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Background: Rhipicephalus sanguineus sensu lato (s.l.) and Ctenocephalides felis are among the most important year-round ectoparasites of dogs. The persistent efficacy of one treatment with fluralaner injectable suspension (Bravecto ® 150 mg/ml powder and solvent for suspension for dogs, referred to as Bravecto ® injectable) was investigated in a negative-controlled, randomised, partially blinded 12-month laboratory study., Methods: A total of 20 dogs were randomly allocated to two equal groups (treatment and control). Treatment-group dogs were injected subcutaneously on study day 0 with the investigational veterinary product at the recommended dose of 15 mg fluralaner/kg body weight (0.1 mL/kg), whereas the control group dogs received saline solution (0.1 mL/kg). Each dog was infested with 50 (25 female, 25 male) adult R. sanguineus s.l. and 100 adult C. felis 2 days before treatment, 5 and 28 days after treatment, and then once monthly for a 12-month period. Live tick and flea counts were performed 48 h after treatment or subsequent infestation, respectively. Efficacy was determined by comparing arithmetic means of the treatment group tick and flea counts with those of the control group. Infestation was considered adequate if at least 25.0% of ticks and 40.0% of fleas were recovered from at least six dogs in the control group at the respective assessment times., Results: Adequate R. sanguineus s.l. and C. felis infestations of control group dogs were observed at each time point. Arithmetic mean treatment group values were significantly lower than those of the control group at all time points. The immediate efficacy when treating existing infestations of R. sanguineus s.l. and C. felis (infestation 2 days before treatment), was 49.7% and 89.7%, respectively. The persistent efficacy against post-treatment re-infestations was 94.4-100% against R. sanguineus s.l. and 92.2-100% against C. felis. Seven dogs in the control group developed flea allergy dermatitis due to the repeated re-infestations over the study period, whereas no dogs in the treatment group were affected. No clinically relevant side effects were observed over the entire study period., Conclusions: The fluralaner injectable suspension (Bravecto ® injectable) provides 1 year of efficacy against R. sanguineus s.l. and C. felis infestations in dogs following a single treatment, allowing once-yearly treatment, which can significantly improve owner compliance with year-round protection of dogs., (© 2024. The Author(s).)

Iloperidone, a second-generation USFDA approved antipsychotic and BCS class II drug shows poor oral bioavailability of 28%. The present research deals with optimization of transnasal nanoemulsions of Iloperidone using Design Expert (Version 11) and further surface functionalization with chitosan for potentiating nose to brain delivery. Chitosan functionalized transnasal Iloperidone nanoemulsions were developed using oleic acid, charge inducer, Tween 80, Transcutol HP and chitosan using ultrasonication technique and evaluated. Droplet size, polydispersity index and zeta potential of Iloperidone nanoemulsions was found to be 173 ± 0.5 nm, 0.413 ± 0.2 and - 22.5 ± 0.1 mV while that of chitosan functionalized Iloperidone nanoemulsions was 146.4 ± 0.5 nm, 0.291 ± 0.02 and + 23.6 ± 0.3 mV respectively. Ninhydrin assay, TEM and FTIR studies confirmed surface functionalization of Iloperidone nanoemulsion droplets with chitosan. In vitro release of Iloperidone from nanoemulsions and chitosan functionalized nanoemulsions was 90.41 ± 2.1% and 72.02 ± 0.21% while ex vivo permeation of Iloperidone across goat nasal mucosa was 1270.58 ± 0.023 μg/cm 2 and 1096.13 ± 0.043 μg/cm 2 respectively at the end of 8 h. Studies in RPMI 2650 nasal and Neuro2A brain cell line lines indicated safety of chitosan functionalized transnasal Iloperidone nanoemulsions. Studies in Wistar rats showed increased cataleptic effects, reduced cognitive impairment and anxiety-related behaviour with greater brain accumulation indicating promising potential of this approach in nose to brain drug delivery., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Purpose: To prospectively compare pain intensity and patient-reported outcomes (PROs) after arthroscopic rotator cuff repair (ARCR) between patients who received ultrasound-guided suprascapular nerve block (SSNB) and axillary nerve block (ANB) as well as preincisional parecoxib and patients who received preincisional parecoxib only., Methods: Sixty-one patients receiving ARCR between March 2020 and March 2021 were prospectively enrolled. They were randomly assigned to the peripheral nerve block group (group N, n = 30) or control group (group C, n = 31). Two patients in group C were excluded because of miscommunication. All patients were administered 40 mg of parecoxib intravenously prior to induction of anesthesia. SSNB and ANB were performed after general anesthesia in group N, whereas no nerve block was performed in group C. Pain intensity was compared before surgery, as well as immediately, 24 hours, and 2 weeks after surgery. PROs, including the Oxford Shoulder Score, University of California-Los Angeles shoulder score, and Single Assessment Numeric Evaluation score, were compared before and 6 months after surgery., Results: The numerical rating scale (NRS) score for resting pain was significantly lower in group N (4.9 ± 3.1 vs 7.6 ± 2.5, P < .001) immediately after surgery, but no difference was noted 24 hours after surgery. The resting pain NRS score 2 weeks after surgery was significantly lower in group N (1.4 ± 1.6 vs 2.7 ± 2.7, P = .03), but the scores for movement-evoked pain and night pain were similar. All PROs significantly improved 6 months after surgery in both groups, but there was no difference between the 2 groups., Conclusions: The addition of preoperative ultrasound-guided SSNB and ANB to parecoxib offered better resting pain control immediately and 2 weeks after ARCR, but there was no benefit for PROs 6 months after surgery., Level of Evidence: Level II, prospective randomized controlled trial., Competing Interests: Disclosure All authors (Y-Y.H., Y-T.N., C-H.C., C-A.C., H.S., C-P.Y., H-C.T.) declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Full ICMJE author disclosure forms are available for this article online, as supplementary material., (Copyright © 2024 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Among approaches aimed at reducing Lyme disease risk in the environment, those targeting reservoirs of Borrelia burgdorferi Johnson are promising because they have the potential to reduce both the density of questing Ixodes scapularis Say (Acari: Ixodidea) ticks and the prevalence of B. burgdorferi in the tick population. In this 4-yr field study, we treated a population of wild small mammals with 2 densities of fluralaner baits and investigated the effect of the treatment on 3 parameters of the endemic cycle of B. burgdorferi: (i) the prevalence of infected Peromyscus mice (PIM), (ii) the density of questing nymphs (DON), and (iii) the prevalence of infected questing nymphs (NIP). We demonstrated that fluralaner baiting is effective at reducing tick infestation of Peromyscus mice, the main reservoir of B. burgdorferi in central and northeastern North America, in the laboratory and the field. Results from this study showed a significant decrease in B. burgdorferi infection in mice (odds ratio: 0.37 [CI95: 0.17 to 0.83]). A reduction in the DON between 45.4% [CI95: 22.4 to 61.6] and 62.7% [CI95: 45.9 to 74.2] occurred in treated area when compared with control areas. No significant effect was reported on the NIP. These results confirm the hypothesis that fluralaner baits have an effect on B. burgdorferi endemic cycle, with the potential to reduce the density of B. burgdorferi-infected ticks in the environment. Further studies performed in various habitats and public health intervention contexts are needed to refine and operationalize this approach for reducing Lyme disease risk in the environment., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America.)

A 9-month-old mixed-breed dog developed generalised pustular dermatitis, accompanied by lethargy and hyperthermia, 7 days after oral fluralaner administration. Dermatopathological and microbiological evaluations were consistent with a pustular acantholytic dermatitis. A 4-month course of immunosuppressive therapy resulted in complete remission of lesions, which did not recur after therapy was withdrawn., (© 2024 ESVD and ACVD.)

Background: Canine acaricides with rapid onset and sustained activity can reduce pathogen transmission risk and enhance pet owner experience. This randomized, complete block design, investigator-masked study compared the speed of kill of Amblyomma americanum provided by three monthly-use isoxazoline-containing products., Methods: Eight randomized beagles per group were treated (day 0), per label, with sarolaner (combined with moxidectin and pyrantel, Simparica Trio™), afoxolaner (NexGard™), or lotilaner (Credelio™), or remained untreated. Infestations with 50 adult A. americanum were conducted on days - 7, - 2, 21, and 28, and tick counts were performed on day - 5 (for blocking), and at 4, 8, 12, 24, 48, and 72 h following treatment and subsequent infestations. Efficacy calculations were based on geometric mean live tick counts. A linear mixed model was used for between-group comparisons., Results: On day 0, only lotilaner significantly reduced an A. americanum infestation by 12 h (43.3%; P = 0.002). Efficacy of lotilaner and afoxolaner at 24 h post-treatment was 95.3% and 97.6%, respectively, both significantly different from sarolaner (74%) (P = 0.002, P < 0.001, respectively). On day 21, at 12 h postinfestation, lotilaner efficacy (59.6%) was significantly different from sarolaner (0.0%) (P < 0.001) and afoxolaner (6.3%) (P < 0.001). At 24 h, lotilaner efficacy (97.4%) was significantly different (P < 0.001) from sarolaner and afoxolaner (13.6% and 14.9%, respectively). On day 28, at 12 h postinfestation, lotilaner efficacy (47.8%) was significantly different from sarolaner (17.1%) (P = 0.020) and afoxolaner (9.0%) (P = 0.006). At 24 h, lotilaner efficacy (92.3%) was significantly different from sarolaner 4.9% (P < 0.001) and afoxolaner (0.0%) (P < 0.001). Speed of kill for sarolaner and afoxolaner, but not lotilaner, significantly declined over the study period. Following reinfestation on day 28, neither sarolaner nor afoxolaner reached 90% efficacy by 48 h. By 72 h, sarolaner efficacy was 97.4% and afoxolaner efficacy was 86.3%. Only lotilaner achieved ≥ 90% efficacy by 24 h post-treatment and 24 h postinfestation on days 21 and 28. Time to ≥ 90% efficacy following new infestations consistently occurred 24-48 h earlier for lotilaner compared with sarolaner or afoxolaner., Conclusions: Credelio (lotilaner) has a more rapid onset of acaricidal activity against A. americanum than Simparica Trio (sarolaner-moxidectin-pyrantel) and NexGard (afoxolaner). Only lotilaner's speed of tick kill is sustained throughout the dosing period., (© 2024. The Author(s).)

The demand for the use of fluralaner in an extra label manner is increasing due to lack of efficacious treatment to combat mites and bed bugs in the poultry industry in the United States. Fluralaner residue data in eggs is lacking and residues might cause risks to human health. The present study aimed to determine the depletion profiles of fluralaner in eggs and estimate the drug withdrawal interval in whole eggs by adopting the US Food and Drug administration tolerance limit method with single intravenous (0.5 mg/kg) or transdermal administration (average 58.7 mg/kg) in healthy shaver hens. Hens were treated intravenously or trans-dermally with fluralaner. The eggs were collected daily for 28 d for intravenous treated and for 40 d from the transdermal route group. Fluralaner concentrations in yolk and albumen were determined by mass spectrometry. The greater percentage of fluralaner was observed in yolk when compared to the albumen for both administration routes. Noncompartmental analysis was used to calculate the pharmacokinetic parameters in yolk, albumen and whole egg. The longest apparent half-life confirmed in yolk was 3.7 d for intravenous and 14.3 d for the transdermal route. The withdrawal intervals in whole egg for fluralaner following the intravenous and transdermal administration were 7 d and 81 d, respectively, with maximum residue limits (1.3 µg/g) at 13 d and 171 d, respectively, based on the limit of quantification (0.4 µg/g) from the analytical assay reported by EMA and APVMA., Competing Interests: DISCLOSURES The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

South American Camelids, including alpacas, have gained popularity in Europe as pets and prized wool sources. Skin health concerns, particularly mite infestations, have emerged as a notable problem in these animals. Sarcoptic mange can lead to severe itching, papules, and chronic symptoms such as alopecia, crusts, and emaciation if left untreated. This case report documents a 2-year-old female alpaca suffering from sarcoptic mange. Despite initial treatment with ivermectin, its condition worsened, leading to severe weight loss, abortion, and a continued presence of mites. Considering the lack of effective treatments for sarcoptic mange in alpacas and the unavailability of registered drugs for this species in Italy, fluralaner, a drug previously used in other animal species, has been administered orally at a dosage of 5 mg/kg. Within a week after the treatment with fluralaner, the patient exhibited significant improvement, including the resolution of itching, healing of skin lesions, and an increase in appetite. Follow-up skin scrapings confirmed the absence of mites, and the patient's condition continued to improve. Fluralaner demonstrated to be a highly effective and fast-acting treatment for sarcoptic mange in alpacas, offering potential economic benefits attributed to its single-dose administration., (© 2024. The Author(s).)

Background: Triatoma infestans, Triatoma brasiliensis, Triatoma pseudomaculata and Rhodnius prolixus are vectors of Trypanosoma cruzi, the etiological agent of Chagas disease. Chickens serve as an important blood food source for triatomines. This study aimed to assess the insecticidal activity of fluralaner (Exzolt ® ) administered to chickens against triatomines (R. prolixus, T. infestans, T. brasiliensis and T. pseudomaculata)., Methods: Twelve non-breed chickens (Gallus gallus domesticus) were randomized based on weight into three groups: negative control (n = 4); a single dose of 0.5 mg/kg fluralaner (Exzolt ® ) (n = 4); two doses of 0.5 mg/kg fluralaner (Exzolt ® ) (n = 4). Nymphs of 3rd, 4th and 5th instars of R. prolixus, T. infestans, T. brasiliensis and T. pseudomaculata (all n = 10) were allowed to feed on chickens before treatment, and at intervals of 1, 7, 14, 21, 28, 35 and 56 days after treatment, with insect mortality determined., Results: Treatment with two doses of fluralaner showed higher insecticidal efficacy against R. prolixus, T. infestans and T. brasiliensis compared to the single-dose treatment. Similar insecticidal efficacy was observed for T. pseudomaculata for one and two doses of fluralaner. Insecticidal activity of fluralaner (Exzolt ® ) against triatomine bugs was noted up to 21 and 28 days after treatment with one and two doses of fluralaner, respectively., Conclusions: The results demonstrate that treatment of chickens with fluralaner (Exzolt ® ) induces insecticidal activity against triatomines for up to 28 days post-treatment, suggesting its potential use as a control strategy for Chagas disease in endemic areas., (© 2024. The Author(s).)

Background: Tungiasis is a neglected tropical disease caused by the adult female sand flea (Tunga penetrans). Dogs are considered important reservoirs of T. penetrans in Brazil. The aim of this study was to determine the monthly insecticidal efficacy of a single oral administration of fluralaner at a dose of 10-18 mg/kg (Bravecto ® 1-Month, also registered as Defenza ® in some countries; MSD Animal Health) in dogs naturally infested with T. penetrans., Methods: This clinical trial was conducted in a rural community located in Ilhéus, Bahia, Brazil. A total of 64 dogs were selected and distributed in a completely randomized design between a treated group (TG) that received one single dose of Bravecto ® 1-Month (Defenza ® ) and a negative control group (CG) that received no treatment. Each group was composed of 32 dogs. The evaluations took place on days 0, 7 ± 2, 14 ± 2, 21 ± 2, 28 ± 2, 35 ± 2, and 42 ± 2 post treatment, in which the dogs were inspected to evaluate the infestation stage and classify lesions associated with tungiasis. The primary efficacy was determined from the percentage of treated dogs free of fleas (stage II and III lesions) after administration of the formulation at each evaluation time. Secondary efficacy was based on the number of active lesions (stages II and III) in each group at each evaluation time. The clinical condition of the animals was defined based on the Severity Score for Acute Dog Tungiasis (SCADT), which is related to the number and severity of lesions., Results: The primary efficacy of the product was greater than 95.0% from days 7 to 21 and reached 100.0% between days 28 and 42, with a significant association between treatment and infestation decline (P < 0.025) between days 7 and 42. Secondary drug efficacy was greater than 99.9% from days 7 to 21, reaching 100.0% between days 28 and 42 (P < 0.05). The treated dogs also scored lower on the SCADT than the control animals did during the entire clinical evaluation period (P < 0.05)., Conclusions: A single administration of Bravecto ® 1-Month (Defenza ® ) was effective in eliminating Tunga penetrans infestations, as well as in preventing parasitism for at least 42 days after treatment., (© 2024. The Author(s).)

Background: Aelurostrongylus abstrusus is one of the most important respiratory nematodes of felines. Infections may lead to respiratory clinical signs with varying severity or even death, emphasizing the need for preventive treatment of cats with outdoor access to circumvent patent infections., Methods: Therefore, the preventive efficacy of a spot-on formulation of 280 mg/ml fluralaner and 14 mg/ml moxidectin (Bravecto ® Plus spot-on solution for cats, MSD) against A. abstrusus was evaluated in a negative controlled, randomized and partially blinded efficacy study with 28 purpose-bred cats in a non-terminal design. In three different treatment regimes, the minimum recommended dose of 40 mg fluralaner and 2.0 mg moxidectin/kg bodyweight (BW) was administered once at 12, 8 or 4 weeks (study group G1, G2 and G3, respectively) prior to experimental infection with 300 third-stage A. abstrusus larvae, while G4 served as placebo-treated control., Results: From 30 to 46 days post infection (dpi; SD 114 to 130), faeces were sampled to monitor first-stage larvae (L1) excretion for efficacy determination. Secondary efficacy criteria, including respiratory parameters, serological antibody levels and computed tomography (CT) findings, were assessed once before enrolment (SD -7 to -1) and before infection (SD 75 to 83). After infection, CT evaluation was performed once at 47-50 dpi (SD 131 to 134), and respiratory parameters and antibody levels were regularly assessed twice or once a week, respectively (1 up to 78 dpi, SD 85 up to 162). All animals in the control group excreted L1 by 33-37 dpi and remained positive throughout the study period from 41 to 46 dpi (SD 125 to 130). In the treatment groups, only one animal each of G1 and G2 excreted L1 at two consecutive days, and four cats of G1, two of G2 and three of G3 were positive on single occasions. While the geometric mean (GM) of the maximum number of excreted L1 per 5 g of faeces was 7380.89 in the control group (G4), GMs were significantly lower in the treatment groups with 1.63 in G1, 1.37 in G2 and 0.79 in G3. Thus, based on GMs, the reduction in excreted L1 exceeded 99.9% in all three treatment groups. Based on CT severity scores, all lungs of the animals of the control group showed severe pulmonary changes post infection, whereas lungs of the cats of the treatment groups were either unaltered (4 animals), mildly (11 animals), or moderately altered (5 animals). Moreover, seroconversion was observed in all cats of the control group, but not in those of the treatment groups., Conclusions: The combination of diagnostic methods used in this non-terminal study yielded coherent and reliable results. A single administration of Bravecto ® Plus spot-on solution for cats was well tolerated and effective in the prevention of aelurostrongylosis for at least 12 weeks., (© 2024. The Author(s).)

Background: Orally administered fluralaner (13.64% w/w) is effective for treating canine generalized demodicosis. A study was initiated to assess the efficacy of a novel 5.46% w/w fluralaner chewable tablet formulation for monthly administration in the treatment of this disease., Methods: Client-owned dogs diagnosed with generalized demodicosis were acclimatized to laboratory conditions and randomized to receive either orally administered fluralaner (Bravecto ® 1-Month) (10.0 to 14.4 mg/kg body weight) (n = 8) or topical imidacloprid-moxidectin (Advocate ® for dogs, Elanco) applied per label on days 0, 28, and 56 (n = 8), or more frequently for ongoing severe demodicosis. On days -2, 28, 56, and 84, deep skin scrapings were taken from five sites on each dog for mite identification and counting, and semiquantitative clinical assessments of generalized demodicosis were recorded. Primary efficacy was based upon arithmetic mean mite count reductions relative to pre-treatment., Results: By day 28, mean pre-treatment mite counts, > 600 in both groups, were significantly reduced by 99.7% and 89.5% (both P < 0.001) in the fluralaner and imidacloprid-moxidectin groups, respectively. Parasitological cure (100% reduction in mite counts on days 56 and 84) was achieved in all fluralaner-treated dogs (100%) and in two imidacloprid-moxidectin-treated dogs (25%). In the imidacloprid-moxidectin group, the reduction in mean mite counts was 89.5% (day 28), 94.4% (day 56), and 97.5% (day 84). All study dogs were free of crusts on days 56 and 84. Scales resolved by day 84 in all fluralaner-treated dogs and in three imidacloprid-moxidectin-treated dogs. All fluralaner-treated dogs and five imidacloprid-moxidectin-treated dogs had > 90% hair regrowth on day 84., Conclusion: Three consecutive monthly orally administered treatments with fluralaner (5.46% w/w) flavored chewable tablets (minimum dose rate 10 mg/kg body weight) eliminated Demodex canis mites from dogs diagnosed with generalized demodicosis., (© 2022. The Author(s).)

Ampakines are synthetic molecules that allosterically modulate AMPA-type glutamate receptors. We tested the hypothesis that delivery of ampakines to the intrathecal space could stimulate neural drive to the diaphragm. Ampakine CX717 (20 mM, dissolved in 10 % HPCD) or an HPCD vehicle solution were delivered via a catheter placed in the intrathecal space at the fourth cervical segment in urethane-anesthetized, mechanically ventilated adult male Sprague-Dawley rats. The electrical activity of the phrenic nerve was recorded for 60-minutes following drug application. Intrathecal application of CX717 produced a gradual and sustained increase in phrenic inspiratory burst amplitude (n = 10). In contrast, application of HPCD (n = 10) caused no sustained change in phrenic motor output. Phrenic burst rate, heart rate, and mean arterial pressure were similar between CX717 and HPCD treated rats. We conclude that intrathecally delivered ampakines can modulate phrenic motor output. This approach may have value for targeted induction of spinal neuroplasticity in the context of neurorehabiliation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Dogs are the reservoir host of Leishmania infantum, the agent of zoonotic visceral leishmaniasis (VL), which is transmitted by the bite of phlebotomine sand flies. The sand fly Phlebotomus perniciosus is the main vector of zoonotic VL in the western Mediterranean region. Fluralaner has been shown to effectively kill this vector. The aim of this study was to evaluate the insecticidal efficacy of oral fluralaner in dogs bitten by P. perniciosus., Methods: Two parallel-group, negative-controlled, randomized, masked laboratory trials with equivalent designs were performed in two different locations using two different pathogen-free laboratory-bred P. perniciosus strains for the challenge. In each trial, 12 purpose-bred beagles, initially ranked on natural attractiveness to sand flies, were randomly allocated to two groups (6 animals/group). Dogs in one group received fluralaner orally at the approved dose on day 0, and dogs in the control group were not treated. Each dog was subsequently exposed to an average of 70 unfed live sand fly females on days 1, 28, 56 and 84. Viability of blood-fed females was then evaluated for up to 96 h after exposure, and insecticidal efficacy was measured as the survival rate of flies fed on the fluralaner-treated dogs versus that of dogs in the control group. Significance was calculated for the proportion of live fed sand fly counts from treated versus control group dogs., Results: Comparison of the survival proportions between treated and control groups showed that fluralaner insecticidal efficacy was highly significant in both trials (P < 0.001 or P < 0.01 in different assessments) through to day 56. In the first trial, efficacy reached 100% on days 1 and 28, and 99.1% on day 56; in the second trial, the insecticidal efficacy was 98.5, 100 and 85.9%, respectively on the same days. On day 84, efficacy was in the range of 53-57% (P < 0.05) in the first trial and 0% in the second trial., Conclusion: A single oral fluralaner administration to dogs under laboratory conditions results in strong and reproducible insecticidal efficacy against P. perniciosus for at least 8 weeks., (© 2021. The Author(s).)

The effective treatment of brain tumors is a considerable challenge in part because of the presence of the blood-brain barrier (BBB) that limits drug delivery. Glioblastoma multiforme (GBM) is an aggressive and infiltrative primary brain tumor with an extremely poor prognosis after standard-of-care therapy with surgery, radiotherapy (RT), and chemotherapy. DNA damage response (DDR) pathways play a critical role in DNA repair in cancer cells, and inhibition of these pathways can potentially augment RT and chemotherapy tumor cell toxicity. The ataxia telangiectasia and Rad3-related protein (ATR) kinase is a key regulator of the DDR network and is potently and selectively inhibited by the ATR inhibitor berzosertib. Although in vitro studies demonstrate a synergistic effect of berzosertib in combination with temozolomide, in vivo efficacy studies have yet to recapitulate this observation using intracranial tumor models. In the current study, we demonstrate that delivery of berzosertib to the brain is restricted by efflux at the BBB. Berzosertib has a high binding affinity to brain tissue compared with plasma, thereby leading to low free drug concentrations in the brain. Berzosertib distribution is heterogenous within the tumor, wherein concentrations are substantially lower in normal brain and invasive tumor rim (wherein the BBB is intact) when compared with those in the tumor core (wherein the BBB is leaky). These results demonstrate that high tissue binding and limited and heterogenous brain distribution of berzosertib may be important factors that influence the efficacy of berzosertib therapy in GBM. SIGNIFICANCE STATEMENT: This study examined the brain delivery and efficacy of berzosertib in patient-derived xenograft models of glioblastoma multiforme (GBM). Berzosertib is actively effluxed at the blood-brain barrier and is highly bound to brain tissue, leading to low free drug concentrations in the brain. Berzosertib is heterogeneously distributed into different regions of the brain and tumor and, in this study, was not efficacious in vivo when combined with temozolomide. These factors inform the future clinical utility of berzosertib for GBM., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Repeated short episodes of hypoxia produce a sustained increase in phrenic nerve output lasting well beyond acute intermittent hypoxia (AIH) exposure (i.e., phrenic long-term facilitation; pLTF). Pretreatment with ampakines, drugs which allosterically modulate AMPA receptors, enables a single brief episode of hypoxia to produce pLTF, lasting up to 90 min after hypoxia. Here, we tested the hypothesis that ampakine pretreatment would enhance the magnitude of pLTF evoked by repeated bouts of hypoxia. Phrenic nerve output was recorded in urethane-anesthetized, mechanically ventilated, and vagotomized adult male Sprague-Dawley rats. Initial experiments demonstrated that ampakine CX717 (15 mg/kg iv) caused an acute increase in phrenic nerve inspiratory burst amplitude reaching 70 ± 48% baseline (BL) after 2 min ( P = 0.01). This increased bursting was not sustained (2 ± 32% BL at 60 min, P = 0.9). When CX717 was delivered 2 min before a single episode of isocapnic hypoxia (5 min, [Formula: see text] = 44 ± 9 mmHg), facilitation of phrenic nerve burst amplitude occurred (96 ± 62% BL at 60 min, P < 0.001). However, when CX717 was given 2 min before three, 5-min hypoxic episodes ([Formula: see text] = 45 ± 6 mmHg) pLTF was attenuated and did not reach statistical significance (24 ± 29% BL, P = 0.08). In the absence of CX717 pretreatment, pLTF was observed after three (74 ± 33% BL at 60 min, P < 0.001) but not one episode of hypoxia (1 ± 8% BL at 60 min, P = 0.9). We conclude that pLTF is not enhanced when ampakine pretreatment is followed by repeated bouts of hypoxia. Rather, the combination of ampakine and a single hypoxic episode appears to be ideal for producing sustained increase in phrenic motor output. NEW & NOTEWORTHY Pretreatment with ampakine CX717 created conditions that enabled an acute bout of moderate hypoxia to evoke phrenic motor facilitation, but this response was not observed when ampakine pretreatment was followed by intermittent hypoxia. Thus, in anesthetized and spinal intact rats, the combination of ampakine and one bout of hypoxia appears ideal for triggering respiratory neuroplasticity.

Background: Triatomines are responsible for the vector transmission of the protozoan parasite Trypanosoma cruzi, which causes Chagas disease. Triatoma brasiliensis is the main vector of the parasite in Brazil, and dogs are an important reservoir of the parasite. The aim of this study was to evaluate the insecticidal effect of fluralaner (Bravecto ® ) on T. brasiliensis after a blood meal in treated dogs., Methods: Healthy mongrel dogs (n = 8) were recruited from the Zoonoses Control Center (ZCC) in the city of Natal, Rio Grande do Norte, Brazil, and randomized into two groups, a fluralaner (Bravecto ® )-treated group (n = 4) and a control group (n = 4). Colony-reared third-, fourth- and fifth-instar nymphs of T. brasiliensis nymphs (n = 10) were allowed to feed on dogs from both groups for 30-40 min, once monthly, for up to 12 months. Bug mortality was observed up to 5 days after each blood meal., Results: Mortality in triatomines which had a blood meal on fluralaner (Bravecto ® )-treated dogs was 100% for up to 7 months after treatment, with mortality decreasing to 66.4% after 8 months, 57% after 9 months, 35% after 10 months, 10% after 11 months and 0% after 12 months. The mortality of triatomines that fed on non-treated control dogs was always ≤ 2.5%., Conclusions: Our results suggest that fluralaner (Bravecto ® ) treatment of dogs induces long-term mortality of T. brasiliensis after the blood meal. This is a potential approach to be used to control vector transmission of T. cruzi, the etiological agent of Chagas disease, especially in endemic areas., (© 2021. The Author(s).)

In order to achieve a desired therapeutic effect in schizophrenia patients and to maintain their mental wellbeing, pharmacological therapy needs to be continued for a long time, usually from the onset of symptoms and for the rest of the patients' lives. The aim of our present research is to find out the in vivo effect of chronic treatment with atypical neuroleptic iloperidone on the expression and activity of cytochrome P450 (CYP) in rat liver. Male Wistar rats received a once-daily intraperitoneal injection of iloperidone (1 mg/kg) for a period of two weeks. Twenty-four hours after the last dose, livers were excised to study cytochrome P450 expression (mRNA and protein) and activity, pituitaries were isolated to determine growth hormone-releasing hormone (GHRH), and blood was collected for measuring serum concentrations of hormones and interleukin. The results showed a broad spectrum of changes in the expression and activity of liver CYP enzymes, which are important for drug metabolism (CYP1A, CYP2B, CYP2C, and CYP3A) and xenobiotic toxicity (CYP2E1). Iloperidone decreased the expression and activity of CYP1A2, CP2B1/2, CYP2C11, and CYP3A1/2 enzymes but increased that of CYP2E1. The CYP2C6 enzyme remained unchanged. At the same time, the level of GHRH, GH, and corticosterone decreased while that of T 3 increased, with no changes in IL-2 and IL-6. The presented results indicate neuroendocrine regulation of the investigated CYP enzymes during chronic iloperidone treatment and suggest a possibility of pharmacokinetic/metabolic interactions produced by the neuroleptic during prolonged combined treatment with drugs that are substrates of iloperidone-affected CYP enzymes.

Background: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours., Methods: We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m 2 , gemcitabine 875 mg/m 2 and cisplatin 60 mg/m 2 ., Results: Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m 2 (days 2 and 9) + gemcitabine 1000 mg/m 2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease., Conclusions: Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs., Clinical Trial Identifier: NCT02157792., (© 2021. The Author(s).)

Background: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. We assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of berzosertib plus cisplatin., Methods: Adult patients with advanced solid tumours refractory or resistant to standard of care therapies received ascending doses of cisplatin (day 1) and berzosertib (days 2 and 9) every 3 weeks (Q3W)., Results: Thirty-one patients received berzosertib (90-210 mg/m 2 ) and cisplatin (40-75 mg/m 2 ) across seven dose levels. The most common grade ≥3 treatment-emergent adverse events were neutropenia (20.0%) and anaemia (16.7%). There were two dose-limiting toxicities: a grade 3 hypersensitivity reaction and a grade 3 increase in alanine aminotransferase. Berzosertib 140 mg/m 2 (days 2 and 9) and cisplatin 75 mg/m 2 (day 1) Q3W was determined as the recommended Phase 2 dose. Cisplatin had no apparent effect on berzosertib pharmacokinetics. Of the 31 patients, four achieved a partial response (two confirmed and two unconfirmed) despite having previously experienced disease progression following platinum-based chemotherapy., Conclusions: Berzosertib plus cisplatin is well tolerated and shows preliminary clinical activity in patients with advanced solid tumours, warranting further evaluation in a Phase 2 setting., Clinical Trials Identifier: NCT02157792., (© 2021. The Author(s).)

Objective: Little is known about the efficacy of perioperative intravenous (IV) non-opioid medication administration in patients undergoing orthopedic surgery. The objective of this study was to determine the efficacy of perioperative parecoxib in patients with unstable ankle fractures who were scheduled to undergo surgery., Patients and Methods: In this double-blinded, prospective, randomized controlled trial, 40 patients who underwent open reduction and internal fixation for unstable ankle fractures were randomly allocated to the parecoxib group (parecoxib 40 mg IV 30 min before surgery and then 40 mg IV every 12 h for the initial 48 h postoperatively [n=20]) or the placebo group (saline [n=20]). The efficacy of pain control was assessed according to the total morphine used. Pain intensity (at rest/ambulation) and pain relief (at rest/ambulation) were assessed using the verbal numerical rating score (VNRS) and verbal numerical rating percentage (VNRP), respectively. Subjective rating of medication was performed by each patient. All outcomes were recorded by trained personnel who were blinded to the patient group allocation., Results: The mean patient age was 49.3±18.0 years. There were no significant differences between the two groups in terms of pain intensity, pain relief, patients' subjective ratings of the medication at both the preoperative and postoperative periods, total quantity of morphine used, side effects, and acute complications of surgery (p>0.05). The mean length of hospital stay tended to be shorter in the parecoxib group than in the placebo group (6 vs. 9.9 days; p=0.183)., Conclusions: Although the perioperative administration of parecoxib did not provide significantly better postoperative pain control or reduce the opioid requirement relative to placebo, its use led to a shorter hospital stay.

Tropifexor (NVP-LJN452) is a highly potent, selective, nonsteroidal, non-bile acid farnesoid X receptor agonist for the treatment of nonalcoholic steatohepatitis. Its absorption, metabolism, and excretion were studied after a 1-mg oral dose of [ 14 C]tropifexor was given to four healthy male subjects. Mass balance was achieved with ∼94% of the administered dose recovered in excreta through a 312-hour collection period. Fecal excretion of tropifexor-related radioactivity played a major role (∼65% of the total dose). Tropifexor reached a maximum blood concentration (C max ) of 33.5 ng/ml with a median time to reach C max of 4 hours and was eliminated with a plasma elimination half-life of 13.5 hours. Unchanged tropifexor was the principal drug-related component found in plasma (∼92% of total radioactivity). Two minor oxidative metabolites, M11.6 and M22.4, were observed in circulation. Tropifexor was eliminated predominantly via metabolism with >68% of the dose recovered as metabolites in excreta. Oxidative metabolism appeared to be the major clearance pathway of tropifexor. Metabolites containing multiple oxidative modifications and combined oxidation and glucuronidation were also observed in human excreta. The involvement of direct glucuronidation could not be ruled out based on previous in vitro and nonclinical in vivo studies indicating its contribution to tropifexor clearance. The relative contribution of the oxidation and glucuronidation pathways appeared to be dose-dependent upon further in vitro investigation. Because of these complexities and the instability of glucuronide metabolites in the gastrointestinal tract, the contribution of glucuronidation remained undefined in this study. SIGNIFICANCE STATEMENT: Tropifexor was found to be primarily cleared from the human body via oxidative metabolism. In vitro metabolism experiments revealed that the relative contribution of oxidation and glucuronidation was concentration-dependent, with glucuronidation as the predominant pathway at higher concentrations and the oxidative process becoming more important at lower concentrations near clinical exposure range. The body of work demonstrated the importance of carefully designed in vivo and in vitro experiments for better understanding of disposition processes during drug development., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Backgroud: Postoperative pain following total knee arthroplasty (TKA) may hamper patients from a rapid recovery and increase perioperative blood loss and stress on the cardiovascular system. Therefore, our objective was to assess perioperative outcomes after TKA in patients who were not candidates for the additional nonsteroidal anti-inflammatory drugs (NSAIDs) in a multimodal pain control regimen., Methods: Propensity score matching for age, sex, body mass index, American Society of Anesthesiologists class, and preoperative hemoglobin level was conducted on patients undergoing unilateral TKA, and thereby 52 patients remained in each group. The control group comprised patients who received parenteral parecoxib every 12 hours during the first 48 hours after TKA. The No-NSAIDs group did not receive NSAIDs because of known contraindications. Identical postoperative pain control including intravenous patient-controlled analgesia was applied for all patients. Visual analog scale (VAS) score for pain, knee flexion, blood loss, serum cardiac troponin-T (cTnT), and length of stay (LOS) were determined., Results: The No-NSAIDs group had significantly higher VAS scores in 6-96 hours and consumed more morphine at 24 hours and 48 hours after the surgery than the control group. The No-NSAIDs group had significantly less knee flexion at 48 hours ( p = 0.045) and tended to have more emesis and longer LOS than the control group. The blood loss of the No-NSAIDs and control group was 552.52 mL and 397.65 mL ( p = 0.02), respectively, and blood transfusion rate was 23.1% and 17.3% ( p = 0.63), respectively. The cTnT of the No-NSAIDs group rose over the first 48 hours and was significantly higher than that of the control group at 48 hours., Conclusions: Patients who were not candidates for NSAIDs had significantly higher pain scores and consumed more morphine after TKA. They also tended to have greater blood loss and the rising of cardiac biomarkers during the first 48 hours after TKA. Hence, these patients may benefit from supplementary analgesia and appropriate perioperative monitoring., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported., (Copyright © 2021 by The Korean Orthopaedic Association.)

The heat shock protein 90 inhibitor, luminespib, has demonstrated potent preclinical activity against numerous cancers. However, clinical translation has been impeded by dose-limiting toxicities that have necessitated dosing schedules which have reduced therapeutic efficacy. As such, luminespib is a prime candidate for reformulation using advanced drug delivery strategies that improve tumor delivery efficiency and limit off-target side effects. Specifically, thermosensitive liposomes are proposed as a drug delivery strategy capable of delivering high concentrations of drug to the tumor in combination with other chemotherapeutic molecules. Indeed, this work establishes that luminespib exhibits synergistic activity in lung cancer in combination with standard of care drugs such as cisplatin and vinorelbine. While our research team has previously developed thermosensitive liposomes containing cisplatin or vinorelbine, this work presents the first liposomal formulation of luminespib. The physico-chemical properties and heat-triggered release of the formulation were characterized. Cytotoxicity assays were used to determine the optimal drug ratios for treatment of luminespib in combination with cisplatin or vinorelbine in non-small cell lung cancer cells. The formulation and drug combination work presented in this paper offer the potential for resuscitation of the clinical prospects of a promising anticancer agent.

Background: The study objective was to examine cat owner ectoparasiticide purchases in the United States and estimate the impact of purchase gaps on timely ectoparasite protection administration. These purchase gaps lead to periods of time when cats are unprotected from ectoparasites., Methods: Ectoparasiticide purchase transactions for individual cats from 671 U.S. veterinary clinics from January 1, 2017 through June 30, 2019 were evaluated to determine time "gaps" between doses of ectoparasiticides purchased in a defined 12-month period. Ectoparasiticides examined were topically applied products that contained fluralaner, fipronil/(S)-methoprene/pyriproxyfen, imidacloprid/pyriproxyfen or selamectin as active ingredients. The duration of protection following administration of one dose was 8-12 weeks for the fluralaner-containing product and one month for the other products., Results: Ectoparasiticide purchase records were obtained from 114,853 cat owners and analysis found that most owners bought ≤ 6 months of protection during the year, with 61-75% (depending on the product) purchasing just 1-3 months of protection. The size of the average purchase gap was determined for all dose combinations out to 12 months of protection (5-7 doses for fluralaner and 12 doses for the other three products dosed monthly. The largest gaps occurred between the first and second doses and the second and third doses. Average purchase gaps for the four different products between doses 1 and 2 ranged from 11.2 to 13.9 weeks and between doses 2 and 3 ranged from 7.7 to 12.2 weeks. The fraction of purchases separated by gaps and the average length of the gap tended to decrease with increasing number of doses purchased. Owners purchasing the 8 to 12-week duration product containing fluralaner provided ectoparasite protection ("doses plus gap period") for a larger proportion of each 2-dose period compared with owners purchasing products administered monthly., Conclusions: When cat owners purchase flea and tick medication, gaps between subsequent purchases reduces the proportion of time ectoparasite protection can be provided. The duration of the gap between doses has an impact on the effectiveness of flea/tick medication because it inserts a period without flea and tick protection between doses of flea and tick medication. The gaps between purchases were shorter and the period of ectoparasite protection was larger for owners purchasing a 12-week product than for owners purchasing a monthly product.

Multimodal pain management protocol effectively relieves pain following simultaneous bilateral total knee arthroplasty (SBTKA) but is associated with administration of large amounts of opioids in the perioperative period. In this prospective, randomized, assessor-blinded, single-surgeon clinical trial, the goal was to validate the efficacy of an opioid-sparing protocol for SBTKA with a reduced opioid dose, while achieving similar pain relief with few adverse events. Fifty-six patients who had undergone SBTKA were randomly allocated to receive either an opioid-sparing or opioid-based protocol. The primary outcome parameters were visual analogue scale (VAS) scores at rest, with movement, and cumulative morphine dose, through time. Secondary outcome parameters included drug-related adverse events and range of motion with continuous passive motion device, through time. In the opioid-sparing group, a lower VAS score with movement at postoperative 24 and 72 h was observed compared with the opioid-based group, but the difference did not reach the minimal clinically importance difference. A reduced cumulative morphine dose was noted in the opioid-sparing group at postoperative 24, 48 and 72 h. In conclusion, the opioid-sparing protocol may be used as an alternative modality for pain management following SBTKA. Similar pain relief effects may be achieved utilizing a reduced cumulative opioid dose, with few opioid related adverse events.

Background: Capillaria aerophila and Capillaria boehmi parasitize the respiratory system of wild and domestic carnivores. Capillaria aerophila inhabits the trachea and bronchi of dogs and cats, while C. boehmi affects the nasal cavities and sinuses of dogs. In dogs the infection may be subclinical or characterized by varying respiratory distress., Methods: The present study evaluated the efficacy of an oral formulation containing milbemycin oxime and afoxolaner (NEXGARD SPECTRA ® ) in dogs naturally infected with C. aerophila and/or C. boehmi from three enzootic areas of Italy. Dogs were enrolled pending fecal examination and molecular confirmation of respiratory capillarioses. Dogs were allocated in two groups: Group 1 (G1, 25 dogs), treated with a negative control product with no anthelmintic activity (afoxolaner, NEXGARD ® ), and Group 2 (G2, 26 dogs), treated with NEXGARD SPECTRA ® . At the day of treatment administration (Day 0), all dogs were clinically examined. Dogs were again subjected to clinical and fecal examinations at Days 28 (± 4) and 56 (± 2). The primary criterion for treatment efficacy was the reduction of fecal Capillaria egg counts in G2 compared with G1. The regression of/recovery from baseline clinical signs was considered as a further efficacy criterion., Results: Percentage reduction of fecal Capillaria egg counts in the NEXGARD SPECTRA ® group compared to the control group was > 97% on Day 28 and 100% on Day 56, respectively (p < 0.05 for both time points). Twelve of the 13 dogs in the NEXGARD SPECTRA ® group with respiratory signs prior to treatment were free of clinical signs at the end of the study. Conversely, the six control group dogs with respiratory signs prior to treatment remained symptomatic., Conclusions: Results of the present study showed that NEXGARD SPECTRA® was safe and highly efficacious in the reduction of C. aerophila and C. boehmi eggs after one treatment with a complete reduction of the egg output after the second administration associated with a recovery from respiratory signs.

Objective: To compare efficacy and safety of parecoxib and paracetamol for treatment of acute renal colic due to ureteric stones., Materials and Methods: A randomized, double blinded, controlled trial included adult patients presented to emergency department with acute renal colic due to ureteric calculi between June 2019 and August 2020. Patients with hypersensitivity to either drug, peptic ulcer, coronary ischemia, peripheral vascular or cerebrovascular disease, hepatic impairment (Child-Pugh score >10) or chronic kidney disease stage 4 or 5 were excluded. Eligible patients were randomized to group 1 who received 1g intravenous Paracetamol infusion or group 2 who received 40mg intravenous Parecoxib infusion. Pain analogue score was evaluated before treatment and 30 minutes afterwards. The primary endpoint was the need for rescue analgesia for persistent pain. Safety was evaluated by the incidence of adverse events., Results: The study included 203 patients (102 in group 1 and 101 in group 2). Pretreatment patients' data were comparable for both groups. The mean pain analogue score decrease from 7.6 to 3.8 in paracetamol group (P <.001) and from 7.8 to 3.4 in parecoxib group (P <.001). Rescue analgesia were needed in 36 patients (35.3%) in paracetamol group and 27 patients (26.7%) in parecoxib group (P = .187). Minor adverse events developed in 2 patients (2%) in paracetamol group and 3 patients (3%) in parecoxib group (P=0.683)., Conclusion: Paracetamol and Parecoxib were effective for treatment for patient with acute renal colic. Both treatments showed comparable results in reduction of pain and need for rescue analgesia with minimal adverse events., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The feline lungworm Aelurostrongylus abstrusus affects the lower respiratory tract in cats worldwide. As infections may lead to chronic respiratory changes or even death, preventive treatment in cats with outdoor access is warranted., Methods: The preventive efficacy of a spot-on solution (Bravecto® Plus spot-on solution for cats, MSD) against cat aelurostrongylosis was evaluated using three different preventive treatment regimes in a negative controlled, randomized and partially blinded laboratory efficacy study with 31 purposed-bred cats. The minimum recommended dose of 2.0 mg moxidectin + 40 mg fluralaner/kg bodyweight was applied once 12 (Group [G]1), 8 (G2) or 4 (G3) weeks before experimental infection with 300 third-stage larvae (L3) of A. abstrusus. Another group served as untreated control (G4). Individual faecal samples were analysed as of day 30 post infection (pi) to monitor larvae excretion. Necropsy was performed at days 47-50 pi. The lungs were examined macroscopically for pathological findings and (pre-)adult worms were counted to assess preventive efficacy., Results: Beginning at day 32-40 pi, all cats of the control group were constantly shedding larvae of A. abstrusus, whereas only one animal of G1 excreted larvae at several consecutive days. In addition, two cats of G1 and G3 and three of G2 were positive on a single occasion. The geometric mean (GM) of the maximum number of excreted larvae was 7574.29 in the control group compared to 1.10 (G1), 1.19 (G2) and 0.53 (G3), resulting in a GM reduction of > 99.9% in all treatment groups. All lungs of the control animals showed severe or very severe alterations at necropsy, while in 94.44% of the treated cats lung pathology was rated as absent or mild. The GM number of (pre-)adult A. abstrusus retrieved from the lungs was 26.57 in the control group, 0.09 in G1 and 0.00 in G2 and G3. Thus, GM worm count reduction was 99.66% in G1 and 100% in G2 and G3., Conclusions: A single application of Bravecto® Plus spot-on solution at a dose of 2.0 mg moxidectin + 40 mg fluralaner/kg bodyweight reliably prevents cat aelurostrongylosis for at least 12 weeks.

Objective: To evaluate safety and tolerability and exploratory efficacy end points for gaboxadol (OV101) compared with placebo in individuals with Angelman syndrome (AS)., Methods: Gaboxadol is a highly selective orthosteric agonist that activates δ-subunit-containing extrasynaptic γ-aminobutyric acid type A (GABA A ) receptors. In a multicenter, double-blind, placebo-controlled, parallel-group trial, adolescent and adult individuals with a molecular diagnosis of AS were randomized (1:1:1) to 1 of 3 dosing regimens for a duration of 12 weeks: placebo morning dose and gaboxadol 15 mg evening dose (qd), gaboxadol 10 mg morning dose and 15 mg evening dose (bid), or placebo morning and evening dose. Safety and tolerability were monitored throughout the study. Prespecified exploratory efficacy end points included adapted Clinical Global Impression-Severity and Clinical Global Impression-Improvement (CGI-I) scales, which documented the clinical severity at baseline and change after treatment, respectively., Results: Eighty-eight individuals were randomized. Of 87 individuals (aged 13-45 years) who received at least 1 dose of study drug, 78 (90%) completed the study. Most adverse events (AEs) were mild to moderate, and no life-threatening AEs were reported. Efficacy of gaboxadol, as measured by CGI-I improvement in an exploratory analysis, was observed in gaboxadol qd vs placebo ( p = 0.0006)., Conclusion: After 12 weeks of treatment, gaboxadol was found to be generally well-tolerated with a favorable safety profile. The efficacy as measured by the AS-adapted CGI-I scale warrants further studies., Clinicaltrialsgov Identifier: NCT02996305., Classification of Evidence: This study provides Class I evidence that, for individuals with AS, gaboxadol is generally safe and well-tolerated., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose: Berzosertib (formerly M6620) is the first-in-class inhibitor of ataxia-telangiectasia and Rad3-related protein, a key component of the DNA damage response, and being developed in combination with chemotherapy for the treatment of patients with advanced cancers. The objectives of this analysis were to characterize the pharmacokinetics (PK) of berzosertib across multiple studies and parts, estimate inter-individual variability, and identify covariates that could explain such variability., Methods: A population PK analysis was performed using the combined dataset from two phase I clinical studies (NCT02157792, EudraCT 2013-005100-34) in patients with advanced cancers receiving an intravenous infusion of berzosertib alone or in combination with chemotherapy. The analysis included data from 240 patients across 11 dose levels (18-480 mg/m 2 ). Plasma concentration data were modeled with a non-linear mixed-effect approach and clinical covariates were evaluated., Results: PK data were best described by a two-compartment linear model. For a typical patient, the estimated clearance (CL) and intercompartmental CL were 65 L/h and 295 L/h, respectively, with central and peripheral volumes estimated to be 118 L and 1030 L, respectively. Several intrinsic factors were found to influence berzosertib PK, but none were considered clinically meaningful due to a very limited effect. Model simulations indicated that concentrations of berzosertib exceeded p-Chk1 (proximal pharmacodynamic biomarker) IC 50 at recommended phase II doses in combination with carboplatin, cisplatin, and gemcitabine., Conclusions: There was no evidence of a clinically significant PK interaction between berzosertib and evaluated chemo-combinations. The covariate analysis did not highlight any need for dosing adjustments in the population studied to date., Clinical Trial Information: NCT02157792, EudraCT 2013-005100-34.

The majority of schizophrenia patients have cognitive deficits as a separate symptom cluster independent of positive or negative symptoms. Current medicines, unfortunately, cannot provide clear benefits for cognitive symptoms in patients. Recent findings showed decreased α7 nicotinic acetylcholine receptor (nAChR) expressions in subjects with schizophrenia. α7 nAChR full/partial agonists and positive allosteric modulators (PAMs) may be valuable drug candidates to treat cognitive deficits of disease. This study comparatively investigated the effect of α7 nAChR agonist (A-582941), type I PAM (CCMI), type II PAM (PNU-120596), and the antipsychotic drug (clozapine) on behavioral, molecular, and immunohistochemical parameters in a subchronic MK-801 model of schizophrenia in male rats. Novel object recognition (NOR) and Morris water maze (MWM) tests were performed to evaluate recognition and spatial memories, respectively. Gene and protein expressions of parvalbumin, glutamic acid decarboxylase-67 (GAD67), and α7 nAChR were examined in the rats' hippocampal tissue. The subchronic MK-801 administration produced cognitive deficits in the NOR and MWM tests. It also decreased the protein and gene expressions of parvalbumin, GAD67, and α7 nAChR in the hippocampus. Clozapine, A-582941, and PNU-120596 but not CCMI increased the parvalbumin and α7 nAChR expressions and provided benefits in recognition memory. Interestingly, clozapine and CCMI restored the MK-801 induced deficits on GAD1 expression and spatial memory while A-582941 and PNU-120596 were ineffective. These results indicated that α7 nAChR agonist, type I and type II PAMs may provide benefits in different types of cognitive deficits rather than a complete treatment in schizophrenia., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Sarcoptic mange causes significant animal welfare and occasional conservation concerns for bare-nosed wombats (Vombatus ursinus) throughout their range. To date, in situ chemotherapeutic interventions have involved macrocytic lactones, but their short duration of action and need for frequent re-administration has limited treatment success. Fluralaner (Bravecto®; MSD Animal Health), a novel isoxazoline class ectoparasiticide, has several advantageous properties that may overcome such limitations., Methods: Fluralaner was administered topically at 25 mg/kg (n = 5) and 85 mg/kg (n = 2) to healthy captive bare-nosed wombats. Safety was assessed over 12 weeks by clinical observation and monitoring of haematological and biochemical parameters. Fluralaner plasma pharmacokinetics were quantified using ultra-performance liquid chromatography and tandem mass spectrometry. Efficacy was evaluated through clinical assessment of response to treatment, including mange and body condition scoring, for 15 weeks after topical administration of 25 mg/kg fluralaner to sarcoptic mange-affected wild bare-nosed wombats (n = 3). Duration of action was determined through analysis of pharmacokinetic parameters and visual inspection of study subjects for ticks during the monitoring period. Methods for diluting fluralaner to enable 'pour-on' application were compared, and an economic and treatment effort analysis of fluralaner relative to moxidectin was undertaken., Results: No deleterious health impacts were detected following fluralaner administration. Fluralaner was absorbed and remained quantifiable in plasma throughout the monitoring period. For the 25 mg/kg and 85 mg/kg treatment groups, the respective means for maximum recorded plasma concentrations (C max ) were 6.2 and 16.4 ng/ml; for maximum recorded times to C max , 3.0 and 37.5 days; and for plasma elimination half-lives, 40.1 and 166.5 days. Clinical resolution of sarcoptic mange was observed in all study animals within 3-4 weeks of treatment, and all wombats remained tick-free for 15 weeks. A suitable product for diluting fluralaner into a 'pour-on' was found. Treatment costs were competitive, and predicted treatment effort was substantially lower relative to moxidectin., Conclusions: Fluralaner appears to be a safe and efficacious treatment for sarcoptic mange in the bare-nosed wombat, with a single dose lasting over 1-3 months. It has economic and treatment-effort-related advantages over moxidectin, the most commonly used alternative. We recommend a dose of 25 mg/kg fluralaner and, based on the conservative assumption that at least 50% of a dose makes dermal contact, Bravecto Spot-On for Large Dogs as the most appropriate formulation for adult bare-nosed wombats.

Farnesoid X receptor (FXR) agonists are emerging as potential therapeutics for the treatment of various metabolic diseases, as they display multiple effects on bile acid, lipid, and glucose homeostasis. Although the steroidal obeticholic acid, a full FXR agonist, was recently approved, several side effects probably due to insufficient pharmacological selectivity impede its further clinical application. Activating FXR in a partial manner is therefore crucial in the development of novel FXR modulators. Our efforts focusing on isoxazole-type FXR agonists, common nonsteroidal agonists for FXR, led to the discovery a series of novel FXR agonists bearing aryl urea moieties through structural simplification of LJN452 (phase 2). Encouragingly, compound 11k was discovered as a potent FXR agonist which exhibited similar FXR agonism potency but lower maximum efficacy compared to full agonists GW4064 and LJN452 in cell-based FXR transactivation assay. Extensive in vitro evaluation further confirmed partial efficacy of 11k in cellular FXR-dependent gene modulation, and revealed its lipid-reducing activity. More importantly, orally administration of 11k in mice exhibited desirable pharmacokinetic characters resulting in promising in vivo FXR agonistic activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The objective of this experimental study was to assess the insecticidal efficacy of afoxolaner (NexGard ® ) against bedbugs (Cimex lectularius) on dogs. For each challenge, 20 bedbugs were placed in two chambers positioned in contact to the dog's skin for 15 min, after which live fed parasites were counted and incubated for survival evaluations. On Day 0, 7 dogs assigned to the treated group were administered afoxolaner orally at the registered dose. All 14 dogs were challenged on Days 1, 7, 14, 21 and 28, and the collected live fed C. lectularius incubated for 72 h (Day 1), and 72 h and 96 h (Days 7, 14, 21 and 28) for survival evaluation. The percent feeding in the control group ranged from 95% to 98.6% and the percent of live fed bedbugs at 96 h ranged from 99.3% to 100% in the control group, demonstrating the viability of the strain and their capacity to feed on dogs. Significantly fewer live fed bedbugs were counted in the treated group, compared to the control group, at all time-points. The reduction of live fed C. lectularius in the afoxolaner group was 41.4% at 72 h after the Day 1 challenge, and 77.2%, 82.7%, 85.0% and 63.5% at 96 h after the Days 7, 14, 21 and 28 challenges, respectively. It is hypothesized that monthly treatment of dogs with afoxolaner could help in preventing a bed bug population from installing in a household if bedbugs bite dogs in the presence of humans., (© F. Beugnet et al., published by EDP Sciences, 2021.)

Background: Fluralaner is a novel isoxazoline compound and the only systemically distributed ectoparasiticide approved in the United States for redosing at up to 12-week intervals for flea and tick control in cats. Other feline ectoparasiticides, including other systemic isoxazolines, are approved for redosing at monthly intervals. A survey developed in 2016 to assess the satisfaction, preference, and adherence of dog owners prescribed fluralaner as an ectoparasiticide with the treatment and veterinary flea and tick protection recommendations was adapted for completion by cat owners in the USA., Aim: The study objective was to use cat-owner survey data obtained at US veterinary practices to assess client satisfaction and utilization practices for fluralaner, and to evaluate owner adherence to current flea and tick control recommendations., Methods: US veterinary practices ( n = 26) were asked to obtain completed surveys for up to 25 active clients who were currently treating their cats with a topical preparation of fluralaner for flea and tick control. Clients who had previously used flea and tick products for cats other than fluralaner were enrolled in the study. Participating cat owners completed an 11-question survey on their satisfaction with, preference for, and adherence to treatment recommendations for topically applied fluralaner as a feline flea and tick control medication., Results: The average cat in this study had a mean (± SD) body weight of 5.1 (± 0.9) kg and was 7.1 (±1.4) years old. Most cats lived in a home versus an apartment and more than half spent some time outside. Satisfaction was assessed with a 5-point Likert scale, with nearly all cat owners (97%) indicating that they were satisfied or very satisfied with fluralaner. Most of them (66%) had previously used other monthly flea and tick products for cats. Owners were not excluded if they had previously used a canine flea and tick product. The extended dosing interval up to 12 weeks was the most frequently selected benefit of fluralaner. Nearly 9 out of 10 respondents indicated they readministered fluralaner mostly on time or delayed by a few days, and most said they were more likely to give a repeat dose of fluralaner at the recommended redosing interval compared to monthly products. 87% of the responding cat owners preferred topical fluralaner over the monthly flea and tick products they had used., Conclusion: The extended dosing interval of up to 12 weeks was the leading preference factor and the key driver of user satisfaction with fluralaner leading to improved adherence to redosing recommendations. Cat owners said they were more likely to administer fluralaner at the recommended redosing interval compared to monthly products, indicating that less frequent redosing contributes to improved adherence., Competing Interests: The authors are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, which provided the funding for the study.

The poultry red mite (PRM), Dermanyssus gallinae, a potential vector of pathogens to animals and humans, causes impaired bird welfare. A study investigated changes in behavioural variables, physiological biomarkers, and health parameters following acaricidal treatment of PRM infestation of laying hens on a commercial farm. Mite traps determined the challenge to 12,700 hens before and after drinking water administration of the acaricide, fluralaner (Exzolt®, 0.5 mg/kg; Weeks 0 and 1). Weekly daytime direct observations and night-time video recordings monitored bird behaviours from Weeks -6 through +6. Blood samples were collected from randomly-selected birds (Weeks -6, -1, and +6). Following treatment, mite count reductions (>99%) were statistically significant (P < 0.0001), as were night-time reductions in the percent of hens showing activity, preening, head scratching (all P < 0.0001), and head shaking (P = 0.0007). Significant daytime reductions were observed in preening and head scratching (both P < 0.0001), head shaking (P = 0.0389), severe feather pecking (P = 0.0002), and aggressive behaviour (P = 0.0165). Post-treatment, comb wounds were significantly reduced (P = 0.0127), and comb colour was significantly improved (P < 0.0001). Heterophil/lymphocyte ratio was significantly reduced at Weeks 1 and 6 (P = 0.0009 and P < 0.0001, respectively). At Week 6, blood corticosterone (P = 0.0041) and total oxidant status (P < 0.0001) were significantly reduced, and haemoglobin and mean corpuscular haemoglobin significantly increased (P < 0.0001). Farm production records indicated that those post-treatment improvements were accompanied by significant reductions in weekly mortality rate (P = 0.0169), and significant recovery in mean weekly egg weights (P < 0.0001) and laying rate (P < 0.0001). The improvements in behavioural variables, physiological biomarkers, and health parameters that were observed following the elimination of PRM on a commercial farm indicate that infestations can be a cause of reduced hen welfare., Competing Interests: The authors have read the journal’s policy and have the following competing interests: MSD Animal Health Innovation GmbH provided funds used for this study to the Autonomous University of Barcelona (UAB) where the investigator and first author DT is employed. EZ, IP, RD and ET are employees of MSD Animal Health. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Exzolt® (fluralaner) is manufactured by MSD Animal Health. There are no other marketed products associated with this research to declare.

A veterinarian and pet owner survey (Project Jake) examined the use and safety of isoxazoline parasiticides given to dogs. Data were received during August 1-31, 2018 from a total of 2,751 survey responses. Forty-two percent (1,157) reported no flea treatment or adverse events (AE), while 58% (1594) had been treated with some parasiticide for flea control, and of those that received a parasiticide, the majority, or 83% (1,325), received an isooxazoline. When any flea treatment was given, AE were reported for 66.6% of respondents, with no apparent AE noted for 36.1%. Project Jake findings were compared to a retrospective analysis of publicly available Food and Drug Administration (FDA) and European Medicines Agency (EMA) reported AE. The number of total AE reported to FDA and EMA were comparable, although a 7 to 10 times higher occurrence of death and seizures was reported from the EMA or from outside the United States (US). Serious AE responses for death, seizures and neurological effects reported in our survey were higher than the FDA but moderately lower than the EMA reports. These sizable global data sets combined with this pre- and post-parasiticide administration survey indicated that isoxazoline neurotoxicity was not flea- and tick-specific. Post-marketing serious AE were much higher than in Investigational New Drug (IND) submissions. Although the labels have recently been updated, dogs, cats and their caregivers remain impacted by their use. These aggregate data reports support the need for continued cross-species studies and critical review of product labelling by regulatory agencies and manufacturers., (© 2020 The Authors. Veterinary Medicine and Science Published by John Wiley & Sons Ltd.)

Background: Successful canine sarcoptic mange treatment requires immediate efficacy to eliminate active mites, and sustained activity to prevent re-infestation from in-contact animals and fomites. With extended acaricidal activity, fluralaner has been shown to be effective for treating this disease. To confirm this potential under field conditions, two fluralaner formulations were administered to mite-infested, client-owned dogs., Methods: Households qualified for inclusion if they had at least one dog positive for Sarcoptes scabiei mites, confirmed by skin scraping, and at least one dog with clinical signs evocative of sarcoptic mange. Households were allocated to groups of dogs to receive a single treatment with either oral (Bravecto ® chewable tablets, MSD Animal Health) or topical (Bravecto ® Spot-on, MSD Animal Health), fluralaner at a dose of ≥ 25 mg/kg (range 25-56 mg/kg) on Day 0, or two treatments with oral sarolaner (Simparica ® tablets, Zoetis) (Days 0 and 28) at ≥ 2 mg/kg (2-4 mg/kg). All dogs in each household were treated with the same product. On the enrolment day and subsequently on Days 28, 56 and 84, deep skin scrapings were taken from at least five different body areas judged to be most likely to have active mite infestation. At each visit, the dog's mange-associated skin lesions were recorded, and pruritus level was assessed., Results: There were 98 participating households and 135 dogs enrolled across Albania, France, Italy and Portugal. On Day 28, more than 90% of dogs in each group were negative for mites. On Days 56 and 84, all study dogs were free of mites and most dermatological signs of sarcoptic mange had resolved. There were no treatment-related adverse events in any group., Conclusions: A single treatment of client-owned, sarcoptic mange-affected dogs with either fluralaner chewable tablets or fluralaner spot-on formulation proved a safe and effective treatment of infestations with S. scabiei var. canis, maintained through 84 days (12 weeks) after treatment.

Introduction: Schizophrenia has a prevalence of approximately 1% in the general population, with 15.2 per 100,000 persons affected. Iloperidone is a second-generation antipsychotic drug approved for the treatment of schizophrenia in adults. It acts primarily by D2/5HT2a receptor antagonism, with greater affinity for the 5HT2a receptor than for the D2 receptor., Areas Covered: This article discusses iloperidone and aims to provide useful information for clinicians to determine which circumstances would best suit the use of iloperidone to treat schizophrenic patients. In this review, the authors briefly discuss schizophrenia and its treatment, before they discuss properties of iloperidone, its indications, approval process, and adverse effects. Finally, the authors review the specific strengths and weaknesses of the medication., Expert Opinion: Iloperidone would be an attractive option in patients who are particularly prone to EPS, or who are showing prominent negative symptoms, as well as cognitive deficits. Its availability only in an oral formulation makes it a better option for patients with good medication adherence, and though it could be useful in patients prone to weight gain or hepatic dysfunction on other second generation antipsychotics, it should be used with caution in patients prone to side effects related to alpha adrenergic blockade.

Purpose: Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin., Patients and Methods: This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies., Results: Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m 2 . A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m 2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate., Conclusion: To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed.

Background: Evidence for the use of short-term daily parenteral parecoxib for refractory or uncontrolled non-surgical cancer pain is limited. This study aimed to characterise the real-world off-label use and report on clinical experiences in an Australian cancer cohort., Methods: Eligible patients received at least one dose of parecoxib of an intended three-day course between October 2015 and December 2018. Data were collected to characterise the parecoxib treatment cohort (cancer diagnosis, metastases, sites and types of pain and prior analgesia). Parecoxib-related adverse events, pain scores (worst and median), and concurrent opioid use were assessed at 24 h pre (T0) and 24 (T1), 48 (T2), 72 (T3) and 96 h (T4) post first parecoxib dose., Results: Sixty-five patients (39 males and 26 females) and 68 courses of parecoxib (three patients treated twice) were included in analyses: metastatic disease (86%), bone pain (54%) and taking ≥3 classes of analgesic medications (69%). Pain types varied (46% non-specific, 22% neuropathic and 32% other). Most (94%) received parecoxib by subcutaneous administration. Following parecoxib, median 24-h pain scores and worst pain scores improved for 59% (40/68) and 50% (34/68) of patients, respectively. In the first 24 h (T0 to T1), median (4 vs. 2, p < 0.01) and worst (6 vs. 5, p < 0.01) pain scores were reduced and sustained to T4 (4 vs. 2.5, p = 0.01). Breakthrough analgesia requirements reduced for 63% (43/68) of patients, while total concurrent opioid use remained constant. Mean/median oral morphine equivalence for T0 vs. T1 was 111 mg/75 mg vs. 162 mg/90 mg, (p > 0.8). Two patients ceased parecoxib due to renal/liver function abnormalities and two experienced mild injection-site reactions., Conclusions: In this real-world study, parecoxib was utilised as adjunctive therapy in a select patient cohort to contribute to reduced pain scores with no new safety signals. Prospective randomised studies in larger cohorts would improve understanding of the effects of parecoxib.

Background: An extended duration flea and tick medication of the isoxazoline class (fluralaner) was introduced in 2014 in the United States and other countries. A survey was developed in 2016 to gauge dog owner adherence with veterinary recommendations around the administration of preventive flea and tick medications. Current fluralaner-using dog owners were also asked to compare their experience with opinions on monthly flea and tick products., Aim: To survey dog owners who were current users of fluralaner on their opinions, experiences, and attitudes around the administration of flea and tick medications to their dogs in light of current veterinarian recommendations., Methods: Dog owners in the United States (US), United Kingdom (UK), and Australia that gave fluralaner oral chews to their dogs were asked to compare their experience using fluralaner (12-week dosing) and monthly flea and tick medications. The survey responses of dog owners in the UK and Australia were compared against responses to a similar survey conducted in the US in 2017. Surveys were completed by dog owners who were in the clinic for any reason other than a sickness visit. Additionally, veterinarians that prescribed fluralaner from all three countries provided their annual flea and tick treatment recommendation for dogs., Results: A sample of veterinarians from the US, UK, and Australia that prescribe fluralaner recommend that dog owners obtain approximately 12 months of flea protection per year and 9-12 months of tick protection per year. A variable proportion of owners (22%-90%) reported that their dog participates in outdoor and social activities associated with an increased flea and tick exposure risk. A similarly variable proportion of owners reported prior experience of finding fleas (24%-50%) or ticks (18%-35%) on their dogs. All participating owners treated their dogs currently with fluralaner and most (68%-77%) had previously treated their dog with monthly flea and tick products. The convenience of 12-week dosing and less frequent dosing were the most frequently identified product qualities associated with their choice of an extended effect flea and tick treatment., Conclusion: Most veterinarians surveyed in this survey recommended year-round use of a flea and tick medication for dogs in the US, UK, and Australia. Dog owners recalled the veterinary recommendation for flea and tick prevention as 8-10 months per year. Most dog owners from the clinics in the US, UK, and Australia had used shorter-acting (monthly) flea/tick medications previously. The majority of those who currently gave fluralaner doses to their dogs were "satisfied" or "very satisfied" with the extended duration flea and tick product. Preference for a 12-week duration medication over monthly re-treatment was also high (82%-92%) in all three countries and was associated with convenience., Competing Interests: All authors are employees of MSD Animal Health. Study funding was provided by MSD Animal Health.

Background: To investigate the effect of intravenous injection of dexmedetomidine combined with parecoxib sodium on sedation and anxiety and stress response of tracheal intubation in patients undergoing functional endoscopic sinus surgery., Methods: One hundred twenty patients undergoing endoscopic sinus surgery were randomly divided into four groups: group DP, group D, group P and group N. The blood pressure (BP), heart rate (HR), blood oxygen saturation (SPO2), EEG, bispectral index (BIS), Ramsay sedation score and state anxiety questionnaire (SAI) were recorded before administration (T0), 10 min (T1), 20 min (T2) and 30 min (T3) after administration. After 30 min, endotracheal intubation was performed after anesthesia induction. The BP, HR, SPO2 were recorded 1 min before intubation (T4), intubation (T5), 3 min (T6) after intubation, 5 min (T7) after intubation, and blood samples were collected from patients before administration and after intubation 2 min to detect serum cortisol (Cor), adrenalin (E) norepinephrine (NE) and blood glucose (BS)., Results: There was no significant difference in Ramsay sedation score before anesthesia, but the Ramsay sedation score in group D、DP was significantly higher than that in group P and group N, the BIS, BP, HR and anxiety scores were significantly lower than those in the group P and group N (p < 0.05). There was no significant difference in Ramsay sedation score, BIS value, anxiety score and BP, HR between group D and group DP (p > 0.05). Compared with T4, there was no significant difference in BIS and BP, HR in group D, group DP and group P (p > 0.05), but the BIS, BP and HR in group N were significantly higher than T4, (p < 0.05). Three minutes after intubation there was no statistical difference in the changes of Cor, E, NE and BS values compared with before intubation in group P and group DP (p > 0.05), but the changes of Cor, E, NE and BS values were significantly lower than that in group N (p < 0.05). Compared with T0, the values of NE, E, Cor, BS decreased in group D, DP and P at T4, group DP decreased more significantly than group D (p < 0.05). while the NE, E, Cor, BS of T6 are at the same level as the base value. In group N, the NE, E, Cor, BS of T4 were at the same level of T0, but significantly higher at T6.And at T6, NE and E in group D, P and N were significantly different from those in group DP (p < 0.05)., Conclusion: Preoperative intravenous infusion of dexmedetomidine combined with parecoxib sodium by functional nasal endoscopy can not only calm and resist anxiety, but also better prevent stress response of endotracheal intubation, which is a safe and effective way of preoperative medication., Trial Registration: ChiCTR-OPN-17010444 . Prospectively registered on 16 January 2017.

Sarcoptic mange is a pruritic, contagious, ectoparasitic skin disease that affects mammals, including the domestic dog. The objective of this study was to evaluate and compare the efficacy of afoxolaner plus milbemycin oxime (NexGard Spectra) and afoxolaner alone (NexGard) as treatments for sarcoptic mange in naturally infested dogs. A total of 142 dogs naturally infested with Sarcoptes scabiei was evaluated. The dogs were diagnosed by microscopic examinations of skin scrapings. The dogs were divided into 2 groups: 96 dogs were treated with a combined dosage of 2.50 to 5.36 mg/kg body weight (BW) of afoxolaner and 0.50 to 1.07 mg/kg BW of milbemycin oxime and 46 dogs were treated with 2.50 mg/kg BW of afoxolaner alone. The presence or absence of pruritus and lesions were evaluated using an analogous scale on days 7, 14, 21, 28, and 56 after receiving the treatment. Data obtained were analyzed by Student's t -test ( P ≤ 0.05). The single oral treatment of afoxolaner plus milbemycin oxime resulted in a significant reduction in pruritus of 87.4% at 28 d after treatment ( P ≤ 0.05). Resolution of the lesions after treatment was variable, with a significant decrease ( P ≤ 0.05) observed within the first 14 d, although this parameter continued to improve until the end of the study on day 28, when a decrease of 96% was observed. By the end of the study, a single dose of either the afoxolaner alone or the afoxolaner combined with milbemycin oxime was effective in significantly reducing the signs associated with sarcoptic mange during a 56-day evaluation period., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

Background: Amblyomma americanum and Rhipicephalus sanguineus (sensu lato) nymphs commonly feed on and transmit pathogens to dogs (Canis familiaris). Control of immature and adult tick life stages is necessary to fully protect animals. We evaluated efficacy of oral fluralaner (Bravecto ® ) against induced infestations with A. americanum and R. sanguineus (s.l.) nymphs on dogs in two experiments., Methods: In each experiment, 10 dogs were administered oral fluralaner chewable tablets one time on Day 0 at a targeted minimum dose of 25 mg/kg body weight and 10 dogs remained non-treated controls. Dogs were infested with two groups of 50 A. americanum nymphs and two groups of 50 R. sanguineus (s.l.) nymphs on Days -1, 6, 28, 56 and 84. At 48 h and 72 h post-infestation, nymphs were collected from dogs, assessed as live or dead, and enumerated into categories defining attachment and engorgement status. Fluralaner efficacy was determined in separate analyses against all live nymphs and against live-fed nymphs, i.e. live nymphs that were attached to dogs at the time of collection and/or were engorged. Fluralaner was considered effective when mean numbers of live ticks were reduced in fluralaner-treated dogs by ≥ 90%., Results: Fluralaner efficacy against all live and live-fed A. americanum nymphs in the first experiment was > 94% on all collection days. Efficacy against all live R. sanguineus (s.l.) nymphs in the first experiment was  > 96% on all collection days  excluding the 48 h counts for infestations on Days 28 (83.7%), 56 (82.9%) and 84 (86.7%); efficacy against live-fed R. sanguineus (s.l.) nymphs was > 95% on all 48 h/72 h count days. Fluralaner efficacy against all live A. americanum nymphs in the second experiment was > 93% on all collection days for 8 weeks excluding the 48 h count for infestation on Day 56 (87.8%); efficacy against live-fed A. americanum nymphs was > 91% on all count days for 8 weeks. Efficacy against all live R. sanguineus (s.l.) nymphs in the  second experiment was > 91% on all 72 h collection days  except for infestations on Days 28 (76.8%) and 56 (86.3%); efficacy against live-fed R. sanguineus (s.l.) nymphs was 100% on all 72 h count days., Conclusions: A single administration of oral fluralaner to dogs is effective against A. americanum and R. sanguineus (s.l.) nymphs for up to 12 weeks.

Background: Recent reports indicate that the isoxazoline compounds have the potential to provide safe and effective treatment of canine generalized demodicosis, a condition that has been traditionally difficult to cure. Controlled field studies are needed to confirm this potential. A study was therefore initiated to investigate the efficacy of a single oral or spot-on treatment with fluralaner, an isoxazoline, compared with multiple topical treatments with imidacloprid-moxidectin, in dogs naturally affected by generalized demodicosis., Methods: Veterinary clinics in 5 European countries enrolled 134 dogs diagnosed with generalized demodicosis. Dogs were randomized to treatment with either fluralaner chewables, fluralaner spot-on, or topical imidacloprid-moxidectin in a 2:2:1 ratio. Both fluralaner formulations were administered once, at the approved dose rate, on Day 0. Imidacloprid-moxidectin was administered per label on Day 0, and every 4 weeks, more frequently if necessary. At each visit (Days 0, 28, 56, 84), dogs were monitored for demodectic mites using deep skin scrapings and observed for health and for severity of skin lesions. Treatment was considered efficacious if more than 90% of the dogs were free of live mites at both Days 56 and 84., Results: Of 124 dogs completing the study, 57 were diagnosed with juvenile-onset demodicosis and 67 with the adult-onset form. A single treatment with oral or spot-on fluralaner was efficacious, each eliminating mites from at least 98.0% of treated dogs on Days 56 and 84. Against juvenile-onset demodicosis, efficacy of the oral and spot-on formulations was 96.0% and 100%, respectively, and against adult-onset demodicosis 100% and 96.7%. Multiple administrations of imidacloprid-moxidectin were not efficacious, eliminating mites from 87.5% of dogs (92.0% with juvenile-onset demodicosis cured; 81.8% with adult-onset demodicosis). All groups showed a marked reduction in skin lesions by Day 28, with continuing clinical improvement at each subsequent visit through Day 84. There were no treatment-related adverse events., Conclusions: A single administration of fluralaner chewables or fluralaner spot-on is highly effective against with juvenile-onset and adult-onset forms of generalized canine demodicosis. Topically applied imidacloprid-moxidectin at weekly to monthly intervals over the 84-day study did not achieve the proportion of mite-free dogs required to demonstrate efficacy.

Background: Postoperative opioid analgesia may cause respiratory depression. We assessed whether following total hip arthroplasty, placebo-adjusted reductions in morphine consumption at 48 hours with parecoxib (47.0%), propacetamol (35.1%) or parecoxib plus propacetamol (67.9%) translated into a reduction in hypoxemic events., Methods: This was a post hoc analysis of a randomized, placebo-controlled, noninferiority study. Patients were randomly assigned to receive intravenous parecoxib (40 mg twice daily), propacetamol (2 g 4 times daily), parecoxib plus propacetamol (40 mg twice daily + 2 g 4 times daily) or placebo. Dose, date and time of morphine administration via patient-controlled analgesia were monitored throughout the study. In patients not receiving supplemental oxygen, peripheral blood oxygenation was assessed continuously for 48 hours after surgery. Hypoxemia was defined as peripheral oxygen saturation less than 90%. The times and oximeter readings of hypoxemic events were recorded. Pearson correlation coefficient was used to assess for correlations between cumulative morphine consumption at 48 hours and mean number of hypoxemic events., Results: A significantly smaller proportion of patients who received the combined treatment with parecoxib and propacetamol had hypoxemia versus placebo (2.8% v. 13.2%, p < 0.05), and the mean number of hypoxemic events was significantly smaller for parecoxib (0.12), propacetamol (0.06) and parecoxib plus propacetamol (0.03) versus placebo (0.36; all p < 0.05). There was no correlation between the reduction in cumulative morphine consumption at 48 hours and the mean number of hypoxemic events in any treatment group (all p > 0.1)., Conclusion: Following total hip arthroplasty, a greater than 70% reduction in morphine consumption may be necessary to translate into a corresponding reduction in hypoxemic events., Competing Interests: M. Essex, P. Salomon and S. Pan are employees of Pfizer and have stock or stock options with Pfizer. F. Camu has acted as consultant to pharmaceutical companies and health authorities, outside the submitted work. R. Cheung was an employee of Pfizer at the time of study conduct. No other competing interests were declared., (© 2020 Joule Inc. or its licensors.)