RESUMEN
Unmanaged tick and sucking lice infestations negatively impact the health and production potential of cattle. Described herein are two non-interference dose confirmation studies evaluating the efficacy of a single administration of a new fixed-dose combination injectable (FDCI) endectocide consisting of 0.2 mg/kg doramectin + 6.0 mg/kg levamisole hydrochloride, against either laboratory-induced Rhipicephalus microplus infestations in Australia or naturally acquired sucking lice (Linognathus vituli) infestations in the US. This FDCI is available as Dectomax V® in Australia and New Zealand and as Valcor® in the United States. To evaluate therapeutic efficacy against R. microplus, 12 calves were each exposed to 10 infestations of â¼5000 larvae per infestation between Days -24 and -2. Calves were either treated on Day 0 with the FDCI or left untreated (control). Additional R. microplus infestations of â¼5000 larvae were conducted on Day 2 and then three times weekly to also evaluate persistent efficacy of the FDCI. Tick collections were conducted daily from Day -3. Group mean live tick counts, egg production, and egg viability were analyzed for significant differences between the two groups. To determine efficacy of the FDCI against lice, 24 cattle with active sucking lice infestations based on Day -7 counts were allocated to two groups and treated on Day 0 with either saline (control) or the FDCI. Lice counts were conducted weekly from Day 14 through 42 and again on Day 56. Mean group lice counts on each count day were compared between treatment groups. In the R. microplus study presented here, cattle in Queensland, Australia treated with the FDCI (Dectomax V®) showed > 90 % reduction in tick counts based on arithmetic means within 48 h of treatment when compared to untreated cattle, and counts were > 95 % reduced from post-treatment Day 5 through Day 30. In the sucking lice study conducted in the US, the FDCI (Valcor®) displayed 100 % efficacy against sucking lice infestations (L. vituli) from first count day (Day 14 post-treatment) through Day 35 and then 99.9 % efficacy through Day 56 post-treatment. No treatment-related adverse events were reported for cattle in either study. Using R. microplus and sucking lice as representative ectoparasites, these studies demonstrate the ectoparasite activity of doramectin is retained in the new FDCI.
Asunto(s)
Anoplura , Enfermedades de los Bovinos , Insecticidas , Infestaciones por Piojos , Rhipicephalus , Infestaciones por Garrapatas , Animales , Bovinos , Infestaciones por Piojos/tratamiento farmacológico , Infestaciones por Piojos/veterinaria , Levamisol/uso terapéutico , Insecticidas/uso terapéutico , Enfermedades de los Bovinos/tratamiento farmacológico , Enfermedades de los Bovinos/parasitología , Larva , Infestaciones por Garrapatas/tratamiento farmacológico , Infestaciones por Garrapatas/veterinaria , Infestaciones por Garrapatas/parasitologíaRESUMEN
BACKGROUND: Assessment of the safety of heartworm preventatives in dogs with pre-existing patent heartworm (Dirofilaria immitis) infections is necessary because rapid adult worm and microfilarial death can lead to severe clinical complications, including thromboembolism and anaphylactic shock in dogs. The aim of this study was to determine the clinical safety of Simparica Trio® (sarolaner, pyrantel, moxidectin) in heartworm-infected dogs and the degree of microfilaricidal and adulticidal activity of three consecutive monthly treatments of Simparica Trio. METHODS: Twenty-four laboratory Beagle dogs were implanted with 10 male and 10 female D. immitis (ZoeKY isolate), and once infection was patent, they were randomized equally among three groups to receive no treatment, 1× or 3× the maximum recommended label dose of Simparica Trio. Dogs in the treated groups received Simparica Trio on days 0, 28 and 56. In-life assessments included body weight, physical examinations, clinical observations, daily general health observations, a quantitative estimate of food consumption and blood collections for pharmacokinetic (PK) analysis, microfilariae (MF) counts and D. immitis antigen testing. At the end of the study the heart, lungs and pleural and peritoneal cavities were examined for adult D. immitis worms. RESULTS: Simparica Trio was generally well tolerated. Emesis occurred at low frequency in all groups including control. Abnormal stool occurred occasionally in the 1× and 3× groups throughout the 3-month study. Fever (> 104 °F/40 °C) was recorded in one 1× and one 3× dog 1 day after the first dose and resolved by the following day. No severe hypersensitivity reactions occurred. The mean number of circulating microfilariae (MF) counts in the control group increased from 12,000/ml at study start (Day 0) to > 20,000/ml at Day 28 and remained > 20,000/ml for the duration of the study. The least squares means of circulating MF were reduced by 69.8% on Day 1 and 97.4% on Day 7 for the 1× group and remained at > 99% lower than the control group for the remainder of the study. Similarly, least squares means of circulating MF were reduced by 85.3% on Day 1 and 93.9% on Day 7 for the 3× group and remained > 98% lower than the control group for the remainder of the study. At the end of the study, the mean number of implanted adult worms recovered was < 10 per sex in all groups with 90%, 85% and 75% of live adult heartworms recovered in control, 1× and 3× treatment groups, respectively. Low numbers of dead adult worms were recovered in 1× and 3×, with none in control. Following each dose, the moxidectin and sarolaner AUC and Cmax had close to dose proportional increases. CONCLUSIONS: This study demonstrated that Simparica Trio (sarolaner, pyrantel, moxidectin) was well tolerated when administered to heartworm-positive dogs at 1× and 3× the maximum recommended dose at 28-day intervals for 3 consecutive months. Simparica Trio significantly reduced microfilaria counts in both treatment groups, without significant clinical consequences. At the doses administered, Simparica Trio had minor adulticidal activity but resulted in no clinical sequelae.
Asunto(s)
Dirofilaria immitis , Dirofilariasis , Enfermedades de los Perros , Animales , Perros , Femenino , Masculino , Administración Oral , Dirofilariasis/tratamiento farmacológico , Enfermedades de los Perros/tratamiento farmacológico , Macrólidos/efectos adversos , Microfilarias , Pirantel , Resultado del TratamientoRESUMEN
BACKGROUND: Fecal examinations in pet cats and dogs are key components of routine veterinary practice; however, their accuracy is influenced by diagnostic methodologies and the experience level of personnel performing the tests. The VETSCAN IMAGYST system was developed to provide simpler and easier fecal examinations which are less influenced by examiners' skills. This system consists of three components: a sample preparation device, an automated microscope scanner, and analysis software. The objectives of this study were to qualitatively evaluate the performance of the VETSCAN IMAGYST system on feline parasites (Ancylostoma and Toxocara cati) and protozoan parasites (Cystoisospora and Giardia) and to assess and compare the performance of the VETSCAN IMAGYST centrifugal flotation method to reference centrifugal and passive flotation methods. METHODS: To evaluate the diagnostic performance of the scanning and algorithmic components of the VETSCAN IMAGYST system, fecal slides were prepared by the VETSCAN IMAGYST centrifugal flotation technique with pre-screened fecal samples collected from dogs and cats and examined by both an algorithm and parasitologists. To assess the performance of the VETSCAN IMAGYST centrifugal flotation technique, diagnostic sensitivity and specificity were calculated and compared to those of conventional flotation techniques. RESULTS: The performance of the VETSCAN IMAGYST algorithm closely correlated with evaluations by parasitologists, with sensitivity of 75.8-100% and specificity of 93.1-100% across the targeted parasites. For samples with 50 eggs or less per slide, Lin's concordance correlation coefficients ranged from 0.70 to 0.95 across the targeted parasites. The results of the VETSCAN IMAGYST centrifugal flotation method correlated well with those of the conventional centrifugal flotation method across the targeted parasites: sensitivity of 65.7-100% and specificity of 97.6-100%. Similar results were observed for the conventional passive flotation method compared to the conventional centrifugal flotation method: sensitivity of 56.4-91.7% and specificity of 99.4-100%. CONCLUSIONS: The VETSCAN IMAGYST scanning and algorithmic systems with the VETSCAN IMAGYST fecal preparation technique demonstrated a similar qualitative performance to the parasitologists' examinations with conventional fecal flotation techniques. Given the deep learning nature of the VETSCAN IMAGYST system, its performance is expected to improve over time, enabling it to be utilized in veterinary clinics to perform fecal examinations accurately and efficiently.
Asunto(s)
Enfermedades de los Gatos/parasitología , Aprendizaje Profundo , Enfermedades de los Perros/parasitología , Parásitos/aislamiento & purificación , Enfermedades Parasitarias en Animales/diagnóstico , Algoritmos , Ancylostoma/aislamiento & purificación , Animales , Gatos , Centrifugación/métodos , Pruebas Diagnósticas de Rutina , Perros , Heces/parasitología , Giardia/aislamiento & purificación , Hospitales Veterinarios , Oocistos/aislamiento & purificación , Recuento de Huevos de Parásitos/métodos , Enfermedades Parasitarias en Animales/parasitología , Sensibilidad y Especificidad , Toxocara/aislamiento & purificaciónRESUMEN
BACKGROUND: Fecal examination is an important component of routine companion animal wellness exams. Sensitivity and specificity of fecal examinations, however, are influenced by sample preparation methodologies and the level of training and experience of personnel who read fecal slides. The VETSCAN IMAGYST system consists of three components: a sample preparation device, a commercially available scanner, and an analysis software. The VETSCAN IMAGYST automated scanner and cloud-based, deep learning algorithm, locates, classifies, and identifies parasite eggs found on fecal microscopic slides. The main study objectives were (i) to qualitatively evaluate the capabilities of the VETSCAN IMAGYST screening system and (ii) to assess and compare the performance of the VETSCAN IMAGYST fecal preparation methods to conventional fecal flotation techniques. METHODS: To assess the capabilities of VETSCAN IMAGYST screening components, fecal slides were prepared by the VETSCAN IMAGYST centrifugal and passive flotation techniques with 100 pre-screened fecal samples collected from dogs and cats and examined by both the algorithm and parasitologists. To determine the diagnostic sensitivity and specificity of the VETSCAN IMAGYST sample preparation techniques, fecal flotation slides were prepared by four different techniques (VETSCAN IMAGYST centrifugal and passive flotations, conventional centrifugal flotation, and passive flotation using OVASSAY® Plus) and examined by parasitologists. Additionally, required sample preparation and scanning times were estimated on a subset of samples to evaluate VETSCAN IMAGYST ease-of-use. RESULTS: The algorithm performance of the VETSCAN IMAGYST closely matched that of the parasitologists, with Pearson's correlation coefficient (r) ranging from 0.83-0.99 across four taxa of parasites, Ancylostoma, Toxocara, Trichuris and Taeniidae. Both VETSCAN IMAGYST centrifugal and passive flotation methods correlated well with conventional preparation methods on all targeted parasites (diagnostic sensitivity of 75.8-100%, specificity of 91.8-100%, qualitative agreement between methods of 93.8-94.5%). Sample preparation, slide scan and image analysis were completed within 10-14 min by VETSCAN IMAGYST centrifugal and passive flotations, respectively. CONCLUSIONS: The VETSCAN IMAGYST scanning system with the VETSCAN IMAGYST sample preparation methods demonstrated a qualitative match in comparison to the results of parasitologists' examinations with conventional fecal flotation techniques. The VETSCAN IMAGYST is an easy-to-use, next generation qualitative and possibly quantitative diagnostic platform that brings expert clinical results into the hands of veterinary clinics.
Asunto(s)
Aprendizaje Profundo , Heces/parasitología , Helmintiasis Animal/diagnóstico , Recuento de Huevos de Parásitos/métodos , Ancylostoma/aislamiento & purificación , Animales , Enfermedades de los Gatos/diagnóstico , Enfermedades de los Gatos/parasitología , Gatos , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/parasitología , Perros , Sensibilidad y Especificidad , Taenia/aislamiento & purificación , Toxocara/aislamiento & purificación , Trichuris/aislamiento & purificaciónRESUMEN
Revolution®/Stronghold® Plus, a topical endectocide incorporating 6 mg/kg selamectin plus 1 mg/kg sarolaner, is approved for use in cats to prevent heartworm disease. The efficacy of selamectin has not previously been evaluated against any macrocyclic lactone (ML)-resistant heartworm strains in cats for prevention of heartworm disease. In this study, an experimental combination formulation of selamectin (6 mg/kg) plus sarolaner (2 mg/kg) was assessed for preventing the development of a ML-resistant strain of Dirofilaria immitis in cats. Forty purpose-bred domestic shorted-haired cats (20 males; 20 females) from 7-9 months of age and negative for heartworm antigen prior to study inclusion were used. On Day -30, cats were inoculated with 100 D. immitis L3 (ZoeMO strain) subcutaneously in the inguinal area. Cats were randomly allocated to one of the following four treatments with associated dosing regimens: T01 (vehicle-treated control on Days 0, 28, and 56), T02 (single dose of selamectin plus sarolaner combination on Day 0 only), T03 (selamectin plus sarolaner combination on Days 0, 28, and 56) or T04 (single dose of selamectin on Day 0 only). All treatments were administered topically in an isopropyl alcohol-based formulation. Selamectin was administered at 6 mg/kg in both standalone and combination formulations. Sarolaner was administered at 2 mg/kg. Cats were necropsied on Day â¼145 (â¼175 days post infection) and adult worms were counted. Nine of ten cats in the control group (T01) were infected with adult worms (range, 1-23; geometric mean, 3.5). In contrast, all cats in T03 had zero heartworms. Only two cats in T02 (0-3; 0.2) and a single cat in the T04 (0-1; 0.1) had heartworms. Compared to T01 (control cats), all treated cats had significantly (p < 0.0001) reduced worm burdens, with treatment efficacies of 100% (T03), 93.5% (T02) and 98% (T04). A topical combination of selamectin (6 mg/kg) plus sarolaner (2 mg/kg) was 100% efficacious in preventing the development of an ML-resistant strain of D. immitis (ZoeMO) in cats when administered as three consecutive monthly treatments. A single dose was highly (93.5%) but incompletely effective.
Asunto(s)
Antinematodos/farmacología , Azetidinas/farmacología , Enfermedades de los Gatos/prevención & control , Dirofilaria immitis/efectos de los fármacos , Dirofilariasis/prevención & control , Ivermectina/análogos & derivados , Compuestos de Espiro/farmacología , Administración Tópica , Animales , Enfermedades de los Gatos/parasitología , Gatos , Dirofilariasis/parasitología , Femenino , Ivermectina/farmacología , MasculinoRESUMEN
BACKGROUND: Moxidectin has previously shown limited efficacy (≤ 44.4%) against confirmed macrocyclic lactone (ML)-resistant Dirofilaria immitis strains at 3 µg/kg after single and multiple oral dosages. Three studies were conducted to evaluate higher oral moxidectin doses for efficacy against confirmed ML-resistant D. immitis strains. METHODS: Dogs were inoculated with 50 D. immitis L3 and randomly allocated to treatments. Study 1: 6 groups of dogs (n = 8) were inoculated with JYD-34 (Day - 30) and treated as follows: T01, negative control; T02-T05, moxidectin at 3, 6, 12 or 24 µg/kg, respectively, on Day 0 only; T06, moxidectin at 3 µg/kg on Days 0, 30 and 60. Study 2: 10 groups of dogs (n = 5) were inoculated (Day - 30) with either JYD-34 (T01, T03-05) or ZoeLA (T02, T06-T10) and treated as follows: T01 and T02, negative controls; T03-T05, moxidectin at 24, 40 or 60 µg/kg, respectively, on Days 0, 28 and 56; T06 and T09, moxidectin at 3 or 60 µg/kg on Day 0 only; T07, T08 and T10, moxidectin at 24, 40 or 60 µg/kg, respectively, on Days 0, 28 and 56. Study 3: 5 groups of dogs (n = 5) were inoculated with ZoeMO (Day - 28) and treated as follows: T01, negative control; T02, moxidectin at 3 µg/kg moxidectin on Day 0 only; T03-T05, moxidectin at 24, 40 or 60 µg/kg, respectively, on Days 0, 28 and 56. All dogs were necropsied for adult heartworm recovery ~ 4-5 months post-inoculation. RESULTS: All moxidectin-treated dogs showed significantly lower worm counts than controls. The efficacy of moxidectin administered once at 3 µg/kg was 19% (JYD-34), 44.4% (ZoeLA) and 82.1% (ZoeMO). Increasing both the dose and the number of dosages of moxidectin improved efficacy, with 100% protection obtained using three dosages of moxidectin at either 40 µg/kg (JYD-34, ZoeMO) or 60 µg/kg (ZoeLA). Three dosages of 24 µg/kg were also highly effective, providing ≥ 98.8% efficacy for all three strains. CONCLUSIONS: Increasing both the dose and number of consecutive monthly dosages of moxidectin improved the efficacy against ML-resistant heartworms. Based on these data and other technical considerations, the 24 µg/kg dose was considered the optimal dose for further commercial development.
Asunto(s)
Antinematodos/administración & dosificación , Quimioprevención/métodos , Dirofilaria immitis/aislamiento & purificación , Dirofilariasis/prevención & control , Enfermedades de los Perros/prevención & control , Macrólidos/administración & dosificación , Administración Oral , Animales , Dirofilaria immitis/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Carga de Parásitos , Resultado del TratamientoRESUMEN
BACKGROUND: Dirofilaria immitis is a filarial parasite of dogs that can cause serious or fatal cardiopulmonary disease. Three studies were conducted to evaluate the efficacy and safety of monthly treatment with moxidectin in a chewable tablet product in combination with sarolaner and pyrantel to prevent heartworm disease in dogs after experimental challenge and in a clinical field study in the USA. METHODS: In two laboratory studies, dogs (8 per group) that had been inoculated 30 days prior with 50 third-stage D. immitis larvae were randomized to treatment on Day 0 with placebo or combination product, at the minimum dose of 24 µg/kg moxidectin, 2 mg/kg sarolaner and 5 mg/kg pyrantel (as pamoate salt). Study 2 also included groups treated with tablets containing moxidectin-alone (24 µg/kg) or sarolaner-alone (2 mg/kg). Efficacy was evaluated ~ 5 months after inoculation by adult heartworm counts at necropsy. In the field study, 410 dogs ≥ 8 weeks-old from 23 USA veterinary clinics were treated for 11 months with either combination product at 24-48 µg/kg moxidectin, 2-4 mg/kg sarolaner and 5-10 mg/kg pyrantel (n = 272) or Heartgard® Plus (ivermectin/pyrantel) at the label recommended dose rate (n = 138). Efficacy was evaluated on Day 330 using antigen and microfilaria testing to assess adult heartworm infection. RESULTS: In the laboratory studies, there were no heartworms recovered from any dog treated with the combination product or moxidectin alone and all dogs treated with placebo or sarolaner-alone were infected with 20-44 adult heartworms. In the field study, all dogs treated with the combination product tested negative for heartworm infection on Day 330, whereas two dogs treated with Heartgard® Plus tested positive. The Heartgard® Plus-treated dogs that tested heartworm positive were from the lower Mississippi River Valley region, where heartworm resistance has been confirmed to occur. The combination product was well tolerated in all studies. CONCLUSIONS: In laboratory studies, no heartworms were recovered from dogs treated with a single dose of the novel combination product containing moxidectin, sarolaner and pyrantel. Additionally, in the field study no dog tested positive for adult heartworm infection when dosed with the combination product monthly for 11 months, while two dogs treated with Heartgard® Plus tested positive.
Asunto(s)
Antinematodos/administración & dosificación , Azetidinas/administración & dosificación , Quimioprevención/métodos , Dirofilariasis/prevención & control , Enfermedades de los Perros/prevención & control , Macrólidos/administración & dosificación , Pirantel/administración & dosificación , Compuestos de Espiro/administración & dosificación , Administración Oral , Animales , Dirofilaria immitis/efectos de los fármacos , Perros , Quimioterapia Combinada/métodos , Placebos/administración & dosificación , Resultado del Tratamiento , Estados UnidosRESUMEN
Two randomised, single-masked, multi-center field studies were conducted in the United States in cats presented as veterinary patients. The first study evaluated the efficacy and safety of a topically applied formulation of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus, Zoetis) against natural flea infestations; the second study evaluated its efficacy against natural ear mite infestations. The product was administered topically by the cats' owners at the dose range provided in the market product of 6.0-12.0 mg selamectin and 1.0-2.0 mg sarolaner per kg bodyweight. Imidacloprid plus moxidectin (Advantage® Multi for Cats, Bayer) was used as a positive control in both studies at the label dosage. In the flea study, treatments were administered on Days 0, 30, and 60. Efficacy was calculated based on the mean percent reduction of live flea counts on Days 30, 60, and 90 relative to the pre-treatment count. In the ear mite study, a single treatment was applied on Day 0 and efficacy was determined on Days 14 and 30 based on the presence or absence of ear mites. In both studies, patients were randomly allocated to treatments in the ratio of 2:1, selamectin plus sarolaner: imidacloprid plus moxidectin. In the two studies, 405 cats received treatment with selamectin plus sarolaner; of these, 256 cats received three monthly treatments in the flea study. There were no serious adverse reactions to treatment with selamectin plus sarolaner; health issues noted were typical of the normal ailments or minor traumatic injuries expected in the general cat population and were similar in both treatment groups. Efficacy against fleas based on geometric (arithmetic) means was 97.2% (95.9%), 99.5% (99.4%), and 99.8% (99.8%) in the selamectin plus sarolaner group and was 79.7% (70.5%), 91.4% (77.3%), and 95.5% (87.4%) in the imidacloprid plus moxidectin group on Days 30, 60, and 90, respectively. Flea counts for the selamectin plus sarolaner group were significantly lower than the counts for the imidacloprid plus moxidectin group at all time-points after treatment administration on Day 0 (P < 0.001). Treatment reduced the clinical signs of flea allergy dermatitis (alopecia, dermatitis/pyodermatitis, erythema, pruritus, scaling, and papules) in affected cats by 86.7%-100% in the selamectin plus sarolaner group and by 66.7%-100% in the imidacloprid plus moxidectin group. In the ear mite study, a single application of selamectin plus sarolaner resulted in the clearance of mites from 87.5% of cats within 14 days and 94.4% of cats within 30 days of treatment. The respective percentages of mite-free cats in the imidacloprid plus moxidectin group were 64.0% and 72.0%. There were significantly more cats with no mites noted in the selamectin plus sarolaner group than in the imidacloprid plus moxidectin group on Day 14 and Day 30 (P ≤ 0.018). Selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus) administered topically at monthly intervals for three months was well tolerated and highly effective for the treatment and prevention of natural infestations of fleas on cats presented as veterinary patients. Clinical signs of flea allergy dermatitis improved in affected cats following treatment administration. A single topical treatment was also safe and highly effective for the treatment of ear mite infestations in naturally infested cats.
Asunto(s)
Acaricidas/administración & dosificación , Azetidinas/administración & dosificación , Enfermedades de los Gatos/tratamiento farmacológico , Infestaciones por Pulgas/veterinaria , Insecticidas/administración & dosificación , Ivermectina/análogos & derivados , Infestaciones por Ácaros/veterinaria , Compuestos de Espiro/administración & dosificación , Administración Tópica , Animales , Enfermedades de los Gatos/prevención & control , Gatos , Composición de Medicamentos/veterinaria , Femenino , Infestaciones por Pulgas/tratamiento farmacológico , Infestaciones por Pulgas/prevención & control , Ivermectina/administración & dosificación , Macrólidos/administración & dosificación , Masculino , Infestaciones por Ácaros/tratamiento farmacológico , Infestaciones por Ácaros/prevención & control , Ácaros/efectos de los fármacos , Neonicotinoides/administración & dosificación , Nitrocompuestos/administración & dosificación , Distribución Aleatoria , Siphonaptera/efectos de los fármacosRESUMEN
Three controlled studies were conducted to investigate the efficacy of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus) in preventing feline heartworm disease in cats. In all studies, cats were inoculated with 100 Dirofilaria immitis third stage larvae on Day -30. In the first study, cats were treated with selamectin plus sarolaner as a single dose on Day 0 or as three consecutive monthly doses on Days 0, 28 and 56. In the second and third studies, cats were treated with either sarolaner alone on Day 0, selamectin plus sarolaner on Day 0 or selamectin plus sarolaner as three consecutive monthly doses on Days 0, 28 and 56. In all three studies, dosages were 6 mg/kg selamectin plus 1 mg/kg sarolaner or 1 mg/kg sarolaner alone. Control cats were given a placebo containing inert formulation ingredients (vehicle). All treatments were administered at a single site topically to the skin cranial to the scapulae. Cats were humanely euthanized on Day 145/146 (i.e., 175/176 post-inoculation), and adult D. immitis worms were recovered and enumerated. Across the three studies, adult heartworms were recovered from 87 to 100% of control cats, with geometric mean worm counts ranging from 2.1 to 5.4. No adult D. immitis worms were recovered from cats treated with selamectin plus sarolaner. Cats treated with sarolaner alone were not protected against D. immitis infection, showing geometric mean worm counts of 1.9 to 2.4. In these studies, selamectin (6 mg/kg) plus sarolaner (1 mg/kg) was 100% effective in preventing heartworm development in cats when administered topically as one dose 30 days after inoculation or as three consecutive monthly doses starting 30 days post-inoculation. These studies demonstrated that a single topical administration of selamectin plus sarolaner at the recommended dosage was completely effective in preventing the development of D. immitis in cats.
Asunto(s)
Azetidinas/administración & dosificación , Enfermedades de los Gatos/prevención & control , Dirofilariasis/prevención & control , Ivermectina/análogos & derivados , Compuestos de Espiro/administración & dosificación , Administración Tópica , Animales , Antiparasitarios , Gatos , Dirofilaria immitis , Combinación de Medicamentos , Ivermectina/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Monthly topical and sustained-release injectable formulations of moxidectin are currently marketed; however, an oral formulation, while approved at a dose of 3 µg/kg, is not currently marketed in the United States. Although resistance of heartworms to all macrocyclic lactone (ML) heartworm preventives (ivermectin, milbemycin, selamectin and moxidectin) has been demonstrated, to date no data have been reported on the effectiveness of oral moxidectin against recent isolates of Dirofilaria immitis. METHODS: A total of nine studies were conducted to determine the efficacy of moxidectin against a range of older and recently sourced heartworm isolates. Dogs (groups of three to eight) were inoculated with 50 D. immitis infective larvae (L3) from nine different isolates (MP3, Michigan, JYD-34, ZoeMO-2012, ZoeKy-2013, ZoeLA-2013, GCFL-2014, AMAL-2014 and ZoeAL-2015) and treated 28-30 days later with single oral doses of 3 µg/kg of moxidectin. Additionally, one group of dogs that was inoculated with JYD-34 was treated monthly for 3 consecutive months beginning 30 days post inoculation. Dogs were held for approximately 4 months after the initial (or only) treatment and then necropsied for recovery of adult heartworms. RESULTS: A single dose of 3 µg/kg of moxidectin was 100% effective in preventing the development of five of nine heartworm isolates (MP3, Michigan, ZoeKy, GCFL and ZoeAL isolates), confirming their susceptibility to oral moxidectin at this dose. MP3 and Michigan are isolates sourced from the field more than 9 years ago, while ZoeKy, ZoeAL and GCFL were isolated from the field within the past 2 to 3 years. Against JYD-34, ZoeMO, ZoeLA and AMAL isolates, a single dose of 3 µg/kg of moxidectin was not completely effective, with efficacies of 19%, 82%, 54% and 62%, respectively, demonstrating resistance of these heartworm isolates to oral moxidectin at this dosage. Three consecutive monthly doses of 3 µg/kg of moxidectin were also incompletely effective against the JYD-34 isolate, with an efficacy of 44%. JYD-34 was originally isolated in 2010, while ZoeMO, ZoeLA and AMAL were isolated within the past 2 to 3 years. CONCLUSIONS: A single oral dose (3 µg/mg) of moxidectin was 100% effective in preventing the development of ML-susceptible heartworm isolates while being incompletely effective against ML-resistant isolates.
Asunto(s)
Dirofilaria immitis/efectos de los fármacos , Dirofilariasis/tratamiento farmacológico , Enfermedades de los Perros/tratamiento farmacológico , Filaricidas/administración & dosificación , Macrólidos/administración & dosificación , Animales , Dirofilaria immitis/fisiología , Dirofilariasis/parasitología , Enfermedades de los Perros/parasitología , Perros , Evaluación de Medicamentos , Resistencia a MedicamentosRESUMEN
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.
Asunto(s)
Dirofilaria immitis/efectos de los fármacos , Dirofilariasis/tratamiento farmacológico , Enfermedades de los Perros/tratamiento farmacológico , Filaricidas/administración & dosificación , Lactonas/administración & dosificación , Microfilarias/efectos de los fármacos , Animales , Dirofilaria immitis/fisiología , Dirofilariasis/parasitología , Enfermedades de los Perros/parasitología , Perros , Evaluación de Medicamentos , Femenino , Masculino , Microfilarias/fisiología , MississippiRESUMEN
Three laboratory studies were conducted to determine the appropriate dose of sarolaner, a novel isoxazoline, for the treatment and month-long control of infestations of fleas and ticks on dogs. In the first study, dogs were treated orally with sarolaner suspension formulations at 1.25, 2.5 or 5.0mg/kg, and infested with Dermacentor reticulatus, Rhipicephalus sanguineus ticks and with Ctenocephalides felis felis (cat flea) prior to treatment and then weekly for up to 8 weeks. Fleas and ticks were counted 48h after treatment and after each subsequent infestation at 24h for fleas and 48h for ticks. The lowest dose of sarolaner (1.25mg/kg) provided 100% efficacy against fleas from treatment through Day 35 and 98.4% at Day 56. This dose of sarolaner resulted in 99.7-100% control of both species of ticks through Day 28. In Study 2, dogs were dosed orally with placebo or sarolaner suspension formulations at 0.625, 1.25 or 2.5mg/kg and infested with Ixodes scapularis prior to treatment and weekly for 6 weeks, Amblyomma americanum (pretreatment and Day 26), Dermacentor variabilis (Day 33) and A. maculatum (Day 41). Ixodes scapularis was the most susceptible; the lowest dose (0.625mg/kg) providing>95% efficacy through Day 43. Efficacy against D. variabilis on Day 35 was>95% at 1.25 and 2.5mg/kg, whereas the 0.625mg/kg dose gave only 61.4% efficacy. Amblyomma spp. were the least susceptible ticks; efficacy of the 1.25mg/kg dose at Day 28 for A. americanum was markedly lower (88.5%) than achieved for D. reticulatus (100%) at Day 28 and also lower than for D. variabilis at Day 35 (96.2%). In Study 3, dogs were dosed orally with placebo or sarolaner in the proposed commercial tablet (Simparica™) at 1.0, 2.0 or 4.0mg/kg, and infested with A. maculatum, one of the ticks determined to be dose limiting, prior to treatment and then weekly for 5 weeks. All doses gave 100% control of the existing infestation. The two highest dosages resulted in >93% control of subsequent challenges for 5 weeks. There was no significant improvement in efficacy provided by the 4.0 mg/kg dose over the 2.0mg/kg dose (P>0.05) at any time point. The 2.0mg/kg dose was superior to the 1.0mg/kg on Day 14 (P=0.0086) and as efficacy for 1.0mg/kg declined below 90% at Day 28, a single 1mg/kg dose would not provide a full month of tick control. Thus, 2.0mg/kg was selected as the sarolaner dose rate to provide flea and tick control for at least one month following a single oral treatment.
Asunto(s)
Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/prevención & control , Infestaciones Ectoparasitarias/veterinaria , Administración Oral , Animales , Perros , Relación Dosis-Respuesta a Droga , Infestaciones Ectoparasitarias/prevención & control , Insecticidas/administración & dosificación , Isoxazoles/administración & dosificación , Siphonaptera , Garrapatas , Resultado del TratamientoRESUMEN
The novel isoxazoline ectoparasiticide, sarolaner, was identified during a lead optimization program for an orally-active compound with efficacy against fleas and ticks on dogs. The aim of the discovery program was to identify a novel isoxazoline specifically for use in companion animals, beginning with de novo synthesis in the Zoetis research laboratories. The sarolaner molecule has unique structural features important for its potency and pharmacokinetic (PK) properties, including spiroazetidine and sulfone moieties. The flea and tick activity resides in the chirally pure S-enantiomer, which was purified to alleviate potential off-target effects from the inactive enantiomer. The mechanism of action was established in electrophysiology assays using CHO-K1 cell lines stably expressing cat flea (Ctenocephalides felis) RDL (resistance-to-dieldrin) genes for assessment of GABA-gated chloride channel (GABACls) pharmacology. As expected, sarolaner inhibited GABA-elicited currents at both susceptible (CfRDL-A285) and resistant (CfRDL-S285) flea GABACls with similar potency. Initial whole organism screening was conducted in vitro using a blood feeding assay against C. felis. Compounds which demonstrated robust activity in the flea feed assay were subsequently tested in an in vitro ingestion assay against the soft tick, Ornithodoros turicata. Efficacious compounds which were confirmed safe in rodents at doses up to 30mg/kg were progressed to safety, PK and efficacy studies in dogs. In vitro sarolaner demonstrated an LC80 of 0.3µg/mL against C. felis and an LC100 of 0.003µg/mL against O. turicata. In a head-to-head comparative in vitro assay with both afoxolaner and fluralaner, sarolaner demonstrated superior flea and tick potency. In exploratory safety studies in dogs, sarolaner demonstrated safety in dogs≥8 weeks of age upon repeated monthly dosing at up to 20mg/kg. Sarolaner was rapidly and well absorbed following oral dosing. Time to maximum plasma concentration occurred within the first day post-dose. Bioavailability for sarolaner was calculated at >85% and the compound was highly protein bound (>99.9%). The half-life for sarolaner was calculated at 11-12 days. Sarolaner plasma concentrations indicated dose proportionality over the range 1.25-5mg/kg, and these same doses provided robust efficacy (>99%) for ≥35days against both fleas (C. felis) and multiple species of ticks (Rhipicephalus sanguineus, Ixodes ricinus and Dermacentor reticulatus) after oral administration to dogs. As a result of these exploratory investigations, sarolaner was progressed for development as an oral monthly dose for treatment and control of fleas and ticks on dogs.
Asunto(s)
Enfermedades de los Perros/prevención & control , Infestaciones Ectoparasitarias/veterinaria , Isoxazoles , Administración Oral , Animales , Perros , Infestaciones Ectoparasitarias/prevención & control , Semivida , Insecticidas/farmacocinética , Insecticidas/farmacología , Insecticidas/normas , Isoxazoles/farmacocinética , Isoxazoles/farmacología , Isoxazoles/normas , Siphonaptera/efectos de los fármacos , Garrapatas/efectos de los fármacosRESUMEN
Over the last decade, the isoxazoline motif has become the intense focus of crop protection and animal health companies in their search for novel pesticides and ectoparasiticides. Herein we report the discovery of sarolaner, a proprietary, optimized-for-animal health use isoxazoline, for once-a-month oral treatment of flea and tick infestation on dogs.
Asunto(s)
Antiparasitarios/química , Antiparasitarios/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Infestaciones por Pulgas/veterinaria , Isoxazoles/química , Isoxazoles/uso terapéutico , Infestaciones por Garrapatas/veterinaria , Animales , Antiparasitarios/farmacología , Ctenocephalides/efectos de los fármacos , Perros , Femenino , Infestaciones por Pulgas/tratamiento farmacológico , Isoxazoles/farmacología , Masculino , Rhipicephalus sanguineus/efectos de los fármacos , Siphonaptera/efectos de los fármacos , Infestaciones por Garrapatas/tratamiento farmacológico , Garrapatas/efectos de los fármacosRESUMEN
Haematobia irritans (horn fly) infestation in cattle is responsible for over a billion dollars a year in global economic loss due to decreased milk production and lower feed conversion. There is significant need for new insecticidal agents since current treatments such as organophosphates and pyrethroids suffer from field resistance. Isoxazoline oxime ethers represent a new class of γ-aminobutyric acid (GABA) receptor channel blockers which show good activity (LD(90) = 1.0 µg/mL) against horn flies in an in vitro feed assay and have demonstrated efficacy (>90% reduction at 1.0mg/kg) as a topical treatment in a field study.