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A number of parasiticides are commercially available as companion animal treatments to protect against parasite infestation and are sold in large volumes. These treatments are not intended to enter the wider environment but may be washed off or excreted by treated animals and have ecotoxic impacts. A systematic literature review was conducted to identify the existing evidence for the toxicity of the six most used parasiticides in the UK: imidacloprid, fipronil, fluralaner, afoxolaner, selamectin, and flumethrin. A total of 17,207 published articles were screened, with 690 included in the final evidence synthesis. All parasiticides displayed higher toxicity towards invertebrates than vertebrates, enabling their use as companion animal treatments. Extensive evidence exists of ecotoxicity for imidacloprid and fipronil, but this focuses on exposure via agricultural use and is not representative of environmental exposure that results from use in companion animal treatments, especially in urban greenspace. Little to no evidence exists for the ecotoxicity of the remaining parasiticides. Despite heavy usage, there is currently insufficient evidence to understand the environmental risk posed by these veterinary treatments and further studies are urgently needed to quantify the levels and characterise the routes of environmental exposure, as well as identifying any resulting environmental harm.

Isoxazoline derivatives such as fluralaner, sarolaner, lotilaner, and afoxolaner are a new class of insecticide and acaricide compounds. These compounds are characterised by rapid action and high efficacy over a period of up to several weeks. A method for identifying all four isoxazoline derivatives in animal and human plasma has not been proposed to date. Therefore, the aim of this study was to develop and validate a novel analytical method for the determination of fluralaner, sarolaner, lotilaner, and afoxolaner in laying hen plasma and to revalidate the proposed method in human, canine and feline plasma. The plasma concentrations of isoxazoline derivatives were determined by ultra-high performance liquid chromatography-tandem mass spectrometry. Analytical samples were prepared by precipitating proteins with a mixture of 96% acetonitrile and 4% ammonium hydroxide (v/v). Chromatographic separation was achieved on a chromatographic column (1.8 μm 2.1 × 100 mm) using 0.1% formic acid in water and 0.1% formic acid in acetonitrile with gradient elution. The results indicate that the described method is replicable, linear (r = 0.99), precise (1.66% to 14.97%), accurate (1.19% to 11.67%), selective and sensitive (limit of quantitation = 1 ng/mL). Depending on the studied compound and animal species, total recovery reached 85-99%, and the matrix effect did not exceed 15% in any of the analyses. The proposed method is simple, effective, inexpensive and rapid because it requires only a single-step sample preparation protocol.

Background Amblyomma maculatum is a tick with a broad host range that is undergoing an expansion of its range within the USA. When feeding the predilection sites on the host are the head and ears and due to the long mouthparts, it can cause significant lesions that can lead to infection. It has also been implicated as a vector of Hepatozoon americanum , the causative agent of canine hepatozoonosis and a spotted fever group Rickettsia , Rickettsia parkeri . Methods Two randomized, blinded, negative controlled studies were conducted to determine whether treatment with afoxolaner (NexGard ® , Boehringer Ingelheim) or a combination of afoxolaner, moxidectin, and pyrantel (NexGard ® Plus, Boehringer Ingelheim) effectively treats and controls infestations of A. maculatum on dogs. For each study, ten healthy dogs were randomly assigned to each treatment group. In one study there were three treatment groups: an untreated control, NexGard ® -treated group, and NexGard ® Plus-treated group. The other study had an untreated control group and a NexGard ® Plus-treated group. Dogs were infested with approximately 50 unfed adult A. maculatum prior to treatment for evaluation of efficacy against existing infestations and then three times after treatment for evaluation of persistent efficacy. In each study the appropriate treatment groups were treated with either NexGard ® or NexGard ® Plus with afoxolaner targeted at 2.5 mg/kg, and ten control dogs were untreated. For evaluation of efficacy, live ticks were counted and removed from each dog at 72 h after treatment or subsequent infestations. Results NexGard ® and NexGard ® Plus were > 99% effective against established infestations of A. maculatum compared with the control group ( P  < 0.0001). NexGard ® and NexGard ® Plus were ≥ 92% effective against reinfestation with A. maculatum through Day 31 of the studies ( P  < 0.0001). Conclusions The results of these studies demonstrate that NexGard ® and NexGard ® Plus administered once at or near the minimum recommended dose of 2.5 mg/kg afoxolaner is effective for the treatment of existing A. maculatum infestations and for the control of infestations through Day 31. Graphical Abstract Created in BioRender. Morschhaeuser, B. (2026) https://BioRender.com/081ioe1

Canine sarcoptic mange, caused by Sarcoptes scabiei , is a highly contagious and intensely pruritic skin disease in dogs. It is prevalent worldwide and has zoonotic potential. Therefore, effective treatment is important to safeguard animal welfare and public health. The present clinical field study aimed to confirm the efficacy of NexGard ® Plus, an oral combination of afoxolaner, moxidectin and pyrantel pamoate, in treating dogs naturally infested with S. scabiei . It was a blinded, randomised, single-centre, negative-controlled efficacy study. Twenty naturally infested dogs were allocated into two groups: a group treated on Day 0 and Day 26/28 at the label dose, and an untreated control group. Skin scrapings were conducted similarly, once between Day −6 to 0, then on Days 26/28 and 56 for mite counts. Assessments of clinical signs were conducted at the same time intervals. In the treated group, mite infestations were reduced by 97% after the first treatment and were eliminated (100%) after the second treatment ( p  < 0.0005), while all dogs in the untreated control group remained infested for the whole study. Treated dogs had no pruritus, papules or crusts and clear evidence of hair regrowth by Day 56, unlike the dogs in the control group. This study demonstrated the elimination of S. scabiei mites and significant improvement of sarcoptic mange clinical signs in naturally infested dogs treated with the oral combination of afoxolaner, moxidectin and pyrantel. La gale sarcoptique canine, causée par Sarcoptes scabiei , est une dermatose très contagieuse et extrêmement prurigineuse chez le chien. Elle est répandue dans le monde entier et présente un potentiel zoonotique. Un traitement efficace est donc essentiel pour préserver le bien-être animal et la santé publique. La présente étude clinique de terrain visait à confirmer l’efficacité de NexGard ® Plus, une association orale d’afoxolaner, de moxidectine et de pamoate de pyrantel, dans le traitement des chiens naturellement infestés par S. scabiei . Il s’agissait d’une étude d’efficacité monocentrique, randomisée, en double aveugle et contrôlée par un placebo. Vingt chiens naturellement infestés ont été répartis en deux groupes : un groupe traité aux jours 0 et 26/28 à la dose recommandée, et un groupe témoin non traité. Des prélèvements cutanés ont été effectués de la même manière, une première fois entre le jour −6 et le jour 0, puis aux jours 26, 28 et 56 pour le dénombrement des acariens. L’évaluation des signes cliniques a été réalisée aux mêmes intervalles. Dans le groupe traité, l’infestation par les acariens a diminué de 97% après le premier traitement et a été totalement éliminée (100 %) après le second ( p < 0,0005), tandis que tous les chiens du groupe témoin non traité sont restés infestés pendant toute la durée de l’étude. Les chiens traités ne présentaient ni prurit, ni papules, ni croûtes, et une repousse des poils était clairement visible au jour 56, contrairement aux chiens du groupe témoin. Cette étude a démontré l’élimination des acariens S. scabiei et une amélioration significative des signes cliniques de la gale sarcoptique chez les chiens naturellement infestés traités par l’association orale d’afoxolaner, de moxidectine et de pyrantel.

Background Ophionyssus natricis is the main species of mite that infests captive reptiles. High infestations may result in the host experiencing general discomfort and deleterious effects, even death. Moreover, O. natricis is an important vector of reptile vector-borne diseases and is considered to be the putative vector of the Reptarenavirus, the causal agent of the inclusion body disease. Despite the cosmopolitan distribution of O. natricis in captive reptiles, treatment options are limited. The aim of the present study was to assess the efficacy of afoxolaner (NexGard®; Boehringer Ingelheim, Ingelheim, Germany) in heavily infested, privately owned snakes, evaluate the prevalence of mites and drug availability in the plasma of treated snakes (pharmacokinetics) and perform a clinical examination of animals. Methods The study was conducted in two snake breeding facilities, where many snakes were infested with mites. Each animal was clinically examined and weighed, and mite infestations were assessed on the animals and in their enclosures (environment). Animals were treated with a dose of 2.5 mg afoxolaner per kilogram body weight (2.5 mg/kg) administered orally. All animals were examined pre-treatment (T0) and at various time points post-treatment (T1, 6 h; T2, 24 h; T3, 14 days; T4, 28 days). The collected mites were morphologically identified at the species level and the species identity also confirmed molecularly. Results Overall, 81 snakes from the two participating facilities (i.e. 70 from site 1 and 11 from site 2) were screened, and 31 (38.3%) snakes were found to have at least one mite. All mites were identified morphologically and molecularly as O. natricis. Lampropeltis was the genus of snakes with highest number of infested individuals. Mites were found to be alive on snakes at T1, but at T2 only dead mites were observed, and at T3 and T4 mites were no longer present on the animals or in their environment. No side effects were observed in the treated snakes. Conclusions A single oral administration of afoxolaner at 2.5 mg/kg was a safe treatment for snakes and 100% effective for the eradication of natural O. natricis infestation without the need to treat the environment of the snake. Graphical Abstract

Background Isoxazolines, including sarolaner, lotilaner, afoxolaner and fluralaner, are a class of ectoparasiticides that target gamma-aminobutyric acid receptors (GABARs) in insects and acari. However, their potential action on mammalian GABARs has not been extensively compared. Methods This study investigated the inhibitory effects of these isoxazolines on human and canine GABARs expressed in Xenopus oocytes. Eleven functional GABAR subunit combinations from human and canine isoforms were successfully cloned and expressed. Two-electrode voltage-clamp measurements were performed to determine the inhibitory effects of the isoxazolines. Results Sarolaner, afoxolaner and fluralaner exhibited partial to high inhibition of human and canine GABARs, with fluralaner showing the lowest half-maximal inhibitory concentration (IC 50 ) values (1.9–13 µM). In contrast, lotilaner had little or no inhibitory effect, with IC 50 values > 30 µM for both human and canine GABARs. Conclusions While neurological adverse events have been reported in dogs, particularly in breeds with the multidrug resistance 1 (MDR1) gene mutation, this study suggests that direct inhibition of canine GABARs may not be the primary cause. However, the interpretation of these results represents a challenge, and a direct correlation with documented cases of adverse events remains difficult. Further research is needed to understand the exposure of mammalian GABARs to isoxazolines and the analog-specific safety risks associated with the observed in vitro receptor activities. Graphical Abstract

Afoxolaner, a novel insecticidal and acaricidal drug substance from the isoxazoline family, is efficacious against various parasites among companion animals. In general, afoxolaner drug substance is quite stable in formulated and unformulated forms, when stored under International Council for Harmonization (ICH) guideline storage conditions. Exhaustive stress degradation studies of afoxolaner drug substance were conducted under various stress conditions to obtain an in-depth understanding of potential degradation pathways, including formation mechanisms of potential degradations products of this compound. Stressed degradation studies were carried out in the presence of various type/class of acid, base, and oxidation agents, including thermal and light irradiation. An investigational ultra-high-performance liquid chromatography (UHPLC) method was developed for the purpose of this study. The UHPLC method provided adequate separation of afoxolaner and its major degradation products that were generated in the exhaustively stressed samples. A total of five major degradation products (DPs) were formed under acidic, basic, photolytic, and oxidative stress conditions. Various analytical techniques such as high-resolution tandem mass spectrometry (HRMS/MS–MS) and nuclear magnetic resonance (NMR) were used to identify and propose the most probable chemical structures of the key unknown degradation products in the stressed degradation samples. Adequate amounts of two DPs, namely DP-1 and DP-3, were isolated and purified by semi-preparative high-performance liquid chromatography (HPLC) methods. Subsequently, these two DPs were examined in detail using both 1D and 2D NMR spectroscopy. From the proposed chemical structures of identified degradation products, most probable degradation pathways and formation mechanism is proposed.

Background The sand flea Tunga penetrans is one of the agents of tungiasis, an important parasitic skin disease affecting humans and several mammalian species. Tungiasis is mainly observed in disadvantaged rural and peripheral urban communities in Latin America and sub-Saharan Africa. The dog is a major reservoir of Tunga fleas. Hematophagous adult female Tunga spp. embed and grow in their host’s epidermis and cause cutaneous inflammatory disorders. NexGard Spectra ® is an orally administered endectocide for dogs, a co-formulation of the isoxazoline afoxolaner and the macrocyclic lactone milbemycin oxime. The objective of this study was to assess the efficacy of this product against canine tungiasis. Methods A blinded, negative-controlled field trial was conducted in a Brazilian community known to be highly endemic for tungiasis. Sixty-six dogs naturally infected with live T. penetrans were randomly allocated to a treated group (44 dogs) and an untreated control group (22 dogs). In a first phase, dogs from the treated group were treated on days 0, 30, and 60. Efficacy was evaluated on the basis of the macroscopic parasitic skin lesions (Fortaleza classification) on days 7, 14, 21, 30, 45, 60, 75, and 90. In a second phase, to evaluate natural reinfections, all dogs were treated on day 90 and evaluated every 2 weeks thereafter until at least 30% of dogs were infected with live sand fleas. Results During the first phase, efficacy (reduction in live sand fleas) of 92.4% was demonstrated on day 7. From day 14 until day 90, the efficacy of NexGard Spectra ® was 100%. In the second phase, all dogs were free of live T. penetrans from 15 until 45 days after the day 90 treatment; 60 days post-treatment, 11% of dogs were reinfected, and 75 days post-treatment, 40% of dogs were reinfected. Conclusions NexGard Spectra ® was demonstrated to be highly effective against canine tungiasis. In addition to an obvious beneficial effect on the health and welfare of the treated dog, the use of this product may have a one-health benefit on human cases by controlling the main reservoir of sand fleas. Graphical Abstract

Background Year-round control of canine flea and tick infestations requires owner compliance with recommendations for regular treatments. Compliance failures can result in increased exposure of dogs to tick-borne pathogens and resurgence of flea populations. This study investigated the year-long efficacy of fluralaner 150 mg/ml injectable suspension (BRAVECTO ® injectable), developed to remove the need for multiple owner-administered, within-year treatments. Methods This randomized, examiner-masked, non-inferiority study enrolled household dogs at veterinary clinics in Germany, France, and Spain. Each household contained a primary dog infested with ≥ 4 ticks or ≥ 5 fleas. Additional dogs in each household received the same treatment as the primary dog, either a single injection with fluralaner (15 mg/kg) on day 0, or 12 monthly treatments with oral afoxolaner (NexGard ® ) beginning on day 0. Owners presented their dogs for tick and flea assessments at visits 2 through 10 (days 14, 28, 56, 84, 112, 224, 280, 336, 365). Primary endpoints were the percentages of primary dogs free of live ticks or fleas at visit 10. Secondary endpoints were the percentage reductions of live ticks and fleas in primary dogs. All treated dogs were observed for adverse reactions throughout the study. Results The analyzed per-protocol population included 415 primary dogs (fluralaner 279, afoxolaner 136) from 976 treated dogs (fluralaner 653, afoxolaner 323). From visits 2 through 10, ≥ 95% of primary dogs in each group were tick-free, and ≥ 93% were flea-free. The percentage of dogs free of ticks or fleas was non-inferior ( P  ≤ 0.0048) in the fluralaner group compared to the afoxolaner group at visit 10 and all earlier visits. Compared to baseline, fluralaner-group tick and flea counts were reduced by > 99%; afoxolaner-group tick and flea counts by > 98% and > 97%, respectively. There were no unexpected adverse events in any treated dog in either group, nor any sign of interactions between concomitantly administered vaccines and medications. Conclusions A single subcutaneous fluralaner injection provided a level of tick and flea control equivalent to that of 12 monthly administrations of afoxolaner. The sustained fluralaner efficacy helps maintain canine health by retaining treatment with the veterinarian and eliminating treatment-compliance failures by pet owners between veterinary visits. Graphical Abstract

Amblyomma maculatum , the Gulf Coast tick, is a species of significant veterinary and public health importance, especially because it is a vector of important diseases, such as American canine hepatozoonosis and tidewater spotted fever. Amblyomma maculatum infests a wide range of vertebrates including livestock, dogs, cats, and humans. Two experimental studies were conducted to evaluate the efficacy of afoxolaner formulated in an oral tablet (NexGard ® ) against induced infestations of A. maculatum in dogs. These Good Clinical Practice (GCP) studies used a randomized, negative controlled and masked design. In each study, 10 dogs were allocated to an untreated group and 10 dogs to a treated group, dosed once on Day 0 with a combination of tablets targeting the minimum therapeutic dose (2.5 mg/kg afoxolaner). Dogs were infested with 50 unfed adult A. maculatum on Days −2, 7, 14, 21, 28, and 35 (Study #1), or on Days −1, 14, and 28 (Study #2). Seventy-two (72) hours after treatment and subsequent infestations, ticks were removed and the numbers of live ticks in each group were used for efficacy calculations. At each time-point, all untreated dogs were adequately infested ( i.e. , with more than 12 live ticks), demonstrating a vigorous tick population and an adequate study model. The curative efficacy against established infestations, 72 hours after treatment, was 100% in Study #1 and 99.5% in Study #2. The preventive efficacy, 72 hours after the post-treatment infestations, ranged from 94.6% to 98.9% for five weeks in Study #1, and was ≥98.8% for four weeks in Study #2. Amblyomma maculatum , la tique du Golfe du Mexique, est une espèce d’importance vétérinaire et de santé publique considérable, notamment parce qu’elle est vectrice de maladies graves, telles que l’hépatozoonose canine américaine et la fièvre pourprée des marées. Amblyomma maculatum infeste un large éventail de vertébrés, notamment le bétail, les chiens, les chats et les humains. Deux études expérimentales ont été menées pour évaluer l’efficacité de l’afoxolaner sous forme de comprimé oral (NexGard ® ) contre les infestations induites d’ A. maculatum chez le chien. Ces études, conformes aux Bonnes Pratiques Cliniques (BPC), ont été randomisées, contrôlées par voie négative et en aveugle. Dans chaque étude, 10 chiens ont été répartis en un groupe non traité et 10 chiens en un groupe traité, recevant une dose unique le jour 0 d’une combinaison de comprimés ciblant la dose thérapeutique minimale (2,5 mg/kg d’afoxolaner). Les chiens ont été infestés par 50 A. maculatum adultes à jeun les jours −2, 7, 14, 21, 28 et 35 (étude n° 1), ou les jours −1, 14 et 28 (étude n° 2). Soixante-douze (72) heures après le traitement et les infestations ultérieures, les tiques ont été retirées et le nombre de tiques vivantes dans chaque groupe a été utilisé pour les calculs d’efficacité. À chaque point temporel, tous les chiens non traités étaient adéquatement infestés (c’est-à-dire avec plus de 12 tiques vivantes), démontrant une population de tiques vigoureuse et un modèle d’étude adéquat. L’efficacité curative contre les infestations établies, 72 heures après le traitement, était de 100% (étude n° 1) et de 99,5 % (étude n° 2). L’efficacité préventive, 72 heures après les infestations post-traitement, variait de 94,6 % à 98,9 % pendant cinq semaines dans l’étude n° 1, et était ≥ 98,8 %, pendant quatre semaines dans l’étude n° 2.