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Abstract Background Erythropoietic effects of molidustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, were previously demonstrated in healthy cats. Objective To evaluate the safety and erythropoietic effects of daily PO administration of molidustat in anemic cats with chronic kidney disease (CKD). Animals Twenty-one client-owned CKD cats (4-17 years old) with anemia. Methods Multicenter field study; randomized, masked, and placebo-controlled. Cats were treated PO once daily for 28 days with suspensions of control product (CP; n = 6) or 5 mg/kg of molidustat (n = 15). Hematocrit (HCT) was evaluated at weekly intervals. Individual cat treatment success was defined as a ≥4% point increase in HCT compared to baseline. Results Control group mean HCT remained low throughout the study (20.1%-23.4%). Mean HCT of molidustat-treated cats increased weekly, and a significant increase compared to baseline (23.6%) was first observed on Day 21 (27.3%; P < .001; 95% confidence interval [CI], 1.69-5.67). Compared to CP group, mean HCT was significantly higher on Day 21 (27.3% vs 20.1%; P < .001; 95% CI, 2.91-10.75) but not significantly higher on Day 28 (27.8% vs 23.4%; P = .06; 95% CI, −0.23 to 9.88). The number of individual treatment successes on Day 28 was higher among remaining molidustat-treated cats (7/14) compared to remaining control cats (1/5), but there was no significant difference between groups. Conclusions and Clinical Importance Daily PO molidustat administration may stimulate a clinically relevant erythropoietic response in anemic cats with CKD. This HIF-PH inhibitor may be an alternative for managing anemia in cats compared to recombinant EPO treatment.

Abstract Background Inhibition of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) stimulates erythropoiesis in rats, dogs, monkeys, and humans. Hypothesis/Objective Determine if molidustat, a novel HIF-PH inhibitor, stimulates erythropoiesis in healthy cats. Animals Seventeen healthy adult laboratory cats. Methods Randomized, placebo-controlled study. Cats were treated PO once daily with suspensions of 0 (Group 1; n = 6), 5 (Group 2; n = 6), or 10 (Group 3; n = 5) mg/kg of molidustat. Effects on red blood cell parameters, reticulocyte indices and plasma erythropoietin (EPO) concentrations were evaluated. Molidustat treatment was stopped when hematocrit (HCT) exceeded 60%. Results Compared to placebo, a significant increase in mean HCT was evident starting on Day 14 (Group 2:54.4% vs 40.3%, P < .001, 95% confidence interval [CI] for the difference [8.95-19.28]; Group 3:61.2% vs 40.3%, P < .001, 95% CI [15.48-26.43]) and remained significantly higher for the entire treatment period. In molidustat-treated groups, HCT exceeded 60% on Day 21 (Group 2) and Day 14 (Group 3). Mean HCT in molidustat-treated cats returned to within the reference range (29%-45%) after Day 56 and was numerically comparable to placebo from Day 70 onwards. Red blood cell count and hemoglobin concentrations followed a similar pattern as HCT. Mean EPO concentrations significantly increased after molidustat administration on all assessment days. Molidustat treatments were well tolerated. Conclusions and Clinical Importance Marked erythropoietic effects were identified after daily administration of molidustat to healthy cats and additional studies are warranted to evaluate the effects in anemic cats.

Background Anecdotal reports support the position that the adulticidal heartworm treatment utilizing doxycycline and Advantage Multi®/Advocate® for Dogs (10% imidacloprid + 2.5% moxidectin) has successfully converted antigen-positive dogs to antigen-negative. To date, no controlled experimental studies have demonstrated the adulticidal efficacy of this treatment regimen. The aim of this study was to evaluate the parasitological and clinical efficacy of Advantage Multi® for Dogs (IMD + MOX) and doxycycline in heartworm-infected beagles. Methods This study utilized 16 dogs, 8 dogs in each of non-treated control and treated groups. A total of 16 adult Dirofilaria immitis (Missouri strain) were surgically transplanted into the jugular vein of each study dog. The treatment regimen of monthly IMD + MOX topically (per labeled dosage and administration) for 10 months and 10 mg/kg doxycycline BID orally for 30 days was initiated 30 days post-surgical transplant. Echocardiograms, radiographs, complete blood counts, clinical chemistry profiles, heartworm antigenemia and microfilaremia were evaluated every 4 weeks. Serum samples were assayed for heartworm antigen using the DiroCHEK® heartworm antigen test. The DiroCHEK® was performed according to the manufacturer’s recommendations and read using a spectrophotometer at 490 nm. Results All dogs tested positive for the presence of heartworm antigen post-surgical transplant and prior to treatment. Heartworm antigen levels began declining in treated dogs 3 months post-treatment. Non-treated control dogs remained antigen-positive. No microfilariae were detected in treated dogs after 21 days post-treatment. At necropsy, adult heartworms were recovered from all non-treated control dogs with a range of 10–12 adult worms/dog for an average recovery of 10.6 adult heartworms/dog. In the IMD + MOX- and doxycycline-treated dogs, the range of adult heartworms recovered was 0–2 adult worms/dog, with five dogs having no adult heartworms present. The average adult heartworm recovery was 0.6/dog in the treated group. This treatment regimen demonstrated a 95.9% efficacy in eliminating adult heartworms ( P  < 0.0001). Conclusions This study demonstrated that this treatment regimen successfully eliminated D. immitis microfilariae by 21 days post-treatment, reduced heartworm antigen concentration over time, and had a 95.9% efficacy in the elimination of mature adult heartworms. Based on this study, we conclude that this treatment regimen is a relatively quick, reliable and safe option to treat canine heartworm infection as compared to other treatment regimens involving macrocyclic lactones, when the approved drug melarsomine dihydrochloride is unavailable, contraindicated or declined by an owner unable to afford the more costly treatment or concerned about the potential side effects.

Background The use of heat-treatment in canine and feline serum has been hypothesized to break the formation of antigen-antibody complexes, thereby freeing the heartworm antigen allowing for detection by commercially available heartworm antigen kits. While studies have analyzed the effect of heat-treating serum and plasma samples in the detection of heartworm antigen, these studies have not utilized necropsy verified results for validation. This study evaluated the use of heat-treating serum samples in experimentally infected dogs during adulticidal treatment in comparison with necropsy adult heartworm recovery. Methods As part of a primary study, a total of 16 dogs were experimentally infected with 16 sexually mature adult heartworms using surgical transplantation, allocating 8 dogs in both the control and treated group. Treated dogs received 10 months of topical administration of Advantage Multi® for Dogs (10% Imidacloprid + 2.5% Moxidectin) every 4 weeks and 30 days of 10 mg/kg doxycycline BID. Blood samples were collected from all study animals prior to surgical transplantation of adult heartworms, on study days 0, 1, 3, 7, 14, 21, 28, and every 4 weeks thereafter for the duration of this study. Concentration of heartworm antigen was tested using the DiroCHEK® heartworm antigen test kit using serum samples both pre- and post-heat-treatment. Serum samples were heat-treated at 103 °C in a dry heat block for 10 min and centrifuging at 1818×  g for 20 min. Results There were a total of 4 instances (days 56, 140, 224 and 252) in 3 treated dogs in which a serum sample converted from negative for the detection of heartworm antigen prior to heat-treatment to positive for the detection of heartworm antigen post-heat-treatment. At necropsy, these dogs had no adult heartworms recovered and were all negative on antigen testing prior to and after heat treatment. There was 100% accuracy in the detection of either no infection, or 1–2 adult heartworm infections using the DiroCHEK in serum samples with and without heat-treatment at the time of necropsy. Conclusions The DiroCHEK accurately diagnosed all dogs with live adults recovered at necropsy as heartworm antigen positive and all those dogs with no live adults recovered at necropsy as heartworm antigen negative without the use of heat-treatment for samples taken on the day of necropsy. Therefore, these results indicate that the use of heat-treating serum samples did not provide data of any additional value in the diagnosis of heartworm-positive dogs receiving treatment in this study. Additionally, these results may indicate that the conversion of serum samples from negative to positive for the presence of heartworm antigen with heat-treatment may not always accurately diagnose live adult heartworm infections since no adult heartworms were recovered at necropsy for those dogs in which a conversion event occurred. These conversion events may be detecting residual antigen leftover after all adult worms have died or may even be detecting off- target antigens, which have been denatured during heat-treatment. While a necropsy was not performed at the time of the conversion events, no live adult worms were recovered from any of the dogs in which a conversion event occurred earlier in treatment.

Background Prior work has shown that the levels of moxidectin in dogs treated with Advantage Multi® for Dogs (Bayer Animal Health) remain at a high plasma concentration for the full month after application. The objective of this study was to demonstrate the efficacy of 10% imidacloprid + 2.5% moxidectin topical solution (Advantage Multi® for Dogs, also known as Advocate® for Dogs) for the prevention of heartworm infection and disease 30 days after just one application. Methods Two groups of eight dogs each were included. Dogs in Group 1 received the product (Advantage Multi® for Dogs) while those in Group 2 remained as nontreated controls. All dogs entering the study completed a physical examination including examination for Dirofilaria immitis antigen and circulating microfilariae. Dogs in Group 1 were treated on Study Day (SD) –30 as per the label recommendation. Thirty days later (SD 0) dogs in Groups 1 and 2 were subcutaneously infected in the inguinal region with approximately 50 infective third-stage D. immitis larvae (“Missouri” isolate). Blood was collected on SDs 120 and 147 for examination for D. immitis antigen and circulating microfilariae. On SD 148, all animals were euthanized and necropsied for recovery of adult heartworms. All procedures were performed in accordance with the VICH GL9 guidelines. Results Examination and worm counts made at necropsy showed no heartworms in the treated dogs (Group 1) compared with six of eight nontreated dogs (Group 2) with heartworms (range of 2–33). The treated dogs (Group 1) had significantly fewer heartworms ( p  < 0.05) compared with the nontreated controls (Group 2). Conclusion The results demonstrated that 10% imidacloprid + 2.5% moxidectin topical solution (Advantage Multi® for Dogs) is efficacious for the prevention of heartworm infection and disease all month long with no observation of treatment-related adverse events.

The capability of imidacloprid 10% + flumethrin 4.5% (Seresto®) collars to prevent transmission of Borrelia burgdorferi sensu lato (Bbsl) and Anaplasma phagocytophilum (Ap) by naturally infected ticks was evaluated in two studies with 44 dogs. In each study, one group served as non-treated control, whereas the other groups were treated with the Seresto® collar. All dogs were exposed to naturally Bbsl- and Ap-infected hard ticks (Ixodes ricinus, Ixodes scapularis). In study 1, tick infestation was performed on study day (SD) 63 (2 months post-treatment [p.t.]); in study 2, it was performed on SD 32 (one month p.t.) respectively SD 219 (seven months p.t.). In situ tick counts were performed 2 days after infestation. Tick counts and removals followed 6 (study 1) or 5 days (study 2) later. Blood sampling was performed for the detection of specific Bbsl and Ap antibodies and, in study 1, for the documentation of Ap DNA by PCR. Skin biopsies were examined for Bbsl by PCR and culture (only study 1). The efficacy against Ixodes spp. was 100% at all time points. In study 1, two of six non-treated dogs became infected with Bbsl, and four of six tested positive for Ap; none of the treated dogs tested positive for Bbsl or Ap. In study 2, ten of ten non-treated dogs became infected with Bbsl and Ap; none of the treated dogs tested positive for Bbsl or Ap; 100% acaricidal efficacy was shown in both studies. Transmission of Bbsl and Ap was successfully blocked for up to 7 months.

This study aimed to evaluate the efficacy of an emodepside 2.1 % (w/v)/praziquantel 8.6 % (w/v) topical solution (Profender® spot-on for cats) in the prevention of lactogenic Toxocara cati infections. A controlled test was performed with two groups of 8 cats with confirmed pregnancy. All cats were infected with daily doses of 2000 T. cati eggs for 10 consecutive days starting 50 days post conception to produce an acute infection. Treatment was performed 60 days post conception. Queens in the treatment group received the emodepside/praziquantel solution at the minimum therapeutic dose (3 mg/kg emodepside and 12 mg/kg praziquantel), while the control group was treated with a placebo spot-on. Efficacy was evaluated 56 days post partum by necropsy of one randomly selected kitten of each litter and comparison of the worm burdens between the study groups. Additionally the necropsy results were supported by quantification of worms expelled with the faeces after deworming of the remaining kittens and all queens. The treatment in late pregnancy resulted in an efficacy of 98.7 % (p < 0.0001). All necropsied control kittens were infected (geometric mean 30.6). Seven of 8 kittens from treated mothers were free of T. cati (geometric mean 0.4). Worm counts after deworming reflected the results obtained at necropsy. No side effects of the treatment were observed. It is concluded that treatment with an emodepside/praziquantel spot-on solution during late pregnancy effectively prevents lactogenic transmission of T. cati to the offspring. The study design facilitated the generation of reliable data, while at the same time a minimum number of animals was sacrificed.

Background This controlled laboratory study was designed to evaluate the efficacy of the 10 % imidacloprid/4.5 % flumethrin collar (Seresto®, Bayer Animal Health) against fleas ( Ctenocephalides f. felis ) on cats, when compared to fipronil (9.8 %w/w)/(s)-methoprene (11.8 % w/w) topical spot-on formulation (Frontline® Plus for Cats and Kittens, Merial). Methods Thirty cats were randomized into three groups of ten animals based on pre-treatment flea counts: Group 1: imidacloprid/flumethrin collar; Group 2: fipronil/(s)-methoprene topical spot-on and Group 3: non-treated controls. The imidacloprid/flumethrin collars were applied one time on Day 0, while the fipronil/(s)-methoprene spot-on was administered every 30 days from Day 0 through Day 210. Cats were infested with 100 fleas on study days 0, 7, 14, 29, 59, 89, 119, 149, 179, 209 and 239. All flea counts were conducted by combing to remove fleas on post-treatment days 2, 8, 15, 30, 60, 90, 120, 150, 180, 210 and 240. Results The efficacy of the imidacloprid/flumethrin collar ranged from 98.2 to 100 % for eight months. The efficacy of fipronil/(s)-methoprene spot-on ranged from 68.2 to 99.9 %. Efficacy was < 85 % for fipronil/(s)-methoprene on Days 90, 150 and 210. The flea counts in both treatment groups were significantly fewer than those in the non-treated control group at every post-treatment study day ( P  < 0.0001). In addition, there were significantly fewer fleas in the imidacloprid/flumethrin collar group when compared to the fipronil/(s)-methoprene group on Days 90, 150 and 210 ( P  < 0.0001). Conclusions This study demonstrated that the imidacloprid/flumethrin collar (Seresto®, Bayer Animal Health) maintained excellent ( > 98.2 %) efficacy against fleas on cats for the entire 8 month study. Monthly applications of fipronil/(s)-methoprene (Frontline® Plus for Cats and Kittens, Merial) generally had high, but variable (68.2 to 99.9 %) efficacy over the course of the eight month study. Based on the very high residual efficacy achieved by the imidacloprid/flumethrin collar in this study, veterinarians should expect that this collar will control and eliminate existing flea infestations on cats and in their in-home premises as long as every flea infested host is treated.

This controlled laboratory study demonstrated the residual speed of efficacy of an imidacloprid/flumethrin collar (Seresto®, Bayer) for the control of ticks (Dermacentor variabilis, Amblyomma americanum) at 6 and 12 hours post-infestation on dogs when compared to oral fluralaner (Bravecto®, Merck). Dogs were randomised by pre-treatment tick counts: Group 1) imidacloprid 10 % (w/w)/flumethrin 4.5 % (w/w) collar, 2) fluralaner (dosage 25.1 – 49.4 mg/kg), and 3) non-treated controls. Ticks (50/species/dog) were infested on days 3, 14, 21, 28, 42, and 56 followed by 50 D. variabilis on days 70 and 84. Live and dead attached ticks were counted 6 and 12 hours later. Efficacy against both species at 6 and 12 hours for Group 1 was 94 – 100 %. Efficacy for Group 2 against both species at 6 hours was 4 – 69 %; efficacy at 12 hours was 8 – 100 %. Live (attached and non-attached) tick counts at 6 hours in Group 1 were significantly lower (p ≤ 0.05) than counts in Group 2 and 3 on all days. At 12 hours, live counts were significantly lower (p ≤ 0.05) in Group 1 than Group 2 for D. variabilis from days 56 – 84 and for A. americanum from days 28 – 56. There were significantly fewer (p ≤ 0.05) total ticks (total live and dead attached) on dogs in Group 1 compared to Group 2 and 3 at all time points. This study demonstrated that an imidacloprid/flumethrin collar was highly efficacious (94 – 100 %) at repelling and killing ticks on dogs at 6 and 12 hours post-infestation and was more efficacious than fluralaner as early as 6 hours post-infestation on all challenge days.

This randomised controlled laboratory study demonstrated the residual speed of efficacy of an imidacloprid/flumethrin collar (Seresto®, Bayer) for the control of ticks (Dermacentor variabilis, Amblyomma americanum) at 6 and 12 hours postinfestation on dogs when compared to oral afoxolaner (NexGard®, Merial). Dogs were randomised by pre-treatment tick counts: Group 1) imidacloprid 10 % (w/w) / flumethrin 4.5 % (w/w) collar, 2) afoxolaner chewable (dosage 3.1 – 6.2 mg/kg), and 3) non-treated controls. Ticks (50/species/dog) were infested on days 3, 14, 21, and 28; live (attached and non-attached) and dead attached ticks were counted 6 and 12 hours later. Efficacy against live D. variabilis at 6 hours for Group 1 was 95 – 100 % and for Group 2 was 38 – 48 %; efficacy at 12 hours for Group 1 was 97 – 100 % and for Group 2 was 27 – 59 %. Efficacy against A. americanum at 6 hours for Group 1 was 94 – 100 % and for Group 2 was < 0 – 38 %; efficacy at 12 hours for Group 1 was 98 – 100 % and for Group 2 was 1 – 40 %. Live and total (total live and dead attached) tick counts in Group 1 against both tick species were significantly lower (p ≤ 0.05) than Group 2 and 3 at all time points. The number of live or total ticks on Group 2 dogs was never significantly lower when compared to the respective number of ticks on Group 3 (controls). This study demonstrated that an imidacloprid/flumethrin collar was highly efficacious (94 – 100 %) at repelling and killing ticks on dogs at 6 and 12 hours post-infestation and was more efficacious than afoxolaner on all challenge days.