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Abstract

OBJECTIVE

To estimate the number of patients linked to vet-shopping behavior (the solicitation of controlled substance prescriptions from multiple veterinarians for misuse) in the United States using 2014–2019 data and characterize mandates for veterinarians to examine prescription drug monitoring programs (PDMPs) before prescribing controlled substances as of April 2021.

SAMPLE

National database reporting prescription dispensing from 92% of US pharmacies from 2014 through 2019.

PROCEDURES

The annual number of patients with dispensed prescriptions for opioid analgesics, opioid cough-and-cold medications, or benzodiazepines from ≥ 4 veterinarians was calculated. State veterinary medical associations were contacted for information on veterinarian PDMP use mandates.

RESULTS

From 2014 through 2019, the number of patients with prescriptions for any class of controlled substances from ≥ 4 veterinarians tripled from 935 to 2,875 (+207.5%). The number of patients with opioid cough-and-cold medication prescriptions from ≥ 4 veterinarians rose from 150 to 1,348 (+798.9%). The corresponding number for benzodiazepines rose from 185 to 440 (+137.8%). The corresponding number for opioid analgesics peaked at 868 in 2016 before decreasing to 733 in 2019. In April 2021, 10 states mandated veterinarians to examine PDMP records of owners or animals before prescribing controlled substances; 3 mandates excluded benzodiazepines.

CLINICAL RELEVANCE

Vet shopping in the US may be increasingly common. Mandates for veterinarians to examine PDMPs before prescribing controlled substances might facilitate detection of this behavior. However, benefits of mandates should be weighed against their potential burden on veterinarians.

Open access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To assess drug-drug interactions between cannabidiol (CBD) and phenobarbital (PB) when simultaneously administered to healthy dogs.

ANIMALS

9 healthy, purpose bred Beagles.

PROCEDURES

A 3-phase prospective, randomized pharmacokinetic (PK) interaction study of CBD and PB was performed as follows: phase 1, CBD PK determination and evaluation of CBD tolerability by 3 single-dose CBD (5 mg/kg, 10 mg/kg, and 20 mg/kg) protocols followed by 2-week CBD dosing; phase 2, a single-dose, 3-way, crossover PK study of CBD (10 mg/kg), PB (4 mg/kg), or CBD (10 mg/kg) administration plus PB (4 mg/kg); and phase 3, evaluation of chronic PB (4 mg/kg, q 30 d) administration followed by single-dose CBD (10 mg/kg) PK study.

RESULTS

Although there were variations in CBD PK variables in dogs receiving CBD alone or in conjunction with PB, significance differences in CBD PK variables were not found. No significant difference was observed in PB PK variables of dogs receiving PB alone or with CBD. During chronic CBD administration, mild gastrointestinal signs were observed in 5 dogs. At daily CBD doses of 10 to 20 mg/kg/d, hypoxia was observed in 5 dogs and increased serum alkaline phosphatase (ALP) activities (range, 301 to 978 U/L) was observed in 4 dogs. A significant increase in ALP activity was observed with chronic administration of CBD during phase 1 between day 0 and day 14.

CONCLUSIONS AND CLINICAL RELEVANCE

No significant PK interactions were found between CBD and PB. Dose escalation of CBD or adjustment of PB in dogs is not recommended on the basis of findings of this study.

Free access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To evaluate the effects of housing environment on oral absorption of acetaminophen in dogs.

ANIMALS

6 healthy Beagles.

PROCEDURES

Acetaminophen (325 mg, PO; mean dose, 31.1 mg/kg) was administered in a crossover study design with dogs housed in their normal environment or in a cage in an unfamiliar environment. There was a 7-day washout period between phases. Blood samples were collected for 24 hours following acetaminophen administration, and plasma acetaminophen concentrations were determined with high-pressure liquid chromatography.

RESULTS

A 2-compartment model with lag time was the best fit for both phases of the study. None of the primary or secondary pharmacokinetic parameters were significantly different between the 2 housing environments.

CLINICAL RELEVANCE

Findings suggested that in dogs, housing environment (normal environment vs a cage in an unfamiliar environment) did not significantly affect oral absorption and, by extension, gastric emptying of acetaminophen.

Restricted access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To identify an oral dose of grapiprant for red-tailed hawks (RTHAs; Buteo jamaicensis) that would achieve a plasma concentration > 164 ng/mL, which is considered therapeutic for dogs with osteoarthritis.

ANIMALS

6 healthy adult RTHAs.

PROCEDURES

A preliminary study, in which grapiprant (4 mg/kg [n = 2], 11 mg/kg [2], or 45 mg/kg [2]) was delivered into the crop of RTHAs from which food had been withheld for 24 hours, was performed to obtained pharmacokinetic data for use with modeling software to simulate results for grapiprant doses of 20, 25, 30, 35, and 40 mg/kg. Simulation results directed our selection of the grapiprant dose administered to the RTHAs in a single-dose study. Plasma grapiprant concentration, body weight, and gastrointestinal signs of RTHAs were monitored.

RESULTS

On the basis of results from the preliminary study and simulations, a grapiprant dose of 30 mg/kg was used in the single-dose study. The geometric mean maximum observed plasma concentration of grapiprant was 3,184 ng/mL, time to maximum plasma grapiprant concentration was 2.0 hours, and the harmonic mean terminal half-life was 17.1 hours. No substantial adverse effects were observed.

CONCLUSIONS AND CLINICAL RELEVANCE

Although the single dose of grapiprant (30 mg/kg) delivered into the crop achieved plasma concentrations > 164 ng/mL in the RTHAs, it was unknown whether this concentration would be therapeutic for birds. Further research that incorporates multidose assessments, safety monitoring, and pharmacodynamic data collection is warranted on the use of grapiprant in RTHAs from which food was withheld versus not withheld.

Restricted access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To determine plasma tramadol concentrations in cats following a single dose of oral and transdermal formulations and the pharmacokinetics for and the concentration of tramadol in the transdermal formulation.

ANIMALS

8 healthy client-owned domestic shorthair cats.

PROCEDURES

1 cat was orally administered 1 dose of tramadol (2 mg/kg), and 7 cats received 1 dose of a proprietary compounded tramadol gel product (median actual dose, 2.8 mg/kg) applied to their inner pinnae. Plasma tramadol concentrations were measured with high-performance liquid chromatography–mass spectrometry at fixed times over 24 hours.

RESULTS

Plasma tramadol concentrations were undetectable or much lower (range, < 1 to 4.3 ng/mL) following application of the transdermal formulation, compared with those following oral administration (maximum plasma tramadol concentration, 261.3 ng/mL [at 4 hours]). Tramadol pharmacokinetics for the transdermal formulation could not be determined. Tramadol concentrations of the transdermal gel product exceeded the estimated label dose in all analyzed gel samples, with concentrations greater than the 90% to 110% United States Pharmacopeia standard for compounded drugs.

CONCLUSIONS AND CLINICAL RELEVANCE

Application of 1 dose of the proprietary transdermal formulation did not yield clinically relevant plasma tramadol concentrations in cats. Although this proprietary formulation is currently available to prescribing veterinarians, it should be used with caution.

Restricted access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To determine an optimal ceftazidime dosing strategy in Northern leopard frogs (Lithobates pipiens) by evaluation of 2 different doses administered SC and 1 dose administered transcutaneously.

ANIMALS

44 Northern leopard frogs (including 10 that were replaced).

PROCEDURES

Ceftazidime was administered to frogs SC in a forelimb at 20 mg/kg (n = 10; SC20 group) and 40 mg/kg (10; SC40 group) or transcutaneously on the cranial dorsum at 20 mg/kg (10; TC20 group). Two frogs in each ceftazidime group were euthanized 12, 24, 48, 72, and 96 hours after drug administration. Plasma, renal, and skin concentrations of ceftazidime were measured by means of reversed-phase high-performance liquid chromatography. Four control frogs were used for assay validation.

RESULTS

Mean plasma half-life of ceftazidime in the SC20, SC40, and TC20 groups was 9.01 hours, 14.49 hours, and too low to determine, respectively. Mean maximum plasma ceftazidime concentration was 92.9, 96.0, and 1.3 μg/mL, respectively. For 24 hours after drug administration in the SC20 and SC40 groups, plasma ceftazidime concentration exceeded 8 μg/mL. Renal and skin concentrations were detectable at both doses and routes of administration; however, skin concentrations were significantly lower than renal and plasma concentrations.

CONCLUSIONS AND CLINICAL RELEVANCE

Findings indicated that ceftazidime administration to Northern leopard frogs at 20 mg/kg, SC, every 24 hours would achieve a plasma concentration exceeding the value considered effective against common amphibian pathogens. Transcutaneous administration of the injectable ceftazidime formulation at 20 mg/kg warrants further investigation but is not currently recommended because of a potential lack of efficacy.

Restricted access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To characterize the pharmacokinetics of mycophenolate mofetil (MMF) following single-dose IV or PO administration, characterize the pharmacokinetics of MMF following long-term PO administration, and describe the clinicopathologic effects of long-term MMF administration in horses.

ANIMALS

12 healthy adult horses.

PROCEDURES

In phase 1, 6 horses received a single IV (2.5 mg/kg) or PO (5 mg/kg) dose of MMF in a randomized balanced crossover assessment (≥ 2-week interval between administrations). In phase 2, 6 other horses received MMF for 60 days (5 mg/kg, PO, q 24 h for 30 days and then 5 mg/kg, PO, q 48 h for an additional 30 days).

RESULTS

Following IV (single-dose) or PO (single- or multiple-dose) administration, MMF was rapidly converted to mycophenolic acid. For single-dose PO administration, mean ± SD maximum plasma mycophenolic acid concentration was 1,778.3 ± 441.5 ng/mL at 0.71 ± 0.29 hours. For single-dose IV administration, mean systemic clearance and volume of distribution at steady state were 0.689 ± 0.194 L/h/kg and 1.57 ± 0.626 L/kg, respectively. Following single doses, mean terminal half-life was 3.99 ± 0.865 hours for IV administration and 4.02 ± 1.01 hours for PO administration. The accumulation index following long-term PO administration was 1.0 ± 0.002, and the terminal half-life was 4.59 ± 1.25 hours following the final dose on day 60. None of the horses developed abnormal clinical signs or had any consistently abnormal clinicopathologic findings.

CONCLUSIONS AND CLINICAL RELEVANCE

Further investigation of the clinical efficacy of long-term MMF treatment of horses with autoimmune diseases is warranted.

Full access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To determine the safety and pharmacokinetics of various doses of plant-derived cannabidiol (CBD) versus placebo following repeated oral administration.

ANIMALS

20 healthy adult Beagles.

PROCEDURES

In a randomized, blinded, placebo-controlled trial, dogs were randomized to 5 groups balanced in body weight and sex (n = 4 dogs/group) and received a CBD (1, 2, 4, or 12 mg/kg; from cannabis extract) or placebo oil formulation PO once daily for 28 days. Outcome variables were assessed through daily health observations, veterinary examinations, CBC, and serum biochemical analysis. Blood samples were collected at various time points to estimate 24-hour pharmacokinetic profiles of CBD and selected metabolites (7-carboxy-CBD and 7-hydroxy-CBD).

RESULTS

Repeated CBD administration was well tolerated by dogs, with no clinically important changes in measured safety outcomes. Veterinary examinations revealed no clinically important abnormal findings. Adverse events were mild in severity. Relative to placebo administration, CBD administration at 12 mg/kg/d resulted in more gastrointestinal adverse events (mainly hypersalivation) and significantly higher serum alkaline phosphatase activity. Total systemic exposure to CBD increased on a dose-dependent basis following both acute (first dose) and chronic (28 days) administration. Within each CBD dose group, repeated administration increased total systemic exposure to CBD 1.6- to 3.3-fold. The 24-hour trough plasma CBD concentrations were also dose dependent, with a steady state reached following 2 weeks of administration.

CONCLUSIONS AND CLINICAL RELEVANCE

Repeated, daily oral administration of the CBD formulation led to dose-dependent increases in total systemic exposure to CBD and 24-hour trough plasma concentrations in healthy dogs. These findings could help guide dose selection.

Full access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To evaluate the pharmacokinetics of hydromorphone hydrochloride after IM and IV administration to orange-winged Amazon parrots (Amazona amazonica).

ANIMALS

8 orange-winged Amazon parrots (4 males and 4 females).

PROCEDURES

Hydromorphone (1 mg/kg) was administered once IM. Blood samples were collected 5 minutes and 0.5, 1.5, 2, 3, 6, and 9 hours after drug administration. Plasma hydromorphone concentrations were determined with liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were calculated with a compartmental model. The experiment was repeated 1 month later with the same dose of hydromorphone administered IV.

RESULTS

Plasma hydromorphone concentrations were > 1 ng/mL for 6 hours in 8 of 8 and 6 of 7 parrots after IM and IV injection, respectively. After IM administration, mean bioavailability was 97.6%, and mean maximum plasma concentration was 179.1 ng/mL 17 minutes after injection. Mean volume of distribution and plasma drug clearance were 4.24 L/kg and 64.2 mL/min/kg, respectively, after IV administration. Mean elimination half-lives were 1.74 and 1.45 hours after IM and IV administration, respectively.

CONCLUSIONS AND CLINICAL RELEVANCE

Hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with rapid plasma clearance and a large volume of distribution after IV administration in orange-winged Amazon parrots. Drug elimination half-lives were short. Further pharmacokinetic studies of hydromorphone and its metabolites, including investigation of multiple doses, different routes of administration, and sustained-release formulations, are recommended.

Restricted access
in American Journal of Veterinary Research

Abstract

OBJECTIVE

To determine the pharmacokinetics and efficacy of trazodone following rectal administration of a single dose to healthy dogs.

ANIMALS

6 healthy adult dogs.

PROCEDURES

Each dog received a single dose of trazodone (approx 8 mg/kg) per rectum. Trazodone tablets were crushed into a powder, mixed with 5 mL of tap water, and injected into the rectum via a red rubber catheter. Sedation scores were assigned, and blood samples were collected for determination of plasma trazodone concentration at predetermined times before and after drug administration. Pharmacokinetic parameters were estimated by noncompartmental analysis.

RESULTS

Plasma trazodone concentration remained below the detection limit for 1 dog even though it became moderately sedate. Median (interquartile [25th to 75th percentile] range [IQR]) maximum plasma trazodone concentration and volume of distribution and clearance corrected for bioavailability were 1.00 μg/mL (0.66 to 1.40 μg/mL), 10.3 L/kg (7.37 to 14.4 L/kg), and 639 mL/kg/h (594 to 719 mL/kg/h), respectively. Median time to maximum plasma trazodone concentration and elimination half-life were 15 minutes (range, 15 to 30 minutes) and 12 hours (IQR, 7.99 to 12.7 hours), respectively. All dogs became mildly or moderately sedate, and the extent of sedation was maximal at a median of 30 minutes (IQR, 30 to 60 minutes) after trazodone administration. No adverse effects were observed.

CONCLUSIONS AND CLINICAL RELEVANCE

Rectal administration of trazodone may be a viable option for sedation and treatment of anxiety in dogs for which administration of sedatives and anxiolytics by other routes is contraindicated. Further research is necessary to better elucidate the pharmacokinetics and efficacy of trazodone following rectal administration and determine optimal dosing.

Restricted access
in American Journal of Veterinary Research