Pharmacology of grapiprant,a novel EP4 antagonist: receptor binding,efficacy in a rodent postoperative pain model,and a dose estimation for controlling pain in dogs

Grapiprant is an analgesic and anti‐inflammatory drug in the piprant class that was approved in March 2016 by FDA's Center for Veterinary Medicine for the control of pain and inflammation associated with osteoarthritis (OA) in dogs. Grapiprant functions as a selective antagonist of the EP4 receptor, one of the four prostaglandin E₂ (PGE₂) receptor subtypes. The EP4 receptor mediates PGE₂‐elicited nociception, and grapiprant has been shown to decrease pain in several rat inflammatory pain models. It was also effective in reducing pain associated with OA in humans, providing evidence for its mechanism of action in these species. The estimated canine efficacy dose of between 1.3 and 1.7 mg/kg, p.o. with a methylcellulose suspension, once a day, was predicted based on calculations from comparative affinity of grapiprant to the dog, rat, and human EP4 receptors, serum protein binding, effective doses defined in rat models of pain and inflammation, and human clinical studies. The results of this study guided the doses to be tested in the pilot study and demonstrated the usefulness of the efficacy dose prediction method. The approved commercial tablet dose of grapiprant is 2 mg/kg once a day for the control of pain and inflammation associated with OA in dogs.     

Pharmacokinetic/pharmacodynamic evaluation of grapiprant in a carrageenan‐induced inflammatory pain model in the rabbit

Grapiprant is the novel selective EP4 receptor inhibitor recently issued on the veterinary market for dogs affected by osteoarthritis. The aim of this study was twofold: to evaluate the pharmacokinetics and the pharmacodynamics of grapiprant in the induced inflammatory pain model in the rabbit after a single IV injection of 2 mg/kg; to compare the thermal antinociception effect after 2 mg/kg IV grapiprant, with that generated by 0.5 mg/kg meloxicam SC injected. Rabbits (n = 12) were randomly assigned to two crossover studies (single‐dose, two‐period crossover). The first study group A (n = 3) received a single IV dose of grapiprant at 2 mg/kg dissolved in ethanol. Group B (n = 3) received a single IV injection of ethanol (equivalent volume to grapiprant volume) at the same site. The second study group C (n = 3) received a single SC dose of meloxicam at 0.5 mg/kg. Group D (n = 3) received a single SC injection of 15% ethanol (equivalent volume to grapiprant volume) at the same site. After a 2‐week washout period, the groups were rotated and the experiments repeated. Blood samples (0.7 mL) were collected from the right ear artery at assigned times and grapiprant plasma concentrations determined by a validated HPLC‐FL method. Three hours prior to administration of the drugs, inflammation was induced by SC injection of lambda carrageenan (200 μL, 3% in physiological saline) under the plantar surface of the right hind paw. At a similar time to the blood collection, an infrared thermal stimuli (40 °C) was applied to the plantar surface of the rabbits’ hindlimbs to evaluate the thermal withdrawal latency (TWL). The thermal antinociceptive effect was expressed as maximum possible response (% MPR). Grapiprant plasma concentrations were detectable up to the 10‐h time point (concentration range 17–7495 ng/mL). The grapiprant‐treated group showed a significant increase in TWL from 1 h and up to 10 h after drug administration compared to the control. In contrast, the meloxicam group showed a significant increase in TWL from 4 up to 10 h after drug administration, compared to control. The maximal MPR% was not statistically different between the grapiprant and meloxicam group from 4 to 8 h, while significant differences were shown at 1, 1.5, 2, 10 and 24 h. Given these findings, grapiprant appears to be an attractive option for antinociception in rabbits, due to its rapid onset and extended duration of effect.     

Comparative pharmacokinetics and pharmacodynamics of tablet, suspension and paste formulations of atenolol in cats

This study compared the pharmacokinetic and pharmacodynamic profiles of an extemporaneously prepared (compounded) atenolol paste and suspension for oral administration, against the commercially available divided tablet in healthy cats. Eleven healthy cats (mean: age 4 ± 0.4 year, weight 5.0 ± 0.7 kg) were dosed twice-daily with 12.5 mg atenolol (tablet, paste or suspension) for 7 days in a randomized cross-over design with a 7-day wash-out period. On day 7, an electrocardiogram was performed before and immediately after stress provocation (jugular venipuncture) at prestudy screening, and at 2, 6 and 12 h after morning dosing. Systolic arterial blood pressure (BP) was assessed following the second electrocardiogram. Plasma was collected at prestudy screening, and at 1, 2, 6 and 12 h to measure atenolol plasma concentrations. Mean atenolol dose was 2.5 mg/kg (range: 2.1-3.3 mg/kg). Stress-induced rise in heart rate was attenuated (P < 0.05) at every time point compared to baseline for all formulations. Although the paste significantly attenuated stress-induced elevation in heart rate at all time points, the effect was not consistently equivalent to the tablet. The BP was not altered (P > 0.05) at any time point by any formulation. In conclusion, there were no significant differences (P > 0.05) in any of the pharmacokinetic parameters or pharmacodynamic profiles of the paste and suspension compared to the commercially available tablet.     

Pharmacokinetics of oral morphine sulfate in dogs: a comparison of sustained release and conventional formulations.

The pharmacokinetics and bioavailability (F) of single dose sustained release morphine sulfate (OSRMS) and nonsustained release morphine sulfate (NSRMS) were compared to each other and to a bolus injection of morphine sulfate (MS) intravenously (i.v.) in dogs. Beagles (n = 6) were randomly assigned to 3 treatment groups: namely, OSRMS 15 mg orally, NSRMS 15 mg orally, and 15 mg i.v. Serum samples were drawn at intervals up to 480 min following oral and 420 min following i.v. administration. Serum was analysed for morphine concentration using a radioimmunoassay. Data were analysed using non-compartmental pharmacokinetics. The only statistically significant difference between OSRMS and NSRMS was maximum serum concentration (Cmax). There were trends toward longer time to maximum serum concentration (Tmax) and longer mean absorption time (MAT) for OSRMS when compared to NSRMS, but the differences were not statistically significant (P < 0.05). Pharmacokinetic parameters for both oral formulations exhibited large variability in the rate of absorption of MS from the gastrointestinal tract. Bioavailability of both OSRMS and NSRMS was low (15%-17%). As expected, the area under the concentration vs time curve (AUC) and Cmax for the i.v. data was significantly greater than for both oral groups, and Tmax and mean residence time (MRT) were significantly less following i.v. administration. There were no statistically significant differences among the 3 treatment groups for apparent volume of distribution at steady state (Vdss) or elimination parameters. The OSRMS formulation used in this study provided equivalent bioavailability to NSRMS in dogs, accompanied by large individual variability in drug absorption. It also did not appear that the sustained release formulation provided sufficiently prolonged release of morphine sulfate from the tablet matrix in dogs to allow prolonged dosing intervals compared to NSRMS.     

Pharmacokinetic disposition and arthropathic potential of oral ofloxacin in dogs

We examined the relation between the pharmacokinetic disposition and arthropathic potential of ofloxacin, a new quinolone antibacterial agent, using both male immature (3-month-old) and mature (18-month-old) beagles. Ofloxacin was orally administered to these dogs at 20 mg/kg once daily for 8 consecutive days, and the animals were killed 2 h after the last treatment. Serum ofloxacin concentrations were repeatedly measured on days 1 and 7 by use of high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated. In addition, on day 8, the drug concentrations in the joint synovial fluid and humeral and femoral condyles were measured. Clinico-pathological tests of blood and serum or histopathological examination of bone specimens were also performed. Arthropathy was macroscopically observed in the cartilage surface of all immature dogs, but not in mature dogs. There were, however, no noticeable differences in pharmacokinetic parameters between the two age groups of dogs or between single and 7-day treatments. In contrast to the occurrence of arthropathic lesions, the synovial fluid and condylar drug concentrations in immature dogs was equal to or lower than those in mature dogs, suggesting that the pharmacokinetic disposition of ofloxacin may not be essential for cartilage lesions.     

Firocoxib efficacy preventing urate-induced synovitis, pain, and inflammation in dogs

This positive-control study evaluated the efficacy of firocoxib versus carprofen, deracoxib, and meloxicam for the prevention of pain and inflammation in a urate crystal synovitis model of lameness. Lameness scoring and force plate gait analysis were used to assess efficacy. The resulting lameness scores and force plate ground reaction forces after urate crystal injection were not significantly different among the groups. Relative to each group's baseline (nonlame) score, only the firocoxib group was not significantly lame, based on lameness score, at the model's peak effect.     

Amantadine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) do not always provide sufficient pain relief in dogs with osteoarthritis (OA). HYPOTHESIS: The use of amantadine in addition to NSAID therapy will provide improved pain relief when compared with the use of nonsteroidal analgesics alone in naturally occurring OA in dogs. ANIMALS: Thirty-one client-owned dogs with pelvic limb lameness despite the administration of an NSAID. METHODS: The study was randomized, blinded, and placebo controlled with parallel groups (days 21-42). On day 0, analgesic medications were discontinued. On day 7, all dogs received meloxicam for 5 weeks. On day 21, all dogs received amantadine (3-5 mg/kg once daily per os) or placebo for 21 days, in addition to receiving meloxicam. Assessments were performed before the study and on days 7, 21, and 42. Primary outcome measures were blinded owner assessments of activity using client-specific outcome measures (CSOM) on days 0, 7, 21, and 42. Data were analyzed by a mixed model approach. RESULTS: For CSOM activity, there was a significant time by treatment effect (P=.009). On the basis of the planned post hoc t-tests of postrandomization means, there was a significant difference between treatment groups on day 42 (P=.030), with the amantadine group being more active. CONCLUSIONS AND CLINICAL IMPORTANCE: In dogs with osteoarthritic pain refractory to an NSAID, physical activity is improved by the addition of amantadine. Amantadine might be a useful adjunct therapy for the clinical management of canine osteoarthritic pain.     

Pharmacokinetic profiles of the analgesic flupirtine in dogs after the administration of four pharmaceutical formulations

ObjectiveFlupirtine (FLU) is a non-opioid analgesic with no antipyretic or anti-inflammatory effects which is used in the treatment of pain in humans. There is a substantial body of evidence on the efficacy of FLU in humans but this is inadequate for the recommendation of its off-label use in veterinary clinical practice. The aim of this study was to evaluate the pharmacokinetic profiles of FLU after intravenous (IV), oral immediate release (POIR), oral prolonged release (POPR) and rectal (RC) administrations in healthy dogs.Study designFour-treatment, single-dose, four-phase, unpaired, cross-over design (4 × 4 Latin-square).AnimalsSix adult Labrador dogs.MethodsAnimals in groups 1, 2 and 4 received a single dose of 5 mg kg⁻¹ FLU administered by IV, POIR and RC routes. Group 3 received a single dose of 200 mg subject⁻¹ via the POPR route. The wash-out periods were 1 week. Blood samples (1 mL) were collected at assigned times for 48 hours and plasma FLU concentrations were analysed by a validated HPLC method.ResultsAdverse effects including salivation, tremors and vomiting were noted in the IV group and resolved spontaneously within 10 minutes. These effects did not occur in the other groups. The FLU plasma concentrations were detectable in all of the treatment groups for 36 hours following administration. The pharmacokinetic profiles after extravascular administrations showed similar trends. The bioavailability values after POIR, POPR and RC were 41.93%, 36.78% and 29.43%, respectively. There were no significant differences in pharmacokinetic profiles between the POIR and POPR formulations. A 5 mg kg⁻¹ POIR dose or a 200 mg subject⁻¹ POPR dose gave plasma concentrations similar to those reported in humans after clinical dosing.Conclusion and clinical relevanceThis study provides pharmacokinetic data that can be used to design further studies to investigate FLU in dogs.     

Efficacy of oral famotidine and 2 omeprazole formulations for the control of intragastric pH in dogs

Background: Little is known about the efficacy of commonly used acid suppressants on intragastric pH in dogs. Objective: To compare the effect of oral famotidine, 2 formulations of omeprazole, and placebo on intragastric pH in dogs with a catheter‐free, continuous pH monitoring system. Animals: Six healthy adult mixed‐breed colony dogs. Methods: Utilizing a randomized, 4‐way cross over, open‐label study, dogs were administered famotidine PO (1.0–1.3 mg/kg q12h), omeprazole tablet (1.5–2.6 mg/kg q24h), omeprazole reformulated paste (RP) (Gastrogard, 1.5–2.6 mg/kg q24h), and placebo for 7 days followed by a 10‐day washout period. Radiotelemetric pH capsules were placed with gastroscopy assistance to continuously record intragastric pH for 4 days (days 4–7 of dosing). The percentage of time that intragastric pH was ≥3 and ≥4 was compared among treatment groups using repeated measures of analysis of variance. Tukey's Studentized range test was used to determine which groups were different with α= 0.05. Results: Mean ± SD percent time intragastric pH was ≥3 and ≥4 was 22 ± 8% and 14 ± 6% for famotidine, 63 ± 14% and 52 ± 17% for omeprazole tablet, 54 ± 17% and 44 ± 18% for omeprazole RP, and 6 ± 6% and 5 ± 5% for placebo. Both omeprazole formulations significantly increased intragastric pH compared with famotidine and placebo, but omeprazole tablet and RP was not significantly different from each other. Conclusion: Oral omeprazole tablet and RP provide superior gastric acid suppression to famotidine, and should therefore be considered more effective for the treatment of acid related disorders in dogs.     

Pharmacokinetic analysis of mosapride following intravenous and oral administration in beagle dogs

The aim of this study was to investigate the pharmacokinetic properties of mosapride after intravenous and oral administration to beagle dogs. To obtain the advanced pharmacokinetic parameters of mosapride, both noncompartmental analysis and pharmacokinetic modeling were performed. Twenty beagle dogs were randomly sorted into intravenous (1 mg single administration of mosapride) and oral (5 mg once a day administration of mosapride) groups. Blood samples were collected according to the reported schedule for pharmacokinetics. The plasma concentration of mosapride was analyzed using liquid chromatography–tandem mass spectrometry. According to the pharmacokinetic analysis, the absorption rate of mosapride was 3.14 ± 1.14 hr⁻¹ and oral bioavailability of mosapride was approximately 1%. The one-compartment model well described the pharmacokinetics of mosapride after both intravenous and oral administration to dogs. These findings will help facilitate the determination of the optimal dose regimen of mosapride for dogs with gastrointestinal disorder.     

Effects of oral administration of meloxicam,carprofen, and a nutraceutical on thyroid function in dogs with osteoarthritis

The purpose of this study was to evaluate the effect of the administration of meloxicam; carprofen; and a slow-acting disease modifying osteoarthritis agent, that contains chondroitin sulfate, purified glucosamine, and manganese ascorbate (CS-G-M), on thyroid function in dogs. Forty-six healthy (except for osteoarthritis) euthyroid dogs were blindly assigned to 3 treatment groups: meloxicam, carprofen, and CS-G-M. Each group received the recommended dose of the drug for 60 days. Sixteen other osteoarthritic euthyroid dogs, which received a placebo, were used as a control group to validate the study. For all groups, blood samples were collected on days 0, 30, and 60 to evaluate the serum total and free thyroxine, and endogenous thyrotropin concentrations. There were no significant differences among the treatment groups at each time or within each group over a 60-day period for all parameters. Moreover, none of these values were within the hypothyroid range. Based on the results of this study, the administration of meloxicam, carprofen, and CS-G-M did not affect canine thyroid function evaluation.     

Pharmacokinetic modeling and Monte Carlo simulation of ondansetron following oral administration in dogs

Ondansetron is a potent antiemetic drug that has been commonly used to treat acute and chemotherapy‐induced nausea and vomiting (CINV) in dogs. The aim of this study was to perform a pharmacokinetic analysis of ondansetron in dogs following oral administration of a single dose. A single 8‐mg oral dose of ondansetron (Zofran^®) was administered to beagles (n = 18), and the plasma concentrations of ondansetron were measured by liquid chromatography‐tandem mass spectrometry. The data were analyzed by modeling approaches using ADAPT5, and model discrimination was determined by the likelihood‐ratio test. The peak plasma concentration (C_max) was 11.5 ± 10.0 ng/mL at 1.1 ± 0.8 h. The area under the plasma concentration vs. time curve from time zero to the last measurable concentration was 15.9 ± 14.7 ng·h/mL, and the half‐life calculated from the terminal phase was 1.3 ± 0.7 h. The interindividual variability of the pharmacokinetic parameters was high (coefficient of variation > 44.1%), and the one‐compartment model described the pharmacokinetics of ondansetron well. The estimated plasma concentration range of the usual empirical dose from the Monte Carlo simulation was 0.1–13.2 ng/mL. These findings will facilitate determination of the optimal dose regimen for dogs with CINV.     

Pharmacokinetic evaluation of tramadol and its major metabolites after single oral sustained tablet administration in the dog: a pilot study

The study evaluated the pharmacokinetics of tramadol and its major metabolites O-desmethyltramadol (M1), N-desmethyltramadol (M2) and N-O didesmethyltramadol (M5) following a single oral administration of a sustained release (SR) 100mg tablet to dogs. Plasma tramadol concentration was greater than the limit of quantification (LOQ) in three dogs, M1 was quantified only in one dog while M2 and M5 were quantified in all of the dogs. The median values of C(max) (maximum plasma concentration), T(max) (time to maximum plasma concentration) and T(1/2) (half-life) for tramadol were 0.04 (0.17-0.02)mirog mL(-1), 3 (4-2) and 1.88 (2.211-1.435)h, respectively. M5 showed median values of C(max), T(max) and T(1/2) of 0.1 (0.19-0.09)microg mL(-1), 2 (3-1) and 4.230 (6.583-1.847)h, respectively. M2 showed median values of C(max), T(max) and T(1/2) of 0.22 (0.330-0.080)microg mL(-1), 4 (7-3) and 4.487 (6.395-1.563)h, respectively. The findings suggest that the SR formulation of tramadol may not have suitable pharmacokinetic characteristics to be administered once-a-day as an effective and safe treatment for pain in the dog.     

Comparison of vedaprofen and meloxicam in dogs with musculoskeletal pain and inflammation

In this randomised, multicentre clinical study, dogs with musculoskeletal pain and inflammation were treated with either vedaprofen or meloxicam administered orally at the recommended dose rates. Clinical examinations were carried out regularly and clinical severity scores assigned. In total, 214 cases (73 acute, 141 chronic) were evaluated. Treatment with vedaprofen and meloxicam was continued for 14 and 17 days, respectively, in the acute cases, and 38 and 39 days in the chronic cases. NSAID treatment resulted in a significant improvement in clinical scores. The overall response to treatment ('responders') at the final clinical examination was 89 per cent and 87 per cent in the acute cases and 72 per cent and 65 per cent in the chronic cases in the vedaprofen and meloxicam groups, respectively. Mild transient gastrointestinal signs were observed in both groups (11 per cent vedaprofen, 12 per cent meloxicam). Adverse effects related to NSAIDs resulted in treatment cessation in 5 per cent of the dogs in each group. Vedaprofen and meloxicam were efficacious in, and well tolerated by, most of the dogs in the study.     

Voluntary acceptance and consumption of two oral ciclosporin formulations in dogs: two randomised,controlled studies

Background

Atopic dermatitis (AD) is the most common canine allergic skin disease and can significantly affect the quality of life of affected dogs. Treating canine AD with ciclosporin has been a subject of great interest in recent years. Many studies have provided substantial evidence of ciclosporin efficacy and safety in canine AD management, and for several years ciclosporin has been recognised as a major component of canine AD multimodal therapy. As a chronic condition, canine AD requires life-long medical management and treatment success relies in large part on product ease of administration. Two studies were conducted to assess the comparative voluntary acceptance and consumption of Cyclavance® (Virbac), a new oral liquid formulation of ciclosporin, and Atopica® (Novartis) either added to a small quantity of kibbles (study 1) or administered directly into the dog’s mouth (study 2).

Results

Over the course of the two studies 70 dogs assessed each of the ciclosporin formulations and 320 individual tests were performed for each tested product. Immediate prehension (in less than 2 seconds) occurred significantly more often with Cyclavance® (90.6% of the tests) than with Atopica® (14.4% of the tests) when products were mixed with 30 grams of dry food (p < 0.001). Moreover, Cyclavance® was significantly more often easily accepted than Atopica® (99.3% vs 27.1% of the tests, respectively) when products were administered directly into the dogs’ mouth (p < 0.0001). Cyclavance® was also more often totally consumed (98.3% of the tests) than Atopica® (2.2% of the tests) when mixed with a small amount of food (p < 0.001). However, both products were totally consumed once administered directly into the dogs’ mouth.

Conclusions

By facilitating cicloporin administration and consumption, Cyclavance® liquid formulation offers an interesting alternative to capsules that may improve dosing compliance and therefore the ability to benefit from the therapeutic effects in the long-term treatment of canine AD.     

Pharmacokinetic evaluation of a slow-release cefotaxime suspension in the dog and in sheep

Three Merino ewes were given cefotaxime IM, and 3 were given cefotaxime subcutaneously (50 mg/kg of body weight each); each dose was suspended in 6 ml of oil. Five dogs were also given an oily suspension of cefotaxime subcutaneously (SC) (50 mg/kg of body weight). The plasma concentrations (Cp) and pharmacokinetic data obtained after cefotaxime in the oily suspension was injected IM and SC were compared with data from the same animals after they were given an aqueous solution of cefotaxime by the same routes. Key pharmacokinetic values obtained after cefotaxime was administered IV to sheep and to dogs are discussed. Mean peak Cp (Cpeak) in sheep when given the oily suspension IM was approximately 53 micrograms/ml at 0.18 to 0.40 hour, and that value in sheep given the aqueous preparation was 62 micrograms/ml 0.08 to 0.18 hour. Mean Cpeak values after the oily suspension and the aqueous preparation were injected SC were 11.0 micrograms/ml (between 0.8 and 1 hour) and 51 micrograms/ml (between 0.25 and 1 hour), respectively. Bioavailabilities were approximately 70% after IM injection was done and 90% after SC injection was done. The beta-plasma half-lives were 0.7 hour after IM injection was done and 2.9 hours after SC injection was done. Mean Cpeak in dogs when given the oily suspension SC was 30 micrograms/ml at 1.0 hour, and when dogs were given the aqueous preparation SC, Cpeak was 27 micrograms/ml at 0.6 hour. Absorption was virtually complete after the oily suspension and aqueous preparations were given.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hind limb kinematics during therapeutic exercises in dogs with osteoarthritis of the hip joints

Objective-To assess joint kinematics in dogs with osteoarthritis of the hip joints during walking up an incline or down a decline and over low obstacles and to compare findings with data for nonlame dogs. Animals-10 dogs with osteoarthritis of the hip joints (mean ± SD age, 6.95 ± 3.17 years; mean body weight, 34.33 ± 13.58 kg) and 8 nonlame dogs (3.4 ± 2.0 years; 23.6 ± 4.6 kg). Procedures-Reflective markers located on the limbs and high-speed cameras were used to record joint kinematics during walking up an incline or down a decline and over low obstacles. Maximal flexion, extension, and range of motion of the hip joints were calculated. Results-Osteoarthritis of the hip joints reduced extension of both hip joints and flexion of the contralateral hind limb, compared with flexion of the lame hind limb, during walking down a decline. Walking up an incline resulted in decreased extension of the stifle joint in both hind limbs of osteoarthritic dogs; extension was significantly decreased for the lame hind limb. During walking over low obstacles, maximal flexion of the stifle joint was increased significantly for the contralateral hind limb. Maximal flexion was increased in both tarsal joints. Conclusions and Clinical Relevance-Osteoarthritis of the hip joints led to complex changes in the gait of dogs, which involved more joints than the affected hip joint alone. Each exercise had specific effects on joint kinematics that must be considered when planning a rehabilitation program.     

Efficacy of ivermectin chewable tablets and two new ivermectin tablet formulations against Dirofilaria immitis larvae in dogs.

One hundred four heartworm-free Beagles less than 1 year old were studied to determine the efficacy of ivermectin chewable tablets and of 2 other ivermectin tablet formulations against heartworm larvae. At 30 days after SC inoculation of dogs with infective Dirofilaria immitis larvae, all ivermectin formulations were given orally at dosage of 6 micrograms/kg of body weight. The ivermectin chewable tablets also were given orally at dosage of 2 and 6 micrograms/kg at 30 and 45 days, respectively, after injection of larvae. Replicates of 6 or 8 dogs in each study were formed on the basis of gender and body weight and, within replicates, were randomly allocated to treatment groups. At 30 days after injection of larvae, the additional dogs (in replicates of 8) were assigned to the control group and to the group given ivermectin chewable tablets at dosage of 6 micrograms/kg. All dogs were housed individually. Necropsy was performed approximately 5 or 6 months after larvae were administered. In both trials, all control dogs had heartworms at necropsy (University of Illinois--geometric mean, 35.0; Florida--geometric mean, 26.1). In both trials, the ivermectin chewable tablet (6 micrograms/kg) and both tablet formulations (6 micrograms/kg) given at 30 days after larval injection, and the chewable formulation (6 micrograms/kg) given at 45 days after larval injection were 100% effective (P less than 0.01) in preventing development of induced infection with D immitis.(ABSTRACT TRUNCATED AT 250 WORDS)