Penciclovir pharmacokinetics after oral and rectal administration of famciclovir in African elephants (Loxodonta africana) shows that effective concentrations can be achieved from rectal administration, despite lower absorption.

OBJECTIVE: To evaluate the pharmacokinetics of famciclovir and its metabolite penciclovir following a single dose administered orally and rectally in African elephants (Loxodonta africana). ANIMALS: 15 African elephants (6 males and 9 females) of various ages. METHODS: Famciclovir (15 mg/kg) was administered orally or per rectum once, with at least a three-week washout period between administrations. Blood was collected at 13 different timepoints per administration for 6 elephants, occurring between February and March 2020. An additional 9 elephants were sampled at variable timepoints per administration utilizing a sparse sampling design between July 2020 and January 2021. Plasma famciclovir and penciclovir levels were measured via HPLC and fluorescence detection. Pharmacokinetic analysis was completed in the summer of 2021 using noncompartmental analysis and nonlinear mixed-effects modeling. RESULTS: Famciclovir was not detected in any sample, suggesting complete metabolism. Key pharmacokinetic parameters for penciclovir following oral administration were time to maximum concentration (tmax; 2.12 hours), area under the concentration-versus-time curve (AUC; 33.93 µg·h/mL), maximum observed concentration (Cmax; 3.73 µg/mL), and absorption half-life (t1/2; 0.65 hours). Following rectal administration, the values were: tmax, 0.65 hours; AUC, 15.62 µg·h/mL; Cmax, 2.52 µg/mL; and absorption t1/2, 0.13 hours. CONCLUSIONS: Famciclovir was rapidly metabolized to penciclovir. Oral administration resulted in slower absorption but higher maximum plasma concentration and higher AUC compared to rectal administration. CLINICAL RELEVANCE: African elephants administered famciclovir via oral and rectal routes resulted in measurable serum penciclovir, and these findings may be utilized by clinicians treating viral infections in this species.

The effects of food on the pharmacokinetics of mycophenolate mofetil in healthy horses.

Additional immunomodulatory treatment is needed for the management of immune-mediated disease in horses. Mycophenolate mofetil (MMF) is an immunomodulatory agent used in human and veterinary medicine for the prevention of graft rejection and the management of autoimmune diseases. Few studies exist investigating the pharmacokinetics of MMF in horses. The aim of this study was to evaluate the pharmacokinetics of a single dose of MMF in healthy horses in the fed vs. fasted state. Six healthy Standardbred mares were administered MMF 10 mg/kg by a nasogastric (NG) tube in a fed and fasted state. A six-day washout period was performed between the two doses. No statistically significant differences in mycophenolic acid (MPA) concentrations were seen at any time point apart from 8 h, when plasma metabolite concentrations were significantly higher in the fasted state compared to the fed state (p = .038). Evidence of enterohepatic recirculation was seen only in the fasted state; this did not yield clinical differences in horses administered a single-dose administration but may be significant in horses receiving long-term MMF treatment.

Animal drug shortages limit veterinary therapeutic options and introduce artifacts in antimicrobial sales reporting.

Supply chain issues disrupt veterinary care and cause downstream consequences that alter the practice of veterinary medicine. Antimicrobials are just 1 class of pharmaceuticals that have been impacted by supply chain issues over the last couple of years. Since February 2021, 2 sponsors/manufacturers of penicillin products have reported shortages in the active pharmaceutical ingredient. With the release of the 2021 Summary Report on Antimicrobials Sold or Distributed for Use in Food-Producing Animals by the FDA, a key finding was a 19% decrease in penicillin sales and distribution from 2020 to 2021. Herein, we provide our clinicians' professional perspective regarding how drug shortages, specifically that of penicillin, might contribute to misconstrued patterns in antimicrobial use and what can be done by veterinarians and the FDA to minimize the impact of an antimicrobial drug shortage on animal health and well-being.

THE PHARMACOKINETICS AND PHARMACODYNAMICS OF ORAL PONAZURIL IN THE TREATMENT OF SYSTEMIC ISOSPOROSIS IN PASSERINE BIRDS.

Systemic isosporosis, previously atoxoplasmosis, is a significant cause of mortality in juvenile passerine birds. Recommended treatment regimens are empiric and vary in efficacy. The goal of this study was to determine the pharmacokinetics and pharmacodynamics of ponazuril for treatment of systemic isosporosis. Ponazuril, diluted with water to create an oral suspension (50 mg/ml), was administered (100 mg/kg) to 72 European starlings (Sturnus vulgaris) by a single dose via direct oral gavage (n = 24), a single dose injected into superworm larvae (Zophobas morio; n = 24), or a daily dose mixed with commercial dog food to top-dress feed for 5 d (n = 24). Peak plasma concentrations were 5.84, 2.46, and 9.13 µg/ml for the direct gavage, injected larvae, and top-dressed feed groups, respectively. With repeated dosing, mean plasma concentrations from the top-dressed feed group were maintained between 8.12 to 13.11 µg/ml. Results suggested ponazuril at a dosage of 100 mg/kg administered via direct gavage or top-dressed feed, but not via injected larvae, would exceed the concentrations needed to inhibit merogony of other apicomplexan parasites in cell culture (5 µg/ml). To assess the pharmacodynamics of this dose, seven passerine birds, red-vented bulbuls (Pycnonotus cafer; n = 2), blue-grey tanager (Thraupis episcopus; n = 1), and red-capped cardinals (Paroaria gularis; n = 4), were identified as shedders of systemic Isospora spp. via fecal qPCR. Birds were then treated with ponazuril (100 mg/kg) daily on top-dressed feed for 14 d. Fecal shedding was assessed via qPCR for 6 wk from the initiation of treatment. Treatment was associated with reduction in proportions of fecal shedding during the treatment period and the week following treatment, but shedding resumed in all birds by the end of sampling. Results support that treatment of breeding birds with 100 mg/kg ponazuril could reduce the shedding of active oocysts and decrease risk of clinical infection in susceptible juveniles.

Pharmacokinetics of pimobendan after oral administration to dogs with myxomatous mitral valve disease.

BACKGROUND: Pimobendan is an important therapy for dogs with myxomatous mitral valve disease (MMVD). The pharmacokinetics are reported in healthy dogs but not in dogs with heart disease. HYPOTHESIS/OBJECTIVES: To determine if dog characteristics such as age, breed, body condition score, ACVIM stage of heart disease or biochemical laboratory value alter the pharmacokinetics of orally administered pimobendan and its metabolite in a cohort of dogs with naturally occurring MMVD. ANIMALS: Fifty-seven client-owned dogs with MMVD ACVIM Stage B2, C, or D and administered pimobendan to steady state blood concentrations. METHODS: Prospective, observational study. Samples were collected using a sparse-sampling protocol at specific intervals after administration of pimobendan. Plasma pimobendan and the active metabolite (O-desmethyl-pimobendan, ODMP) concentrations were determined via high-pressure liquid chromatography and fluorescence detection. Data was analyzed via a population pharmacokinetic approach and nonlinear mixed effects modeling (NLME). Numerous covariates were examined in the NLME model. RESULTS: The absorption and elimination half-lives (t1/2 ) were approximately 1.4 and 1 hour for pimobendan and 1.4 and 1.3 hours for ODMP, respectively. Pharmacokinetic parameters were highly variable, especially the values for pimobendan absorption and elimination rate, and absorption rate of ODMP with coefficients of variation of 147.84%, 64.51% and 64.49%, respectively. No covariate evaluated was a significant source of variability. CONCLUSIONS AND CLINICAL IMPORTANCE: The pharmacokinetic parameters were highly variable among this group of dogs with MMVD. The variability was not associated with the dog's age, body weight or condition score, stage of heart disease, dose, serum creatinine, or alkaline phosphatase.

Population pharmacokinetic analysis of enrofloxacin and its active metabolite ciprofloxacin after intravenous injection to cats with reduced kidney function.

BACKGROUND: It is unknown if enrofloxacin accumulates in plasma of cats with reduced kidney function. HYPOTHESIS: To determine if enrofloxacin and its active metabolite ciprofloxacin have reduced clearance in azotemic cats. ANIMALS: Thirty-four cats hospitalized for clinical illness with variable degree of kidney function. METHODS: Prospective study. After enrofloxacin (dose 5 mg/kg) administration to cats, sparse blood sampling was used to obtain 2 compartment population pharmacokinetic results using nonlinear mixed-effects modeling. Plasma enrofloxacin and ciprofloxacin concentrations were measured and summed to obtain the total fluoroquinolone concentration. A model of ciprofloxacin metabolism from enrofloxacin was created and evaluated for covariate effects on clearance, volume of distribution, and the metabolic rate of ciprofloxacin generation from enrofloxacin. RESULTS: Body weight was the only covariate found to affect total fluoroquinolone volume of distribution (effect 1.63, SE 0.19, P < .01) and clearance (effect 1.63, SE 0.27, P < .01). Kidney function did not have a significant effect on total fluoroquinolone clearance (median 440.8 mL/kg/h (range 191.4-538.0 mL/kg/h) in cats with normal kidney function, 365.8 mL/kg/h (range 89.49-1092.0 mL/kg/h) in cats with moderate kidney dysfunction, and 308.5 mL/kg/h (range 140.20-480.0 mL/kg/h) in cats with severe kidney dysfunction (P = .64). Blood urea nitrogen concentration influenced the metabolic generation of ciprofloxacin from enrofloxacin (effect 0.51, SE 0.08, P < .01), but other markers of kidney function did not. CONCLUSIONS AND CLINICAL IMPORTANCE: Adjustment of enrofloxacin dosage is not indicated for azotemic cats.

Revision of fluoroquinolone breakpoints used for interpretation of antimicrobial susceptibility testing of canine bacterial isolates.

The fluoroquinolone antimicrobial agents, enrofloxacin and marbofloxacin, were US Food and Drug Administration (FDA) approved in the United States for use in dogs in 1988 and 1999, respectively. There have been many advances since then concerning the pharmacokinetic-pharmacodynamic (PK-PD) evaluation of fluoroquinolones, and there are data available on the susceptibility of targeted pathogens since the original approval. Using this information, the Clinical and Laboratory Standards Institute (CLSI) Veterinary Antimicrobial Susceptibility Testing Subcommittee (VAST) revised its antimicrobial susceptibility testing breakpoints. The previous breakpoints (used in older editions of CLSI standards) for enrofloxacin in dogs were susceptible (S), ≤ 0.5 µg/mL, intermediate (I) 1-2 µg/mL, and resistant (R) ≥ 4 µg/mL. The new breakpoints are S ≤ 0.06 µg/mL for a dose of 5 mg/kg, 0.12 µg/mL for a dose of 10 mg/kg, 0.25 µg/mL for a high dose of 20 mg/kg, and R ≥ 0.5 µg/mL. The breakpoints of 0.12 and 0.25 µg/mL represent a new susceptible-dose dependent (SDD) category. For marbofloxacin, previous breakpoints were S, ≤ 1 µg/mL, I 2 µg/mL, and R ≥ 4 µg/mL. The new breakpoints are S ≤ 0.12 µg/mL for a dose of 2.8 mg/kg, 0.25 µg/mL for a dose of 5.5 mg/kg (SDD), and R ≥ 0.5 µg/mL. The new breakpoints will be published in the next edition of CLSI-Vet01(S) and deviate considerably from the prior breakpoints. Laboratories are encouraged to revise their testing standards. These changes will likely reduce the unnecessary use of these fluoroquinolones in dogs.

Effects of storage up to 1 year on the in vitro antimicrobial activity of preformulated antibiotic-impregnated calcium sulfate beads.

OBJECTIVE: To compare antimicrobial activity as demonstrated by the zone of inhibition (ZOI) produced by antibiotic-impregnated calcium sulfate (CaSO4 ) beads after storage for 0, 3, 6, 9, and 12 months. STUDY DESIGN: Controlled laboratory study. SAMPLE POPULATION: Three-millimeter diameter CaSO4 beads impregnated with vancomycin (125 mg/mL), or amikacin (250 mg/mL), or without antibiotic (control). METHODS: Calcium sulfate beads were created at the onset of the study. Individual beads were separated in sterile containers and stored in a closed cabinet at room temperature and humidity for 0, 3, 6, 9, or 12 months until testing. The ZOI against methicillin-resistant Staphylococcus pseudintermedius, methicillin-resistant Staphylococcus aureus, and Pseudomonas aeruginosa was recorded with serial replating on a fresh lawn of bacteria every 24 h until beads failed to produce a ZOI. The ZOIs and their changes were compared with mixed-effects linear models. Eluted concentrations of vancomycin measured with high-performance liquid chromatography were reported. RESULTS: At 24 h, ZOIs were comparable regardless of time since formulation, except vancomycin against P. aeruginosa, which failed to generate a ZOI. The daily changes of ZOI and duration of activity of antibiotics did not vary between storage length (p > .05). There was no consistent change in eluted drug concentration between storage length of beads. CONCLUSION: Light protected storage at room temperature for up to 12 months did not impair the in vitro activity of antibiotic-impregnated CaSO4 beads, as demonstrated through ZOIs. CLINICAL SIGNIFICANCE: When stored correctly, antibiotic-impregnated CaSO4 beads can be used at least up to 12 months after formulation.

Antimicrobial agents in small animal dermatology for treating staphylococcal infections.

Abstract: Antibiotic recommendations for treating skin infections have been published many times in the past 30 years. Prior to 2000, the recommendations focused on the use of ß-lactam antibiotics, such as cephalosporins, amoxicillin-clavulanate, or ß-lactamase stable penicillins. These agents are still recommended, and used, for wild-type methicillin-susceptible strains of Staphylococcus spp. However, since the mid-2000s there has been an increase in methicillin-resistant Staphylococcus spp (MRSP). The increase among S pseudintermedius in animals coincided with the increase in methicillin-resistant S aureus that was observed in people near the same time. This increase led veterinarians to reevaluate their approach to treating skin infections, particularly in dogs. Prior antibiotic exposure and hospitalization are identified as risk factors for MRSP. Topical treatments are more often used to treat these infections. Culture and susceptibility testing is performed more often, especially in refractory cases, to identify MRSP. If resistant strains are identified, veterinarians may have to rely on antibiotics that were previously used uncommonly for skin infections, such as chloramphenicol, aminoglycosides, tetracyclines, and human-label antibiotics such as rifampin and linezolid. These drugs carry risks and uncertainties that must be considered before they are routinely prescribed. This article will discuss these concerns and provide veterinarians guidance on the treatment of these skin infections.

PHARMACOKINETICS OF RECTALLY AND ORALLY ADMINISTERED LEVOFLOXACIN IN ASIAN ELEPHANTS (ELEPHAS MAXIMUS).

Appropriate and effective antibiotic use is a critical component of veterinary medicine, but there are variations across species regarding dosage and administration of these drugs. Oral or rectal routes of administration are typically used in elephants, but not all medications can achieve adequate concentrations rectally. The fluoroquinolone antimicrobials are used in elephants because of their favorable antimicrobial spectrum and pharmacokinetics compared with other oral agents. They are commonly used as part of multiple antibiotic regimens for the treatment of tuberculosis (Mycobacterium tuberculosis). The objective of this study was to determine the pharmacokinetic profile of levofloxacin after oral and rectal administration in Asian elephants (Elephas maximus). Dosages of 5 mg/kg orally and 15 mg/kg rectally were evaluated in 13 Asian elephants. Blood was collected at various time points from 0 to 72 h for pharmacokinetic analysis. Pharmacokinetic parameters were determined and reached concentrations above minimum inhibitory concentrations of various bacterial organisms via both routes. A pharmacokinetic-pharmacodynamic assessment was used to estimate appropriate minimal inhibitory concentrations for bacteria that could be potentially treated with this antimicrobial. Based on these findings, levofloxacin may be a consideration for administration orally (5 mg/kg) and rectally (15 mg/kg) in Asian elephants. Antimicrobial stewardship principles, culture and susceptibility of suspected pathogens, and blood level monitoring should be used to tailor administration of levofloxacin in this species.

Pharmacokinetics of a FDA-labeled dose of diclazuril administered orally once weekly to adult horses.

Equine protozoal myeloencephalitis (EPM) has remained a devastating neurological disease of the Americas, especially in young performance horses. Prophylactic treatment strategies with diclazuril have shown to reduce seroprevalence and titer levels to Sarcocystis neurona in healthy horses continuously exposed to the apicomplexan parasite. The goal of this study was to determine if the FDA-labeled dose of 1 mg/kg of 1.56% diclazuril (ProtazilTM) given once weekly to healthy adult horses would achieve steady-state concentrations in plasma known to be inhibitory to S. neurona in cell culture. Five individual diclazuril doses were administered at weekly intervals to 8 adult horses. Blood was collected via venipuncture immediately before (trough concentration) and 10 hours after (peak concentration) each diclazuril administration. Following the fifth dose, additional blood samples were collected every 24 hours after the peak blood collection for 7 days. All plasma samples were analyzed by high-pressure liquid chromatography. The pharmacokinetic analysis was performed using a nonlinear mixed effects model. The mean population-derived peak concentration was 264 ng/mL and the mean terminal half-life was 3.6 days. Thus, the oral administration of an FDA-labeled dose of diclazuril to healthy horses once a week was able to produce steady-state plasma drug concentrations known to inhibit S. neurona in vitro.

Gastrointestinal transit time is faster in Beagle dogs compared to cats.

OBJECTIVE: To characterize gastrointestinal transit times (GITTs) and pH in dogs, and to compare to data recently described for cats. ANIMALS: 7 healthy, colony-housed Beagles. PROCEDURES: The GITTs and pH were measured using a continuous pH monitoring system. For the first period (prefeeding), food was withheld for 20 hours followed by pH capsule administration. Five hours after capsule administration, dogs were offered 75% of their historical daily caloric intake for 1 hour. For the second period (postfeeding), food was withheld for 24 hours. Dogs were allowed 1 hour to eat, followed by capsule administration. Both periods were repeated 3 times. The GITTs and pH were compared to published feline data. RESULTS: The mean ± SD transit times in dogs for the pre- and postfeeding periods, respectively, were esophageal, 3 ± 5 minutes and 13 ± 37 minutes; gastric, 31 ± 60 minutes and 829 ± 249 minutes; and intestinal, 795 ± 444 minutes and 830 ± 368 minutes. The mean ± SD gastrointestinal pH in dogs for the pre- and postfeeding periods, respectively, were esophageal, 6.6 ± 0.6 and 5.7 ± 1.0; gastric, 3.0 ± 1.4 and 1.8 ± 0.3; intestinal, 7.9 ± 0.3 and 7.7 ± 0.6; first-hour small intestinal, 7.6 ± 0.5 and 7.1 ± 0.4; and last-hour large intestinal, 7.9 ± 0.6 and 7.7 ± 1.0. The first-hour small intestinal pH and total transit times varied between dogs and cats depending on feed period (P = .002 and P = .04, respectively). Post hoc analysis revealed significantly shorter total transit times in dogs prefeeding (P = .005; mean ± SD for cats, 2,441 ± 1,359 minutes; for dogs, 828 ± 439 minutes) and postfeeding (P = .03; mean ± SD for cats, 3,009 ± 1,220 minutes; for dogs, 1,671 ± 513 minutes). Total transit time for dogs was also shorter pre- versus postfeeding (P = .003). CLINICAL RELEVANCE: GITT is faster in Beagles compared to cats, but gastrointestinal pH are similar when fed the same diet.

Ceftazidime pharmacokinetics in dogs after intravenous injection and delivered with the RxActuator Mini-Infuser infusion pump.

OBJECTIVE: To test the feasibility of an SC mini-infusion pump to deliver ceftazidime in dogs and produce plasma concentrations sufficient to reach a therapeutic target for 48 hours. SETTING: University research laboratory. ANIMALS: Six healthy Beagle dogs. INTERVENTIONS: Ceftazidime was administered by 2 routes to 6 healthy Beagle dogs. The first route was an IV bolus injection into a cephalic vein at a dose of 25 mg/kg. Blood samples were collected for 8 hours following injection. The second route was a SC infusion for 48 hours using the RxActuator Mini-Infuser wearable SC constant rate infusion pump. Blood samples were collected for 58 hours following application of the pump. All plasma samples were analyzed by high-pressure liquid chromatography and subject to pharmacokinetic analysis. MAIN RESULTS: After the IV bolus injection, there was rapid distribution and elimination. The elimination half-life was 0.95 hours, and the clearance was rapid at 0.176 ml/h/kg. After the 48-hour SC infusion, the half-life was slightly shorter, and the clearance was higher. The percent bioavailability from the SC infusion was approximately 72%. The SC infusion maintained plasma concentration near our target of 8 µg/ml for most of the dose interval but slightly lower after 24 hours. The concentrations below the target were attributed to slight drug loss, less than 100% bioavailability, and faster clearance from SC administration. CONCLUSIONS: This study demonstrated the successful application of the RxActuator Mini-Infuser wearable SC constant rate infusion pump for delivering an antimicrobial needed for serious, and sometimes resistant, infections in dogs.

Impact of gastrointestinal differences in veterinary species on the oral drug solubility, in vivo dissolution, and formulation of veterinary therapeutics.

Many gaps exist in our understanding of species differences in gastrointestinal (GI) fluid composition and the associated impact of food intake and dietary composition on in vivo drug solubilization. This information gap can lead to uncertainties with regard to how best to formulate pharmaceuticals for veterinary use or the in vitro test conditions that will be most predictive of species-specific in vivo oral product performance. To address these challenges, this overview explores species-specific factors that can influence oral drug solubility and the formulation approaches that can be employed to overcome solubility-associated bioavailability difficulties. These discussions are framed around some of the basic principles associated with drug solubilization, reported species differences in GI fluid composition, types of oral dosage forms typically given for the various animal species, and the effect of prandial state in dogs and cats. This basic information is integrated into a question-and-answer section that addresses some of the formulation issues that can arise in the development of veterinary medicinals.

Veterinary antimicrobial prescribing practices for treatment of presumptive sporadic urinary tract infections in dogs examined at primary care practices in the United States (2010-2019).

OBJECTIVE: To describe patterns of antimicrobial prescriptions for sporadic urinary tract infections (UTIs) in dogs in the United States from 2010 through 2019, including times before and after publication of International Society for Companion Animal Infectious Disease (ISCAID) guidelines. SAMPLE: 461,244 qualifying visits for sporadic UTIs. PROCEDURES: Veterinary electronic medical records of a private corporation consisting of > 1,000 clinics across the United States were examined to identify canine visits for potential sporadic UTI between January 1, 2010, and December 31, 2019. Proportions of antimicrobial prescriptions were graphed by month and year to identify changes in prescription patterns over time. Interrupted time series analysis was performed for the aminopenicillins. RESULTS: A total of 461,244 qualifying visits were examined, with 389,949 (85%) of these resulting in at least 1 antimicrobial prescription. Over the 10-year period, the proportion of visits resulting in no antimicrobial prescription increased (14% in 2010 to 19.7% in 2019). Proportions of prescriptions for amoxicillin (38% to 48%) and amoxicillin-clavulanic acid (2.5% to 10%) also increased. Log-linear regression supported that changes in proportions of amoxicillin and amoxicillin-clavulanic acid prescriptions occurred following the 2011 ISCAID guidelines publication, with the proportion of amoxicillin prescriptions increasing by 13% per year (95% CI, 12% to 14%; P < 0.01) and the proportion of amoxicillin-clavulanic acid prescriptions increasing by 0.5% per year (95% CI, 0.2% to 0.8%; P < 0.01). Use of fluoroquinolones and third-generation cephalosporins remained constant. CLINICAL RELEVANCE: Results suggest that efforts to guide antimicrobial use in veterinary clinical practice are having positive effects in this private veterinary company, though continued efforts are warranted.

PHARMACOKINETICS OF A SINGLE DOSE OF INTRAMUSCULAR AND ORAL MELOXICAM IN YELLOW STINGRAYS (UROBATIS JAMAICENSIS).

Elasmobranchs are popular display animals in public aquaria and zoos, but medical management gaps remain in the understanding of the pharmacokinetics of analgesics and pain management in these species. Meloxicam is a nonsteroidal anti-inflammatory drug that has been evaluated intravenously and intramuscularly in teleosts, but has yet to be studied in any elasmobranch species. The pharmacokinetics of meloxicam were determined in 17 yellow stingrays (Urobatis jamaicensis). All stingrays were determined to be healthy from complete physical examinations and baseline bloodwork performed prior to study inclusion. A single dose of 1 mg/kg meloxicam intramuscularly was administered to all rays, followed by a 2 mg/kg oral dose after an 8 wk washout period. Blood samples were collected from the mesopterygial vein at baseline and nine time points up to 96 h after administration of meloxicam. Plasma concentrations were determined using reversed-phase high-performance liquid chromatography. Pharmacokinetic analysis was performed using a noncompartmental technique. The mean peak plasma concentrations for intramuscular and oral meloxicam were 1.29 and 0.42 µg/ml, respectively. The mean terminal half-lives of meloxicam after intramuscular and oral administration were 5.75 and 15.46 h, respectively. Based on these findings, the recommended meloxicam dosage and frequency for yellow stingrays is 2 mg/kg orally once daily. Due to rapid elimination with the intramuscular administration, maintaining clinically relevant plasma concentrations may be difficult using this route. Further studies are needed to determine multidose pharmacokinetics of meloxicam in yellow stingrays, as well as single-dose and multidose pharmacokinetics in other elasmobranch species.

Naloxone and nalmefene absorption delivered by hollow microneedles compared to intramuscular injection.

Naloxone and nalmefene were administered to seven research beagle dogs (mean weight approximately 12 kg) at doses of 0.04 mg/kg and 0.014 mg/kg for naloxone and nalmefene, respectively. Each dose was administered intramuscularly (IM) with a standard IM injection and with a hollow microneedle device array using needles of 1 mm in length. The IM injection was delivered in the epaxial muscles, and the microneedle injection was delivered in the skin over the shoulder of each dog. Each dog received the same injections in a crossover design. Following the injection, blood samples were collected for plasma analysis of naloxone and nalmefene by high-pressure liquid chromatography with mass spectrometry detection (LCMS). The plasma sample concentrations were plotted for observed patterns of absorption and analyzed with non-compartmental pharmacokinetic methods (NCA). The results showed that the injection of naloxone from the microneedle device produced a higher peak concentration (CMAX) by 2.15 × compared the IM injection of the same dose, and time to peak concentration (TMAX) was similar. For the nalmefene injection, the peak was not as high (lower CMAX) by 0.94 × for the microneedle injection compared to the IM injection of the same dose. The microneedle produced an exposure, measured by area under the curve (AUC), that was 0.85 × and 0.58 × as high for naloxone and nalmefene, respectively, than the injection by the IM route. We also observed that although the dose for naloxone was approximately 3 × higher for naloxone compared to nalmefene, the mean peak concentration achieved from the naloxone injection was more than 12 × higher than that from the nalmefene injection. These studies were designed to test the feasibility of using the hollow microneedle array as an effective method of naloxone and nalmefene delivery for emergency treatment of opioid-induced respiratory depression (OIRD). The results of these studies will form the basis of future studies, using the dog as a model, for development of hollow microneedle microarray devices to deliver opioid antagonists for treatment of OIRD in people.

Evaluation of gastrointestinal transit times and pH in healthy cats using a continuous pH monitoring system.

OBJECTIVES: The aim of this study was to characterize gastrointestinal (GI) transit times and pH in healthy cats. METHODS: GI transit times and pH were measured in six healthy, colony-housed, purpose-bred spayed female cats using a continuous, non-invasive pH monitoring system in a sequential order design. For the first period ('pre-feeding'), food was withheld for 20 h, followed by oral administration of a pH capsule. Five hours post-capsule administration, cats were meal-fed by offering them their daily allowance of food for 1 h. For the second period ('post-feeding'), food was withheld for 24 h and cats were fed for 1 h, after which a pH capsule was orally administered. Studies in both periods were repeated three times. GI transit times and pH were compared between the two periods. RESULTS: The median transit times for the pre- and post-feeding periods, respectively, were: gastric - 94 mins (range 1-4101) and 1068 mins (range 484-5521); intestinal - 1350 mins (range 929-2961) and 1534 mins (range 442-2538); and GI - 1732 mins (range 1105-5451) and 2795 mins (range 926-6563). The median GI pH values for the first and second periods, respectively, were: esophageal - 7.0 (range 3.5-7.8) and 4.5 (range 2.9-6.4); gastric - 2.7 (range 1.7-6.2) and 2.0 (range 1.1-3.3); intestinal - 8.2 (range 7.6-8.7) and 7.8 (range 6.7-8.5); first-hour small intestinal - 8.2 (range 7.4-8.7) and 8.3 (range 7.9-8.6); and last-hour large intestinal - 8.5 (range 7.0-8.9) and 7.8 (range 6.3-8.7). Gastric (P <0.0020) and intestinal pH (P <0.0059) were significantly increased in the pre-feeding period compared with the post-feeding period. CONCLUSIONS AND RELEVANCE: Gastric and intestinal pH differed significantly when the capsule was administered 5 h prior to feeding compared with 1 h after feeding. Transit times for both periods showed high degrees of intra- and inter-individual variability.

Phenylbutazone pharmacokinetics in southern white rhinoceros (Ceratotherium simum simum) after oral administration.

Southern white rhinoceros (Ceratotherium simum simum) frequently develop painful conditions, such as traumatic injuries or osteoarthritis, necessitating the administration of pain-relieving medications. One of the preferred treatments is the nonsteroidal anti-inflammatory drug phenylbutazone because of the availability of oral formulations and the familiarity of its use in horses. For the main study, a single oral dose of phenylbutazone at 2 mg/kg was administered to healthy adult rhinoceros (n = 33) housed at six North American zoological institutions. Each rhinoceros had up to four blood samples collected under voluntary behavioural restraint at up to four predetermined time points (0, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 30 and 48 h). Drug analysis was performed by high-performance liquid chromatography. The population pharmacokinetic parameters were calculated with nonlinear mixed-effects modelling, and analysis showed a peak concentration (CMAX ) of 3.8 µg/ml at 1.8 h and an elimination half-life of 9 h. The concentrations achieved were similar to what has been reported for horses and were within the half maximal effective concentration for horses for at least 10 h. A multi-dose trial in five rhinoceros receiving 2 mg/kg orally once daily for five days found mild accumulation at a predicted factor of 1.2. This study represents the first pharmacokinetic data of phenylbutazone in any rhinoceros species.