Efficacy of Felpreva®, a new spot-on formulation containing tigolaner, emodepside and praziquantel, applied as a single application to cats artificially infested with ear mites (Otodectes cynotis).

The efficacy of Felpreva® (Vetoquinol), a new spot-on application containing the novel acaricide and insecticide tigolaner in combination with emodepside and praziquantel, was evaluated in cats artificially infested with ear mites (Otodectes cynotis). A total of three pivotal dose confirmation studies were conducted, two of them designed as non-interference studies. Cats were artificially infested with O. cynotis mites and randomly allocated into groups of 8 cats based on pre-treatment mite counts. Cats were treated once on Day 0, either with Felpreva® (14.5 â€‹mg/kg tigolaner, 3 â€‹mg/kg emodepside and 12 â€‹mg/kg praziquantel) or with placebo. Studies with a non-interference design included two additional groups of cats, treated with Profender® spot-on solution (Vetoquinol) (3 â€‹mg/kg emodepside and 12 â€‹mg/kg praziquantel) and tigolaner as a mono product (14.5 â€‹mg/kg tigolaner). Efficacy was evaluated on Day 28/Day 30 based on total live mite counts after ear flushing. Efficacy was claimed when: (i) at least six control cats per group were adequately infested with mites; (ii) calculated efficacy was ≥ 90% based on geometric mean mite counts; and (iii) the difference in mite counts between Felpreva®-treated cats and control cats was statistically significant (P â€‹≤ â€‹0.05). In two of the three studies, Felpreva®-treated cats were mite-free (100% efficacy) on Day 28/Day 30 and almost full efficacy (99.6%) was seen in the third study. The difference in mite counts between Felpreva®-treated cats and control cats was significant (P â€‹< â€‹0.0001) in all three studies. All control cats were adequately infested in all three studies. The efficacy of Felpreva® against ear mite (Otodectes cynotis) infection in cats was confirmed.

Comparison of Treadmill Gait Between a Pediatric-Aged Individual With SYNGAP1-Related Intellectual Disability and a Fraternal Twin.

SYNGAP1-related Intellectual Disability (SYNGAP1-ID) is a rare neurodevelopmental condition characterized by profound intellectual disability, gross motor delays, and behavioral issues. Ataxia and gait difficulties are often observed but have not yet been characterized by laboratory-based kinematic analyses. This investigation identified gait characteristics of an individual with SYNGAP1-ID and compared these with a neurotypical fraternal twin. Lower limb kinematics were collected with a 12-camera motion capture system while both participants walked on a motorized treadmill. Kinematic data were separated into strides, and stride times calculated. Sagittal plane hip, knee, and ankle joints were filtered and temporally normalized to 100 samples. Minimum and maximum joint angles, range of motion (ROM) and angular velocities were obtained for each joint by stride and averaged for each participant. ROM symmetry between left and right joints was also calculated. Discrete relative phase (DRP) was used to assess coordination and variability between joints within a single limb and compared across limbs. Phase portraits were calculated by joint, and their areas were computed with a MATLAB script. Statistical parametric mapping (SPM) was used to assess differences in joint angle waveforms between participants. P1, the individual with SYNGAP1-ID, displayed significantly reduced stride times relative to the fraternal twin, i.e., P2. A majority of minimum, maximum angles, ROMs, and angular velocities were significantly different between P1 and P2. Phase portrait areas were consistently less in P1 relative to P2 and there were differences in knee and ankle symmetries. DRP showed no differences between individuals, suggesting that P1's coordinative events remained similar to those observed during neurotypical gait (P2). SPM revealed significant differences between the left and right legs at the knee and ankle joints of P1 while P2 joint left and right waveforms were nearly identical for all joints. Additionally, SPM revealed there were significant differences between P1 and P2 for all joints. This investigation identified several major gait features of an individual with SYNGAP1-ID and provided a comprehensive characterization of these features by utilizing both linear and non-linear analyses. While limited in generalizability, this report provides a strong quantitative appraisal of gait in an individual with SYNGAP1-ID as well as an analysis pathway for future investigations.

Evidence for shared neural information between muscle synergies and corticospinal efficacy.

Stroke survivors often exhibit gait dysfunction which compromises self-efficacy and quality of life. Muscle Synergy Analysis (MSA), derived from electromyography (EMG), has been argued as a method to quantify the complexity of descending motor commands and serve as a direct correlate of neural function. However, controversy remains regarding this interpretation, specifically attribution of MSA as a neuromarker. Here we sought to determine the relationship between MSA and accepted neurophysiological parameters of motor efficacy in healthy controls, high (HFH), and low (LFH) functioning stroke survivors. Surface EMG was collected from twenty-four participants while walking at their self-selected speed. Concurrently, transcranial magnetic stimulation (TMS) was administered, during walking, to elicit motor evoked potentials (MEPs) in the plantarflexor muscles during the pre-swing phase of gait. MSA was able to differentiate control and LFH individuals. Conversely, motor neurophysiological parameters, including soleus MEP area, revealed that MEP latency differentiated control and HFH individuals. Significant correlations were revealed between MSA and motor neurophysiological parameters adding evidence to our understanding of MSA as a correlate of neural function and highlighting the utility of combining MSA with other relevant outcomes to aid interpretation of this analysis technique.

Characteristic behaviors associated with gait of individuals with Rett syndrome.

BACKGROUND: Individuals with Rett syndrome (RTT) exhibit impaired motor performance and gait performance, leading to decreased quality of life. Currently, there is no robust observational instrument to identify gait characteristics in RTT. Current scales are limited as individuals with intellectual disorders may be unable to understand instructions. Our primary purpose was to utilize video analysis to characterize the behaviors associated with walking in individuals with RTT and explore the relationship between behaviors during overground and during treadmill walking. METHODS: Fourteen independently ambulatory females with RTT were video-taped and observed during overground and treadmill walking. Their gait was codified into an observational checklist to reveal prominent features associated with gait in this population. RESULTS: Participants exhibited similar rates of freezing, veering, and hand stereotypies between overground and treadmill walking; however, freeze duration was shortened during treadmill walking. Toe walking was prominently exhibited during overground, but not treadmill walking. During both walking modes, participants required extensive external motivation to maintain their walking patterns. CONCLUSIONS: Results identify several gait characteristics observable during overground and treadmill walking. In general, participants behaved similarly during overground and treadmill walking. We conclude that both overground and treadmill walking are appropriate tools to evaluate gait in this population.Implications for rehabilitationLocomotor rehabilitation may increase the quantity of walking performed by the patients, which can alleviate negative effects of the sedentary lifestyle commonly observed in patients with Rett syndrome (RTT).Video analysis of natural walking can be an effective tool to characterize gait in patients with RTT which does not require particular instructions which may not be fully understood.Both overground and treadmill walking are appropriate means of evaluating gait in individuals with RTT.

Kinematics associated with treadmill walking in Rett syndrome.

BACKGROUND AND PURPOSE: Individuals with Rett syndrome suffer from severely impaired cognitive and motor performance. Current movement-related therapeutic programs often include traditional physical therapy activities and assisted treadmill walking routines for those individuals who are ambulatory. However, there are no quantitative reports of kinematic gait parameters obtained during treadmill walking. The purpose of this research was to characterize the kinematic patterns of the lower limbs during treadmill walking as speed was slowly increased. METHODS: Seventeen independently ambulatory females diagnosed with a methyl-CpG-binding protein 2 gene mutation walked on a motorized treadmill while joint kinematics were obtained by a camera-based motion capture system and analysis software. RESULTS: Stride times progressively decreased as treadmill speeds increased. There were significant main effects of speed on sagittal knee and hip ranges of motion and hip velocity. There were large joint asymmetries and variance values relative to other ambulatory patient populations, although variance values decreased as walking speed increased. CONCLUSIONS: The results indicate that individuals with Rett syndrome can adapt their kinematic gait patterns in response to increasing treadmill speed, but only within a narrow range of speeds. We suggest that treadmill training for ambulatory individuals with Rett syndrome may promote improved walking kinematics and possibly provide overall health benefits.Implications for rehabilitationWalking is an activity that can counter the negative impacts of the sedentary lifestyle of many individuals with disabilities, including those individuals with Rett syndrome.Documentation of the lower limb kinematic patterns displayed during walking by ambulatory females with Rett syndrome can be used by clinicians to evaluate their patients' gait performance in response to therapeutic and pharmacological interventions designed to promote walking.The ability to adapt to increases in treadmill speed suggests that a training program of treadmill walking may be effective in promoting improved gait performance in individuals with Rett syndrome.

Effects of Shank Vibration on Lean After-Effect.

Postural adaptability is related to central sensory integration and reweighting efficiency. Incline-interventions lead to lean after-effect (LAE), but it is not fully known how sensory reweighting may affect the magnitude and duration of LAE. We tasked fifteen young and healthy subjects with performing incline-interventions under conditions designed to perturb proprioception during or after the incline-intervention. We found that support surface configuration affected responses to tendon vibration. Additionally, vibration during an incline-intervention did not inhibit LAE, but vibration during an after-effect significantly affected LAE. Results reinforce claims that postural adaptation is based on modifications of central mechanisms of perception, not peripheral shank proprioceptors and improve our understanding of the role of sensory reweighting and sensory integration into postural adaptability.

The Posterior Parietal Cortex Is Involved in Gait Adaptation: A Bilateral Transcranial Direct Current Stimulation Study.

Gait is one of the fundamental behaviors we use to interact with the world. The functionality of the locomotor system is thus related to enriching interactions with our environment. The posterior parietal cortex (PPC) has been found to contribute to motor adaptation during both visuomotor and postural adaptation tasks. Additionally, structural or functional deficits of the PPC lead to impairments in gaits such as shortened steps and increased step width. Based on the aforementioned roles of the PPC, and the importance of gait adaptability, the current investigation sought to identify the role of the PPC in gait adaptation. To achieve this, we performed transcranial direct current stimulation (tDCS) over the bilateral PPC before performing a split-belt treadmill gait adaptation paradigm. We used three stimulation conditions in a within-subject design. tDCS was administered in a randomized and double-blinded order. Following each stimulation session, subjects first performed baseline walking with both belts running at the same speed. Then, subjects walked for 15 min on an uncoupled treadmill, with the belts being driven at a 3:1 speed ratio. Last, they returned to normal (i.e., tied-belt) walking for 5 min. Results from 15 young and healthy subjects identified that subjects required more steps to adapt to split-belt walking following the suppression of the left hemisphere PPC, contralateral to the fast belt. Furthermore, while suppression of the left hemisphere PPC did not increase the number of steps required to re-adapt to tied-belt walking, this condition did lead to increased magnitude of after-effects. Together, these findings indicate that the PPC is involved in locomotor adaptation. These results support previous literature regarding the upper body or postural adaptation and extend these findings to the realm of gait. Results highlight the PPC as a potential target for neurorehabilitation designed to improve gait adaptability.

Non-invasive Brain Stimulation of the Posterior Parietal Cortex Alters Postural Adaptation.

Effective central sensory integration of visual, vestibular, and proprioceptive information is required to promote adaptability in response to changes in the environment during postural control. Patients with a lesion in the posterior parietal cortex (PPC) have an impaired ability to form an internal representation of body position, an important factor for postural control and adaptation. Suppression of PPC excitability has also been shown to decrease postural stability in some contexts. As of yet, it is unknown whether stimulation of the PPC may influence postural adaptation. This investigation aimed to identify whether transcranial direct current stimulation (tDCS) of the bilateral PPC could modulate postural adaptation in response to a bipedal incline postural adaptation task. Using young, healthy subjects, we delivered tDCS over bilateral PPC followed by bouts of inclined stance (incline-interventions). Analysis of postural after-effects identified differences between stimulation conditions for maximum lean after-effect (LAE; p = 0.005) as well as a significant interaction between condition and measurement period for the average position (p = 0.03). We identified impaired postural adaptability following both active stimulation conditions. Results reinforce the notion that the PPC is involved in motor adaptation and extend this line of research to the realm of standing posture. The results further highlight the role of the bilateral PPC in utilizing sensory feedback to update one's internal representation of verticality and demonstrates the diffuse regions of the brain that are involved in postural control and adaptation. This information improves our understanding of the role of the cortex in postural control, highlighting the potential for the PPC as a target for sensorimotor rehabilitation.

Laboratory studies evaluating the efficacy of a novel orally administered combination product containing sarolaner, moxidectin and pyrantel (Simparica Trio™) for the treatment and control of flea infestations on dogs.

BACKGROUND: Five studies were conducted to evaluate a novel oral combination tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio™), for efficacy against induced flea infestations, speed of kill and effects on flea reproduction on dogs. METHODS: Based on pre-treatment flea counts, dogs were randomly allocated to treatment with a single, oral dose of either placebo or Simparica Trio™ at the minimum label dose of 1.2 mg/kg sarolaner, 24 µg/kg moxidectin and 5 mg/kg pyrantel (as pamoate salt) on Day 0. All dogs were infested with approximately 100 unfed, adult fleas (C. felis or C. canis) prior to treatment and weekly for 5 weeks post-treatment. In Studies 1, 2 and 3, the number of viable fleas were comb-counted at 24 h after treatment and after each weekly infestation; Study 2 also included groups treated with tablets containing sarolaner-alone (1.2 mg/kg), moxidectin-alone (24 µg/kg) or pyrantel-alone (5 mg/kg). In Study 4, flea counts were conducted at 3, 4, 8 and 12 h after treatment and subsequent weekly infestations to establish speed of kill. In Study 5 (flea reproduction), dogs were housed in an enclosure designed to facilitate collection of flea eggs. RESULTS: Efficacy of Simparica Trio™ against C. felis was ≥ 99.7% and against C. canis was 100% at 24 h after treatment and after subsequent infestations for at least 35 days. Treatment with sarolaner-alone had similar efficacy to Simparica Trio™, while moxidectin-alone and pyrantel-alone were no different from placebo at most time points. In Study 4, significant flea killing started at 4 h after treatment; by 8 h after treatment, all treated dogs were free of fleas. Following weekly re-infestation, the combination product reduced fleas by ≥ 97.8% within 12 h for 28 days. Simparica Trio™ reduced flea egg-laying by 100% for 35 days. No treatment-related adverse reactions occurred in any study. CONCLUSIONS: A single dose of Simparica Trio™ at the recommended minimum dose provided highly efficacious and rapid treatment within 4 h of existing flea infestations and persistent control of fleas on dogs for 5 weeks. The efficacy against fleas resulted in 100% prevention of flea reproduction for over a month following a single oral dose.

Assessing the Relative Importance of Estuarine Nursery Habitats - a Dungeness Crab (Cancer magister) Case Study.

Estuaries serve as important nurseries for many recreationally and commercially harvested fisheries species. Recent conceptual approaches (i.e., seascape) for assessing the value of estuaries to fisheries have advocated for complex habitat-scale assessments that integrate multiple life-history responses (e.g., abundance, growth, reproduction) and ecological processes across heterogeneous landscapes. Although ecologically compelling, implementing seascape approaches may not be feasible for resource-limited management agencies. In such cases, we propose that resource managers can enhance the identification of fishery-important estuarine habitats by integrating attainable aspects of the seascape approach into a more traditional single response (e.g., abundance) model. Using Dungeness crab (Cancer magister) as a case study, we applied a spatially-explicit hybrid approach to assess the relative contribution of different estuarine habitats to that important fishery species within three Oregon estuaries (Tillamook, Yaquina, and Alsea bays). We measured the abundance of juvenile C. magister from low-tide trawls in estuarine channels and the mosaic of habitat characteristics within defined home-range distances for the crabs. After identifying and reducing strong intercorrelations among habitat variable data, we developed a best-fit model that associated crab abundance with the most influential habitat variables. We found that lower-estuary side channels supported the highest abundance of juvenile crabs; furthermore, crab abundance was positively associated with high salinity and burrowing shrimp (Upogebia pugettensis) density on adjacent unvegetated tidal flats. This hybrid method produced a habitat-specific model that better predicted juvenile C. magister abundance than did a model based on generalized habitat categories.

Comparative efficacy of topical treatments with Revolution® Plus (selamectin and sarolaner) and Bravecto® for Cats (fluralaner) against Ixodes scapularis ticks on cats.

The efficacy of three consecutive monthly treatments with a novel topical product (Revolution® Plus/Stronghold® Plus, Zoetis) containing selamectin in combination with the isoxazoline, sarolaner, was compared with that of another topical isoxazoline, fluralaner [Bravecto® (fluralaner topical solution) for Cats, Merck] against Ixodes scapularis ticks on cats. Twenty-four cats were ranked by pre-treatment tick counts to form groups of three and were randomly allocated to be treated with placebo, the minimum label dosage of Revolution® Plus (6 mg/kg selamectin plus 1 mg/kg sarolaner) or the minimum label dosage of Bravecto® for Cats (40 mg/kg fluralaner) within the groups. On Days 0, 30, and 60, each cat in the placebo and Revolution® Plus-treated groups was treated topically, whereas cats in the Bravecto® for Cats-treated group were treated topically once on Day 0 with fluralaner and, subsequently, these animals were treated with the placebo on Days 30 and 60 to maintain masking. Doses were calculated based on weight to provide the minimum label dosage for each product; the calculated volume of product to be administered was rounded off to the nearest 0.1 mL. The selamectin plus sarolaner-treated cats received effective dosages of 5.29-7.12 mg/kg selamectin and 0.88-1.19 mg/kg sarolaner, while the fluralaner cats received dosages of 35.21-43.16 mg/kg fluralaner. Cats were infested with approximately 50 unfed viable adult I. scapularis ticks on Days 5, 12, 26, 40, 54, 68, 82, and 88. Efficacy was assessed at 48 h after each infestation. There were no adverse reactions to any treatment during the study. The placebo-treated cats maintained adequate tick infestations throughout the study. Three monthly treatments with selamectin plus sarolaner (Revolution® Plus) resulted in high and consistent efficacy against I. scapularis for up to 30 days after each treatment. Based on geometric means, efficacy was ≥99.1% at all time points assessed. Treatment with fluralaner (Bravecto® for Cats) provided high and consistent efficacy of ≥99.3% up to Day 70. On Day 84, efficacy was 90.1%; however, cats from which ticks were recovered on Day 84 had received approximately 4%-12% less than the minimum dosage of 40 mg/kg fluralaner. Three consecutive monthly treatments with Revolution® Plus or a single treatment with Bravecto® for Cats provided >90% control of I. scapularis ticks over a 12-week time period.

Efficacy of three consecutive monthly doses of a topical formulation of selamectin and sarolaner (Revolution® Plus/Stronghold® Plus) compared with a single dose of fluralaner (Bravecto® for Cats) against induced infestations of Ctenocephalides felis on cats.

In a controlled laboratory study, the efficacy against fleas, Ctenocephalides felis, of a single treatment of fluralaner topical solution (Bravecto® for Cats, Merck) was compared with that of three consecutive monthly topical treatments with selamectin and sarolaner (Revolution® Plus, Zoetis). Twenty-four domestic short hair cats were ranked based on host suitability flea counts to form groups of three and were randomly assigned within group to one of three treatments. The first group received a topical treatment with (a) placebo (vehicle control for Revolution® Plus) on Days 0, 30, and 60, (b) 6 mg/kg selamectin and 1 mg/kg sarolaner on Days 0, 30, and 60, or (c) 40 mg/kg fluralaner on Day 0 and placebo (vehicle control for Revolution® Plus) on Days 30 and 60. Because doses were rounded off, the selamectin plus sarolaner-treated cats received effective dosages of 5.25-6.60 mg/kg selamectin and 0.88-1.10 mg/kg sarolaner, while the fluralaner-treated cats received dosages of 34.71-43.08 mg/kg fluralaner. All cats were infested with 100 (±5) fleas on Day -1 and at biweekly intervals after that, from Day 13 to Day 89. Flea comb counts were conducted 24 hours after treatment or after re-infestation. There were no adverse events related to treatment during the study. Except for a single cat from which 20 fleas were recovered on Day 90, all other placebo-treated cats had at least 48 fleas at each count, indicating adequacy of infestation of the controls. Based on geometric mean live flea counts, three consecutive monthly treatments with Revolution® Plus resulted in consistent and high efficacy of ≥98.6% compared with placebo throughout the study. A single treatment with Bravecto® for Cats provided consistent and high efficacy of ≥94.6% on all count days during a period of 12 weeks, the approved duration of efficacy for the product. Based on the efficacy results of the study, both products were equivalent in their ability to control fleas on cats. Use of Bravecto® for Cats every 12 weeks or the consecutive monthly use of Revolution® Plus is expected to provide extended high residual kill over the respective labeled durations of efficacy of the two products.

Neuroemergentism: A Framework for Studying Cognition and the Brain.

There has been virtual explosion of studies published in cognitive neuroscience primarily due to increased accessibility to neuroimaging methods, which has led to different approaches in interpretation. This review seeks to synthesize both developmental approaches and more recent views that consider neuroimaging. The ways in which Neuronal Recycling, Neural Reuse, and Language as Shaped by the Brain perspectives seek to clarify the brain bases of cognition will be addressed. Neuroconstructivism as an additional explanatory framework which seeks to bind brain and cognition to development will also be presented. Despite sharing similar goals, the four approaches to understanding how the brain is related to cognition have generally been considered separately. However, we propose that all four perspectives argue for a form of Emergentism in which combinations of smaller elements can lead to a greater whole. This discussion seeks to provide a synthesis of these approaches that leads to the emergence of a theory itself. We term this new synthesis Neurocomputational Emergentism (or Neuromergentism for short).

Efficacy of a new topical formulation containing selamectin plus sarolaner against three common tick species infesting cats in the United States.

The efficacy of a single topical application of a combination product containing selamectin and sarolaner (selamectin/sarolaner; Revolution® Plus/Stronghold® Plus) was evaluated in seven laboratory studies against Ixodes scapularis (three studies), Dermacentor variabilis (two studies), or Amblyomma maculatum (two studies). In each study, cats were randomly allocated to treatment groups based on pre-treatment host-suitability tick counts. On Days -2, 5, 12, 19, 26 and 33, the cats were infested with unfed adult ticks. On Day 0, cats were treated with either a placebo (vehicle control) or with the spot-on solution at the minimum dose of 6.0 mg selamectin and 1.0 mg sarolaner/kg bodyweight. In one study with I. scapularis and one with D. variabilis an additional group of cats was treated with selamectin alone (Revolution®, Zoetis) at 6.0 mg/kg bodyweight. Tick counts were conducted after treatment and after each weekly re-infestation and efficacy determined relative to placebo-treated animals. There were no treatment-related adverse reactions in any of the studies. Geometric mean live tick counts were significantly (P < 0.05) lower in the selamectin/sarolaner-treated groups compared to the geometric mean tick counts in the placebo-treated groups at all time-points in all studies. For all species, a single topical administration of the selamectin/sarolaner combination resulted in>90% efficacy against existing infestations based on geometric means. Efficacy against weekly re-infestations was >90% based on geometric means for at least 5 weeks for I. scapularis and D. variabilis, and for at least 4 weeks against A. maculatum. Selamectin alone had no efficacy against I. scapularis, where counts on selamectin-treated cats were not significantly different from placebo at all time points (P > 0.05), and for D. variabilis, counts were not significantly different from placebo at 2, 3 and 5 weeks after treatment (P > 0.05) and efficacy was never greater than 85%. Thus, the activity of the sarolaner against three common tick species found on cats in the US is complementary to the existing broad-spectrum parasite control of selamectin. The inclusion of sarolaner with selamectin in a combination product (Revolution® Plus/Stronghold® Plus) provides for the treatment of existing tick infestations and gives at least one month of control against re-infestation following a single topical application.

Response to the Letter to the Editor by Rob Armstrong.

In a recent Letter to the Editor, Armstrong raises concern that the design of the study reported by Six et al. was not consistent with the product label for treatment of Amblyomma americanum, since fluralaner was not re-administered 56 days after the initial treatment. The Authors disagree with this assessment and confirm that the design was appropriate, and therefore the results and conclusions for the entire study period are valid.

Initial evaluations of the effectiveness of spinetoram as a long-acting, oral systemic pulicide for controlling cat flea (Ctenocephalides felis) infestations on dogs.

Spinetoram is a semi-synthetic, spinosyn class natural product derived from fermentation by the actinomycete, Saccharopolyspora spinosa. Based on LD50 (50% lethal dose) values against adult cat fleas (Ctenocephalides felis) using an in vitro contact assay, spinetoram was approximately 4-fold more potent than spinosad. Subsequently, two parallel-arm, randomized block design laboratory studies were conducted to evaluate the effectiveness of orally administered spinetoram against experimental C. felis infestations on dogs, when administered as a single dose or multiple doses over a 6-12h interval. In the first study, 16 mixed-breed dogs were allocated to two treatment groups of eight dogs each, based on pre-treatment flea retention rates: negative (placebo) control; and a single dose of spinetoram at 30mg/kg. In the second study, 32 mixed- and pure-breed dogs were allocated to four treatments groups of eight dogs each, based on pre-treatment flea retention rates: negative (placebo) control; a single dose of 60mg/kg; three sequential 20mg/kg oral doses evenly administered over a 6h period; and three sequential 20mg/kg oral doses evenly administered over a 12h period. In both studies, treatments were administered to dogs in a fed state in order to enhance absorption of spinetoram. Therapeutic efficacy was assessed 24h after treatment and persistent efficacy was assessed 48h after each subsequent flea infestation. The duration of effectiveness was assessed at approximate weekly intervals beginning on Day 5 through Day 56 in the first study, or through Day 105 in the second study. In both studies, treatment efficacy was ≥99% (geometric means) through 44 d, with ≥99% efficacy continuing through 72 d for all three treatments in the second study. Efficacy remained ≥90% for at least 8 weeks with a single 30mg/kg dose; through 13 weeks with three sequential 20mg/kg doses; and through 15 weeks with a single 60mg/kg dose. For all time points and in both studies, spinetoram-treated groups had significantly fewer live fleas relative to their respective negative control group (p<0.05). The pharmacokinetic profile in dogs revealed that the mean plasma concentration of spinetoram required for effectiveness against fleas was maintained for at least 3 months regardless of whether the 60mg/kg total body dose was administered as a single bolus or in three sequential 20mg/kg doses administered over a 6-12h period of time. The results of preliminary in vitro and in vivo studies demonstrate that orally administered spinetoram was well tolerated, and provides long lasting effectiveness against C. felis infestations on dogs.

Comparative speed of kill of sarolaner (Simparica™ Chewables) and fluralaner (Bravecto(®)) against induced infestations of Amblyomma americanum on dogs.

BACKGROUND: The lone star tick, Amblyomma americanum, infests dogs and cats in North America and transmits the pathogens Ehrlichia chaffeensis and Ehrlichia ewingii, which cause monocytic and granulocytic ehrlichiosis in dogs and humans, and Cytauxzoon felis which causes cytauxzoonosis in cats. A parasiticide's speed of kill is important to minimize the direct deleterious effects [related to blood-feeding] of tick infestation and reduce the risk of transmission of tick-borne pathogens. In this study the speed of kill of sarolaner (Simparica™ Chewables) administered monthly for 3 months against A. americanum on dogs was evaluated and compared with a single dose of fluralaner (Bravecto(®)) for 13 weeks. METHODS: Based on pretreatment tick counts, 24 dogs were randomly allocated to treatment with placebo or sarolaner at the label rate (2 to 4 mg/kg) on Days 0, 30 and 60 or with fluralaner (25 to 56 mg/kg) once according to manufacturer's instructions on Day 0. Dogs were examined and live ticks counted at 8, 12, and 24 h after treatment and subsequent re-infestations on Days 14, 28, 42, 58, 76 and 90. Acaricidal efficacy was determined at each time point relative to counts for placebo dogs. RESULTS: Monthly oral doses of sarolaner provided > 95 % efficacy within 24 h of treatment, and consistently provided > 70 % efficacy against subsequent re-infestations with ticks within 24 h over the entire treatment period. Significantly more live ticks were recovered from fluralaner-treated dogs than from sarolaner-treated dogs at 24 h after re-infestation from Day 42 onwards. At 24 h, efficacy of fluralaner was ≤ 20 % from Day 42 to the end of the study on Day 90. There were no adverse reactions to treatment. CONCLUSIONS: In this controlled laboratory evaluation, monthly treatment with sarolaner provided consistent efficacy against A. americanum with > 70 % of ticks killed within 24 h after a single oral dose over the duration of the study. Monthly treatment with sarolaner consistently killed significantly more ticks within 24 h than a single dose of fluralaner from 6 weeks after initial treatment.

Efficacy of fluralaner spot-on solution against induced infestations with Rhipicephalus sanguineus on dogs.

BACKGROUND: The efficacy of fluralaner spot-on solution administered once topically against induced infestations with Rhipicephalus sanguineus was evaluated in dogs over a 12-week post-treatment period. METHODS: Six negative-controlled studies were conducted, involving a total of 112 adult dogs (57 mixed breed, 47 Beagles, eight Labradors). In each study, dogs were randomized to two groups of eight to ten dogs each. On day 0, dogs in each treated group were topically administered fluralaner spot-on solution once at a dose of 25 mg/kg body weight, while dogs in each control group were not treated. Two days before treatment, and on days 28, 56 and 84 after treatment, all dogs were infested with approximately 50 unfed, adult Rh. sanguineus ticks (sex ratio 1:1). Ticks were removed and counted on days 2, 30 (4 weeks), 58 (8 weeks), and 86 (12 weeks) after treatment to assess efficacy. RESULTS: Efficacy against ticks 2 days after treatment was 91.1 % (study 1), 98.4 % (study 2), 100 % (study 3), 97.6 % (study 4), 99.6 % (study 5), and 99.8 % (study 6). At all other assessment time points, tick efficacy was 95.4-100 %. Tick reduction in all treatment groups was significant at all assessment time points (P < 0.0001). CONCLUSIONS: A single topical administration of fluralaner spot-on solution provides a high level of therapeutic and persistent efficacy against Rh. sanguineus ticks over the subsequent 12 weeks.

Efficacy of a novel oral formulation of sarolaner (Simparica™) against five common tick species infesting dogs in the United States.

The efficacy of a single oral treatment with sarolaner (Simparica™, Zoetis), a novel isoxazoline compound, was evaluated against five tick species known to infest dogs in the United States. A total of 10 laboratory studies, two against each species, were conducted using adult purpose-bred mongrels or Beagle dogs. In each study, 16 dogs were randomly allocated to one of two treatment groups based on pre-treatment host-suitability tick counts. Dogs were infested with approximately 50 unfed adult Amblyomma americanum, Amblyomma maculatum, Dermacentor variabilis, Ixodes scapularis or Rhipicephalus sanguineus ticks on Days -2, 5, 12, 19, 26 and 33. On Day 0, dogs were treated with a placebo or a sarolaner tablet providing a minimum dose of 2 mg/kg. Tick counts were conducted 48h after treatment and after each subsequent weekly re-infestation. There were no treatment-related adverse reactions during any of the studies. Dogs in the placebo-treated group maintained tick infestations throughout the studies. Geometric mean live tick counts were significantly lower (P≤0.0001) in the sarolaner-treated group compared to the tick counts in the placebo group at all timepoints. Treatment with sarolaner resulted in ≥99.6% efficacy against existing infestations of all five tick species within 48h. The efficacy against weekly post-treatment re-infestations of all tick species was ≥96.9% for at least 35 days after treatment. Thus, a single dose of sarolaner administered orally at the minimum dosage of 2mg/kg, resulted in excellent efficacy within 48h against existing tick infestations, and against weekly re-infestations for 35 days after treatment. These studies confirmed that administration of the minimum dose of sarolaner will provide rapid treatment of existing infestations and give at least one month of control against re-infestation by the common tick species affecting dogs in the US.