period during which mean plasma concentrations met or exceeded reported efficacious analgesic concentrations in other species, whereas oral administration did not. These results suggested that higher doses may be required for oral administration.

Pharmacokinetics of moxidectin in alpacas following administration of an oral or subcutaneous formulation.

The purpose of this study was to evaluate the pharmacokinetics of moxidectin in alpacas after single subcutaneous injection of a non-aqueous formulation or oral administration of an aqueous drench at 0.2 mg∗kg(-1). Plasma moxidectin concentrations were measured with reverse phase HPLC, and data analyzed using non-compartmental methods. Half-life was longer (p=0.02) after subcutaneous administration than oral (292+/-170 vs 33+/-39 h). The area under the concentration-time curve was greater (p=0.04) following subcutaneous administration (1484.8+/-1049.5 h∗ng∗ml(-1)) than oral (157.6+/-85.9 h∗ng∗ml(-1)). The peak concentration (Cmax) was higher and the after subcutaneous administration, but the difference was not statistically significant (p=0.18). The relative bioavailability of the oral moxidectin to the subcutaneous moxidectin was 11%. The data suggest a higher relative bioavailability following subcutaneous compared to oral administration. Further studies are needed to determine the therapeutic concentrations of moxidectin in alpacas.

Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs.

OBJECTIVE: To determine the pharmacokinetics of orally administered rapamycin in healthy dogs. ANIMALS: 5 healthy purpose-bred hounds. PROCEDURES: The study consisted of 2 experiments. In experiment 1, each dog received rapamycin (0.1 mg/kg, PO) once; blood samples were obtained immediately before and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration. In experiment 2, each dog received rapamycin (0.1 mg/kg, PO) once daily for 5 days; blood samples were obtained immediately before and at 3, 6, 24, 27, 30, 48, 51, 54, 72, 75, 78, 96, 96.5, 97, 98, 100, 102, 108, 120, 144, and 168 hours after the first dose. Blood rapamycin concentration was determined by a validated liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters were determined by compartmental and noncompartmental analyses. RESULTS: Mean ± SD blood rapamycin terminal half-life, area under the concentration-time curve from 0 to 48 hours after dosing, and maximum concentration were 38.7 ± 12.7 h, 140 ± 23.9 ng•h/mL, and 8.39 ± 1.73 ng/mL, respectively, for experiment 1, and 99.5 ± 89.5 h, 126 ± 27.1 ng•h/mL, and 5.49 ± 1.99 ng/mL, respectively, for experiment 2. Pharmacokinetic parameters for rapamycin after administration of 5 daily doses differed significantly from those after administration of 1 dose. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that oral administration of low-dose (0.1 mg/kg) rapamycin to healthy dogs achieved blood concentrations measured in nanograms per milliliter. The optimal dose and administration frequency of rapamcyin required to achieve therapeutic effects in tumor-bearing dogs, as well as toxicity after chronic dosing, need to be determined.

Pharmacokinetics of Compounded Intravenous and Oral Gabapentin in Hispaniolan Amazon Parrots ( Amazona ventralis ).

Neuropathic pain is a manifestation of chronic pain that arises with damage to the somatosensory system. Pharmacologic treatment recommendations for alleviation of neuropathic pain are often multimodal, and the few reports communicating treatment of suspected neuropathic pain in avian patients describe the use of gabapentin as part of the therapeutic regimen. To determine the pharmacokinetics of gabapentin in Hispaniolan Amazon parrots ( Amazona ventralis ), compounded gabapentin suspensions were administered at 30 mg/kg IV to 2 birds, 10 mg/kg PO to 3 birds, and 30 mg/kg PO to 3 birds. Blood samples were collected immediately before and at 9 different time points after drug administration. Plasma samples were analyzed for gabapentin concentration, and pharmacokinetic parameters were calculated with both a nonlinear mixed-effect approach and a noncompartmental analysis. The best compartmental, oral model was used to simulate the concentration-time profiles resulting from different dosing scenarios. Mild sedation was observed in both study birds after intravenous injection. Computer simulation of different dosing scenarios with the mean parameter estimates showed that 15 mg/kg every 8 hours would be a starting point for oral dosing in Hispaniolan Amazon parrots based on effective plasma concentrations reported for human patients; however, additional studies need to be performed to establish a therapeutic dose.

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.

The role of the macrolide tulathromycin in veterinary medicine.

Tulathromycin is the first and only member of the triamilide sub-class of macrolides that is used therapeutically and has been registered in more than 30 countries across America, Europe, Oceania and Asia. The discovery of tulathromycin and its registration in multiple countries has been important for the food animal industry as it has been used successfully to treat economically important conditions such as bovine and porcine respiratory disease, infectious bovine keratoconjunctivitis and interdigital necrobacillosis. Since it was first registered about 8 years ago, considerable information has been generated to help define tulathromycin's role in veterinary medicine as well as setting the basis for new treatment strategies and for the discovery of new macrolides with further applications in veterinary and human medicine. This article reviews this information and examines more recent findings particularly the effects of tulathromycin on the immune response, its pharmacokinetics and pharmacodynamics, its pattern of susceptibility and the identification of genes that may be associated with resistance to the drug.

Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs.

SHetA2 is a heteroarotinoid that has shown selective inhibition of cancer cell growth and an induction of apoptosis without activation of nuclear retinoic acid receptors. In the rat study, SHetA2 was administered in 1% aqueous methylcellulose/0.2% Tween 80 by oral gavage at 0, 100, 500, and 2,000 mg/kg/day for 28 days. The high-dose administration induced decreased activity in male rats, decreased body-weight gains and food consumption, and changes in organ weights. The major metabolite of SHetA2 in rat plasma was monohydroxy SHetA2, which was considerably higher than the parent compound after oral and intravenous administration. Pharmacokinetic analysis showed extremely low (<1%) systemic bioavailability of SHetA2 for all doses tested. The dose of 2,000 mg/kg/day was considered as the lowest observed adverse effect level. The no observed adverse effect level (NOAEL) was 500 mg/kg/day. In the dog study, no toxicity of SHetA2 in 30% aqueous Solutol(®) HS 15 was observed in any tested dose groups (0, 100, 400, and 1,500 mg/kg/day). The major metabolite of SHetA2 in dog plasma was also monohydroxy SHetA2, which was equal to or lower than the parent compound after oral administration. SHetA2 levels in dog plasma were notably higher, when compared to levels in rat plasma. However, exposure was not dose proportional, as exemplified by a lack of proportional increase in maximum concentration or area under the plasma concentration-time curve with increasing dose. The NOAEL was not established and was considered to be above 1,500 mg/kg/day.

Single-dose safety and pharmacokinetic evaluation of fluorocoxib A: pilot study of novel cyclooxygenase-2-targeted optical imaging agent in a canine model.

We evaluated preclinical single-dose safety, pharmacokinetic properties, and specific uptake of the new optical imaging agent fluorocoxib A in dogs. Fluorocoxib A, N-[(5-carboxy-X-rhodaminyl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, selectively binds and inhibits the cyclooxygenase-2 (COX-2) enzyme, which is overexpressed in many cancers. Safety pilot studies were performed in research dogs following intravenous (i.v.) administration of 0.1 and 1 mg/kg fluorocoxib A. Blood and urine samples collected three days after administration of each dose of fluorocoxib A revealed no evidence of toxicity, and no clinically relevant adverse events were noted on physical examination of exposed dogs over that time period. Pharmacokinetic parameters were assessed in additional research dogs from plasma collected at several time points after i.v. administration of fluorocoxib A using high-performance liquid chromatography analysis. The pharmacokinetic studies using 1 mg/kg showed a peak of fluorocoxib A (92±28 ng/ml) in plasma collected at 0.5 h. Tumor specific uptake of fluorocoxib A was demonstrated using a dog diagnosed with colorectal cancer expressing COX-2. Our data support the safe single-dose administration and in vivo efficacy of fluorocoxib A, suggesting a high potential for successful translation to clinical use as an imaging agent for improved tumor detection in humans.

Pharmacokinetics of a long-acting ceftiofur crystalline-free acid formulation in Asian elephants (Elephas maximus).

OBJECTIVE: To determine the pharmacokinetics of a long-acting formulation of ceftiofur, ceftiofur crystalline-free acid (CCFA), following SC injection to Asian elephants (Elephas maximus). ANIMALS: 11 adult Asian elephants. PROCEDURES: Each elephant received CCFA (6.6 mg/kg, SC) in the area caudoventral to the base of an ear. Blood samples were collected from an ear vein immediately prior to and at 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after CCFA administration. Plasma concentrations of desfuroylceftiofur acetamide (the acetamide derivative of ceftiofur) were measured via ultrahigh-pressure liquid chromatography-tandem mass spectrometry. Data were analyzed via a noncompartmental pharmacokinetics approach. RESULTS: The mean ± SD maximum plasma concentration of desfuroylceftiofur acetamide was 1.36 ± 0.74 µg/mL and was detected at 4718 ± 31.30 hours. The mean ± SD area under the curve from time 0 to infinity was 2278 ± 55.8 µg•h/mL, and the mean residence time from time 0 to infinity was 158.2 ± 90.2 hours. The terminal elimination half-life associated with the slope of the terminal phase had a harmonic mean ± pseudo-SD of 83.36 ± 30.01 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Elephants tolerated CCFA at a dose of 6.6 mg/kg, SC, well. Dosing recommendations will depend on the mean inhibitory concentration of ceftiofur for each bacterial pathogen. Desfuroylceftiofur acetamide concentrations remained > 0.25 µg/mL for the entire 168-hour study period, which suggested CCFA would provide clinically relevant antimicrobial activity against certain pathogens for 7 to 10 days.

Pharmacokinetics of ponazuril after oral administration to healthy llamas (Lama glama).

OBJECTIVE: To determine the pharmacokinetics after oral administration of a single dose of ponazuril to healthy llamas. ANIMALS: 6 healthy adult llamas. PROCEDURES: Ponazuril (20 mg/kg) was administered once orally to 6 llamas (day 0). Blood samples were obtained on days 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 14, 21, 28, 35, 42, and 49. Serum ponazuril concentrations were determined by use of a validated reverse-phase high-performance liquid chromatography assay with UV absorbance detection. Pharmacokinetic parameters were derived by use of a standard noncompartmental pharmacokinetic analysis. RESULTS: Mean ± SD area under the serum concentration-time curve was 7,516 ± 2,750 h•mg/L, maximum serum ponazuril concentration was 23.6 ± 6.0 mg/L, and the elimination half-life was 135.5 ± 16.7 hours. Serum concentration of ponazuril peaked at 84 hours (range, 48 to 120 hours) after administration and gradually decreased but remained detectable for up to 35 days after administration. No adverse effects were observed during the study period. CONCLUSIONS AND CLINICAL RELEVANCE: The rate and extent of absorption following oral administration of a single dose of ponazuril were sufficient to result in potentially effective concentrations, and the drug was tolerated well by llamas. At this dose, ponazuril resulted in serum concentrations that were high enough to be effective against various Apicomplexans on the basis of data for other species. The effective ponazuril concentration that will induce 50% inhibition of parasite growth for Eimeria macusaniensis in camelids is currently unknown.

Assessment of oral toxicity and safety of 9-cis-UAB30, a potential chemopreventive agent, in rat and dog studies.

9-cis-UAB30 is a potential chemopreventative agent that has been shown to be effective on many different types of tumors. The safety and toxicity of 9-cis-UAB30 had not been previously established. These studies were conducted to evaluate the potential toxicity and pharmacokinetics in a rodent and a nonrodent species for the purpose of investigational new drug submission. Oral gavage administration of 9-cis-UAB30 at the doses 0, 3, 15, and 100 mg/kg/day to CD® rats for 28 days showed a dose-dependent (although not dose-proportional) increase in plasma drug levels in week 4. The liver was the target organ for toxicity of 9-cis-UAB30. Hepatomegaly along with increases in serum aspartate-aminotransferase and alkaline-phosphatase levels were seen in rats. Moderate hypoalbuminemia and hyperglobulinemia resulted in a decreased albumin/globulin ratio. Histopathology revealed hepatocellular change consistent with hepatic glycogen deposition. Toxicity studies in dogs did not show treatment-related toxicity at doses as high as 100 mg/kg/day (highest dose tested) administered by capsules for 28 days. No effects on the central nervous system (functional observational battery in rats) or cardiovascular function (safety pharmacology study in telemeterized dogs) were seen. The no observed adverse effect level (NOAEL) in the rat studies was 3 mg/kg/day; however, the adverse effects seen in rats receiving 15 mg/kg/day (the least observed adverse effect level) was a slight, but statistically significant, elevation in fibrinogen and decrease in prothrombin time, which may be a sign of some tendency for increased blood coagulation. The NOAEL in the dog study was at least 100 mg/kg/day.

Pharmacokinetics of a long-acting ceftiofur formulation (ceftiofur crystalline free acid) in the ball python (Python regius).

The objective of this study was to determine the pharmacokinetics of a long-acting formulation of ceftiofur crystalline-free acid (CCFA) following intramuscular injection in ball pythons (Python regius). Six adult ball pythons received an injection of CCFA (15 mg/kg) in the epaxial muscles. Blood samples were collected by cardiocentesis immediately prior to and at 0.5, 1, 2, 4, 8, 12, 18, 24, 48, 72, 96, 144, 192, 240, 288, 384, 480, 576, 720, and 864 hr after CCFA administration. Plasma ceftiofur concentrations were determined by high-performance liquid chromatography. A noncompartmental pharmacokinetic analysis was applied to the data. Maximum plasma concentration (Cmax) was 7.096 +/- 1.95 microg/ml and occurred at (Tmax) 2.17 +/- 0.98 hr. The area under the curve (0 to infinity) for ceftiofur was 74.59 +/- 13.05 microg x h/ml and the elimination half-life associated with the terminal slope of the concentration-time curve was 64.31 +/- 14.2 hr. Mean residence time (0 to infinity) was 46.85 +/- 13.53 hr. CCFA at 15 mg/kg was well tolerated in all the pythons. Minimum inhibitory concentration (MIC) data for bacterial isolates from snakes are not well established. For MIC values of < or =0.1 microg/ml, a single dose of CCFA (15 mg/kg) provides adequate plasma concentrations for at least 5 days in the ball python. For MICs > or =0.5 microg/ml, more frequent dosing or a higher dosage may be required.

Serum concentrations of methimazole in cats after a single oral dose of controlled-release carbimazole or sugar-coated methimazole (thiamazole).

Methimazole (thiamazole) is an antithyroid drug commonly used to treat feline hyperthyroidism. It is routinely given twice daily. Carbimazole is a methimazole derivative that is rapidly metabolized to methimazole in vivo. A controlled-release tablet for once-daily carbimazole therapy has recently been developed in an attempt to improve compliance during medical management of feline hyperthyroidism. The results of a crossover study in six cats suggest that the pharmacokinetics of methimazole with a single dose of this controlled-release tablet may be similar to those with a single dose of a sugar-coated methimazole tablet when the two drugs are given at an equimolar dose. The mean half-lives were nearly identical (3.12 hours, sugar-coated methimazole tablets; 3.28 hours, controlled-release carbimazole tablets). The serum concentrations of methimazole at 24 hours were 21.7 ± 28.9 ng/mL in the cats treated with 5-mg sugar-coated methimazole tablets and 28.7 ± 37 ng/mL in the cats treated with 10-mg carbimazole tablets (which provide approximately 25% more methimazole after conversion to the active metabolite).

Determination of carboplatin in canine plasma by high-performance liquid chromatography.

Carboplatin is an antineoplastic drug administered to treat different tumoral conditions in canine oncology. The objective of this study was to validate a high-performance chromatographic (HPLC) method which could be applied in canine pharmacokinetic studies. Following ultrafiltration using a Centrifree device, standards, quality controls and plasma samples were separated by isocratic reversed-phase HPLC on an Inertsil ODS-2 (250 x 4.6 mm i.d.) analytical column and quantified using UV detection at 220 nm. The mobile phase was potassium phosphate (pH 4.5), with a flow-rate of 1.0 mL/min. The procedure produced a linear curve (r(2) > 0.999) over the concentration range 1-200 microg/mL. The lower limit of quantification was 1 microg/mL. The intra-assay and inter-assay precision was approximately 90%. The overall recovery was approximately 90%. The method was illustrated with a preliminary pharmacokinetic analysis on nine dogs treated with carboplatin at our hospital. Carboplatin disposition followed a monocompartmental structure in dogs and was characterized by a short half-life (50 min).

Evaluation of oral itraconazole administration in captive Humboldt penguins (Spheniscus humboldti).

Aspergillus spp. fungal infections are the most common cause of morbidity and mortality in captive penguins. Itraconazole has been the drug of choice for both therapeutic and prophylactic treatment; however, the pharmacokinetic and pharmacodynamic parameters can be highly variable in different species, and it has not been evaluated in penguins. In this study, four preliminary steady-state trials were performed to compare two oral formulations of itraconazole (commercial capsules compared with generic bulk compounded powder) at two different dosages (6 or 12 mg/kg once a day) administered in fish to small groups of captive Humboldt penguins (Spheniscus humboldti). Building on this data, a final steady-state trial was performed with the use of a 7 mg/kg oral dosage twice a day of commercial capsules given in fish to a group of 15 penguins. With sparse sampling, blood was drawn for testing from small subsets of each treatment group at 4-7 time points in the 24-hr period after the final dose of itraconazole on day 14. Steady-state plasma concentrations of itraconazole and hydroxyitraconazole, the major metabolite, were determined by reverse phase high-performance liquid chromatography with fluorescence detection. Treatment with the generic bulk compounded product resulted in plasma levels of itraconazole that were undetectable for 26 out of 30 blood samples, compared with seven out of 20 blood samples for the commercial product at the same dosage. On the basis of study results, an estimated oral dosage of either 8.5 mg/kg twice a day or 20 mg/kg once a day of the commercial itraconazole capsules given in fish would produce adequate steady-state therapeutic blood levels in Humboldt penguins.