Clinical pharmacology of nonsteroidal anti-inflammatory drugs in dogs.

OBJECTIVES: To discuss the clinical pharmacology of currently licensed veterinary NSAIDs and to review gastrointestinal and renal adverse effects as well as drug-drug interactions that have been reported with these drugs. To review the use of NSAIDs in the peri-operative setting and their use in patients with osteoarthritis. To further review the reported effects of NSAIDs on canine articular cartilage and liver as well as the clinical relevance of a washout period. DATABASES USED: PubMed, CAB abstracts and Google Scholar using dog, dogs, nonsteroidal anti-inflammatory drugs and NSAID(s) as keywords. CONCLUSIONS: A good understanding of the mechanisms by which NSAIDs elicit their analgesic effect is essential in order to minimize adverse effects and drug-drug interactions. Cyclooxygenase (COX) is present in at least two active isoforms in the body and is the primary pharmacologic target of NSAIDs. Inhibition of COX is associated with the analgesic effects of NSAIDs. COX is present in the gastrointestinal tract and kidneys, along with other areas of the body, and is also the likely reason for many adverse effects including gastrointestinal and renal adverse effects. The newer veterinary approved NSAIDs have a lower frequency of gastrointestinal adverse effects in dogs compared to drugs such as aspirin, ketoprofen and flunixin, which may be due to differential effects on the COX isoforms. There are currently no published reports demonstrating that the newer NSAIDs are associated with fewer renal or hepatic adverse effects in dogs. NSAIDs remain the cornerstone of oral therapy for osteoarthritis unless contraindicated by intolerance, concurrent therapies or underlying medical conditions. NSAIDs are also effective and frequently used for the management of post-operative pain.

Microfilarial reduction following ProHeart® 6 and ProHeart® SR-12 treatment in dogs experimentally inoculated with a resistant isolate of Dirofilaria immitis.

BACKGROUND: Emerging resistance of heartworms (Dirofilaria immitis) to macrocyclic lactone (ML) preventives is an increasing concern for veterinarians, pet owners and animal health companies that supply heartworm preventives, with recent reports of resistant isolates identified from the Mississippi Delta region of the United States. Products that are effective in eliminating microfilariae (MF) in dogs harboring resistant heartworm infections could be important in reducing the spread of heartworm resistance. The current study was conducted to investigate the potential for ProHeart® 6 (PH 6; Zoetis) and ProHeart® SR-12 (PH 12; Zoetis) to reduce MF in dogs experimentally inoculated with an isolate of D. immitis (ZoeMo-2012) confirmed to be resistant to MLs. METHODS: Twenty-three dogs with preexisting heartworm infections (via surgical transplantation) were randomly allocated to four groups based on pretreatment (Day -14) MF counts. On Day 0, dogs received a subcutaneous injection of either saline (placebo-treated control, 6 dogs), PH 6 (0.17 mg/kg, 6 dogs), PH 12 (0.5 mg/kg, 5 dogs) or a single oral dose of moxidectin powder in a gelatin capsule (0.25 mg/kg, 6 dogs). All dogs were bled for MF counts (modified Knott's test) on Days 0 (pretreatment), 1, 3, 7, 14, 21, 28, 42, 56, and 84. Dogs in control and PH 6 groups were also bled for MF counts on Days 112, 140, and 168. No adverse events associated with treatment were observed for any dog. RESULTS: Average reductions in MF counts compared with controls for PH 6 were 9.7% on Day 1, increasing to 75.0% on Day 7, and further to 86.5% on Day 28. On Day 42, average MF reduction increased to 90.3%. Reductions increased further over the next several months with reductions of 91.3, 96.8, 96.6, and 98.9% on Days 56, 84, 112, and 140, respectively. On Day 168, the reduction was 99.3% (P < 0.0001). Average reductions in MF counts compared with controls for PH 12 were 20.9% on Day 1, increasing to 78.9% on Day 7, and further to 91.2% on Day 28. On Day 84, the reduction was 96.9%. For dogs receiving a single oral moxidectin (0.25 mg/kg) on Day 0, reductions in MF were 86.3% on Day 1 and fluctuated between 74.4 and 83.6% through Day 28. On Days 42 and 56, percentage reductions were 87.1 and 81.8%, respectively, and 92.6% at the final time point (Day 84). CONCLUSION: Both PH 6 and PH 12 were highly effective in reducing the MF levels of a confirmed ML-resistant heartworm isolate following a single dose.

Evaluation of the efficacy of ProHeart® 6 (moxidectin) against a resistant isolate of Dirofilaria immitis (JYD-34) in dogs.

BACKGROUND: In a previous study, it was demonstrated that ProHeart® 6 (PH6) (moxidectin, Zoetis) provided only about 20% efficacy in a small six-dog study against a macrocyclic lactone -resistant Dirofilaria immitis isolate (Jd2009-2) when dogs were inoculated with infective third-stage larvae (L3) at the end of the dosing period (ie, 180 days post treatment). The objective of the current study was to determine the prophylactic efficacy of a moxidectin sustained-release formulation (PH6) against a confirmed macrocyclic lactone-resistant isolate of D. immitis (JYD-34) in dogs when administered by subcutaneous injection at the labeled dose of 0.17 mg/kg 2 days before L3 inoculation. This was intended to model the scenario where dogs become infected with resistant heartworms at the end of the PH6 treatment period (ie, 6 months post treatment) when dogs would routinely be given another injection under normal field use. METHODS: Twelve purpose-bred Beagle dogs (six males and six females) were selected and randomly allocated to two groups, untreated controls and PH6-treated dogs in groups of six each. The dogs were ≥8 months old at the start of the study, and using blood samples collected on Day -7 were shown to be negative for adult heartworm antigen and microfilariae. On Day 0, the dogs in the untreated control group were administered saline subcutaneously by injection, and the dogs in the treated group were administered PH6 according to label instructions. On Day 2, each dog was inoculated in the inguinal area with 50 L3 of D. immitis. The dogs were necropsied on Day 150 (148 days post infection), and the worms were collected and counted. RESULTS: All of the six control dogs were infected and harbored a range of 21 to 37 worms (geometric mean, 25.4; 10.9 males and 13.9 females). Only one of the six PH6 dogs was found to be infected, harboring a single male worm. Efficacy was 99.5% (geometric mean). CONCLUSION: ProHeart® 6 was highly effective in preventing the development of heartworms in dogs challenged with a confirmed macrocyclic lactone-resistant heartworm isolate (JYD-34) 2 days prior to treatment.

Comparison of plasma and interstitial fluid concentrations of doxycycline and meropenem following constant rate intravenous infusion in dogs.

OBJECTIVE: To compare plasma (total and unbound) and interstitial fluid (ISF) concentrations of doxycycline and meropenem in dogs following constant rate IV infusion of each drug. ANIMAL: 6 adult Beagles. PROCEDURE: Dogs were given a loading dose of doxycycline and meropenem followed by a constant rate IV infusion of each drug to maintain an 8-hour steady state concentration. Interstitial fluid was collected with an ultrafiltration device. Plasma and ISF were analyzed by high performance liquid chromatography. Protein binding and lipophilicity were determined. Plasma data were analyzed by use of compartmental methods. RESULTS: Compared with meropenem, doxycycline had higher protein binding (11.87% [previously published value] vs 91.75 +/- 0.63%) and lipophilicity (partition coefficients, 0.02 +/- 0.01 vs 0.68 +/- 0.05). A significant difference was found between ISF and plasma total doxycycline concentrations. No significant difference was found between ISF and plasma unbound doxycycline concentrations. Concentrations of meropenem in ISF and plasma (total and unbound) were similar. Plasma half-life, volume of distribution, and clearance were 4.56 +/- 0.57 hours, 0.65 +/- 0.82 L/kg, and 1.66 +/- 2.21 mL/min/kg, respectively, for doxycycline and 0.73 +/- 0.07 hours, 0.34 +/- 0.06 L/kg, and 5.65 +/- 2.76 mL/min/kg, respectively, for meropenem. The ISF half-life of doxycycline and meropenem was 4.94 +/- 0.67 and 2.31 +/- 0.36 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The extent of protein binding determines distribution of doxycycline and meropenem into ISF. As a result of high protein binding, ISF doxycycline concentrations are lower than plasma total doxycycline concentrations. Concentrations of meropenem in ISF can be predicted from plasma total meropenem concentrations.

Plasma pharmacokinetics and tissue fluid concentrations of meropenem after intravenous and subcutaneous administration in dogs.

OBJECTIVE: To estimate pharmacokinetic variables and measure tissue fluid concentrations of meropenem after IV and SC administration in dogs. ANIMALS: 6 healthy adult dogs. PROCEDURE: Dogs were administered a single dose of meropenem (20 mg/kg) IV and SC in a crossover design. To characterize the distribution of meropenem in dogs and to evaluate a unique tissue fluid collection method, an in vivo ultrafiltration device was used to collect interstitial fluid. Plasma, tissue fluid, and urine samples were analyzed by use of high-performance liquid chromatography. Protein binding was determined by use of an ultrafiltration device. RESULTS: Plasma data were analyzed by compartmental and noncompartmental pharmacokinetic methods. Mean +/- SD values for half-life, volume of distribution, and clearance after IV administration for plasma samples were 0.67 +/- 0.07 hours, 0.372 +/- 0.053 L/kg, and 6.53 +/- 1.51 mL/min/kg, respectively, and half-life for tissue fluid samples was 1.15 +/- 0.57 hours. Half-life after SC administration was 0.98 +/- 0.21 and 1.31 +/- 0.54 hours for plasma and tissue fluid, respectively. Protein binding was 11.87%, and bioavailability after SC administration was 84%. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of our data revealed that tissue fluid and plasma (unbound fraction) concentrations were similar. Because of the kinetic similarity of meropenem in the extravascular and vascular spaces, tissue fluid concentrations can be predicted from plasma concentrations. We concluded that a dosage of 8 mg/kg, SC, every 12 hours would achieve adequate tissue fluid and urine concentrations for susceptible bacteria with a minimum inhibitory concentration of 0.12 microg/mL.