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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.)

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).)

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.

Although several ATR inhibitors are in development, there are unresolved questions regarding their differential potency, molecular signatures of patients with cancer for predicting activity, and most effective therapeutic combinations. Here, we elucidate how to improve ATR-based chemotherapy with the newly developed ATR inhibitor, M4344 using in vitro and in vivo models. The potency of M4344 was compared with the clinically developed ATR inhibitors BAY1895344, berzosertib, and ceralasertib. The anticancer activity of M4344 was investigated as monotherapy and combination with clinical DNA damaging agents in multiple cancer cell lines, patient-derived tumor organoids, and mouse xenograft models. We also elucidated the anticancer mechanisms and potential biomarkers for M4344. We demonstrate that M4344 is highly potent among the clinically developed ATR inhibitors. Replication stress (RepStress) and neuroendocrine (NE) gene expression signatures are significantly associated with a response to M4344 treatment. M4344 kills cancer cells by inducing cellular catastrophe and DNA damage. M4344 is highly synergistic with a broad range of DNA-targeting anticancer agents. It significantly synergizes with topotecan and irinotecan in patient-derived tumor organoids and xenograft models. Taken together, M4344 is a promising and highly potent ATR inhibitor. It enhances the activity of clinical DNA damaging agents commonly used in cancer treatment including topoisomerase inhibitors, gemcitabine, cisplatin, and talazoparib. RepStress and NE gene expression signatures can be exploited as predictive markers for M4344., (©2021 The Authors; Published by the American Association for Cancer Research.)

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).)

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.)

Background: Open cardiac surgical patients may experience severe acute poststernotomy pain. The ultrasound-guided Pecto-intercostal Fascial Block (PIFB) can cover anterior branches of intercostal nerves from T2 to T6. The aim of this study was to investigate the effect of bilateral PIFB in patients undergoing open cardiac surgery., Methods: A group of 108 patients were randomly allocated to either receive bilateral PIFB (PIFB group) or no nerve block (SALI group). The primary endpoint was postoperative pain. The secondary outcome measures included intraoperative and postoperative sufentanil and parecoxib consumption, time to extubation, time to first feces, length of stay in the ICU and the length of hospital stay. Insulin, glucose, insulin resistance and interleukin (IL)-6 at 1, 2, 3 days after surgery were mearsured. The homeostasis model assessment (HOMA-IR) was used to measure perioperative insulin resistance., Results: The PIFB group reported significantly less sufentanil and parecoxib consumption than the SALI group. Compared to the PIFB group, the SALI group had higher Numerical Rating Scale (NRS) pain scores at 24 h after operation both at rest and during coughing. The time to extubation, length of stay in the ICU and length of hospital stay were significantly decreased in the PIFB group compared with the SALI group. The PIFB group had a lower insulin, glucose, IL-6, HOMA-IR level than the SALI group 3 days after surgery., Conclusion: Bilateral PIFB provides effective analgesia and accelerates recovery in patients undergoing open cardiac surgery., Trial Registration: This study was registered in the Chinese Clinical Trial Registry ( ChiCTR 2000030609 ) on 08/03/2020.

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.

Background: Postoperative pain is common and may be severe. Postoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs) reduces patient opioid requirements and, in turn, may reduce the incidence and severity of opioid-induced adverse events (AEs)., Objectives: To assess the analgesic efficacy and adverse effects of single-dose intravenous ketorolac, compared with placebo or an active comparator, for moderate to severe postoperative pain in adults., Search Methods: We searched the following databases without language restrictions: CENTRAL, MEDLINE, Embase and LILACS on 20 April 2020. We checked clinical trials registers and reference lists of retrieved articles for additional studies., Selection Criteria: Randomized double-blind trials that compared a single postoperative dose of intravenous ketorolac with placebo or another active treatment, for treating acute postoperative pain in adults following any surgery., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane.  Our primary outcome was the number of participants in each arm achieving at least 50% pain relief over a four- and six-hour period. Our secondary outcomes were time to and number of participants using rescue medication; withdrawals due to lack of efficacy, adverse events (AEs), and for any other cause; and number of participants experiencing any AE, serious AEs (SAEs), and NSAID-related or opioid-related AEs. For subgroup analysis, we planned to analyze different doses of parenteral ketorolac separately and to analyze results based on the type of surgery performed. We assessed the certainty of evidence using GRADE., Main Results: We included 12 studies, involving 1905 participants undergoing various surgeries (pelvic/abdominal, dental, and orthopedic), with 17 to 83 participants receiving intravenous ketorolac in each study. Mean study population ages ranged from 22.5 years to 67.4 years. Most studies administered a dose of ketorolac of 30 mg; one study assessed 15 mg, and another administered 60 mg. Most studies had an unclear risk of bias for some domains, particularly allocation concealment and blinding, and a high risk of bias due to small sample size. The overall certainty of evidence for each outcome ranged from very low to moderate. Reasons for downgrading certainty included serious study limitations, inconsistency and imprecision. Ketorolac versus placebo Very low-certainty evidence from eight studies (658 participants) suggests that ketorolac results in a large increase in the number of participants achieving at least 50% pain relief over four hours compared to placebo, but the evidence is very uncertain (risk ratio (RR) 2.81, 95% confidence interval (CI) 1.80 to 4.37). The number needed to treat for one additional participant to benefit (NNTB) was 2.4 (95% CI 1.8 to 3.7). Low-certainty evidence from 10 studies (914 participants) demonstrates that ketorolac may result in a large increase in the number of participants achieving at least 50% pain relief over six hours compared to placebo (RR 3.26, 95% CI 1.93 to 5.51). The NNTB was 2.5 (95% CI 1.9 to 3.7). Among secondary outcomes, for time to rescue medication, moderate-certainty evidence comparing intravenous ketorolac versus placebo demonstrated a mean median of 271 minutes for ketorolac versus 104 minutes for placebo (6 studies, 633 participants). For the number of participants using rescue medication, very low-certainty evidence from five studies (417 participants) compared ketorolac with placebo. The RR was 0.60 (95% CI 0.36 to 1.00), that is, it did not demonstrate a difference between groups. Ketorolac probably results in a slight increase in total adverse event rates compared with placebo (74% versus 65%; 8 studies, 810 participants; RR 1.09, 95% CI 1.00 to 1.19; number needed to treat for an additional harmful event (NNTH) 16.7, 95% CI 8.3 to infinite, moderate-certainty evidence). Serious AEs were rare. Low-certainty evidence from eight studies (703 participants) did not demonstrate a difference in rates between ketorolac and placebo (RR 0.62, 95% CI 0.13 to 3.03). Ketorolac versus NSAIDs  Ketorolac was compared to parecoxib in four studies and diclofenac in two studies. For our primary outcome, over both four and six hours there was no evidence of a difference between intravenous ketorolac and another NSAID (low-certainty and moderate-certainty evidence, respectively). Over four hours, four studies (337 participants) produced an RR of 1.04 (95% CI 0.89 to 1.21) and over six hours, six studies (603 participants) produced an RR of 1.06 (95% CI 0.95 to 1.19). For time to rescue medication, low-certainty evidence from four studies (427 participants) suggested that participants receiving ketorolac waited an extra 35 minutes (mean median 331 minutes versus 296 minutes). For the number of participants using rescue medication, very low-certainty evidence from three studies (260 participants) compared ketorolac with another NSAID. The RR was 0.90 (95% CI 0.58 to 1.40), that is, there may be little or no difference between groups.   Ketorolac probably results in a slight increase in total adverse event rates compared with another NSAID (76% versus 68%, 5 studies, 516 participants; RR 1.11, 95% CI 1.00 to 1.23; NNTH 12.5, 95% CI 6.7 to infinite, moderate-certainty evidence). Serious AEs were rare. Low-certainty evidence from five studies (530 participants) did not demonstrate a difference in rates between ketorolac and another NSAID (RR 3.18, 95% CI 0.13 to 76.99). Only one of the five studies reported a single serious AE., Authors' Conclusions: The amount and certainty of evidence for the use of intravenous ketorolac as a treatment for postoperative pain varies across efficacy and safety outcomes and amongst comparators, from very low to moderate. The available evidence indicates that postoperative intravenous ketorolac administration may offer substantial pain relief for most patients, but further research may impact this estimate. Adverse events appear to occur at a slightly higher rate in comparison to placebo and to other NSAIDs. Insufficient information is available to assess whether intravenous ketorolac has a different rate of gastrointestinal or surgical-site bleeding, renal dysfunction, or cardiovascular events versus other NSAIDs. There was a lack of studies in cardiovascular surgeries and in elderly populations who may be at increased risk for adverse events., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

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.

Purpose: This study aimed to investigate the potential beneficial effects of periarticular injection (PAI) of multimodal drugs on the inflammatory response and joint function after hip arthroplasty in elderly patients with osteoporotic femoral neck fractures., Methods: Fifty six elderly patients with unilateral osteoporotic femoral neck fractures were randomly allocated to 2 groups: the PAI group, which received the multimodal drug PAI intraoperatively before incision closure, and the control group, which received an injection of saline at the same time as placebo. The C-reactive protein (CRP), interleukin-1β (IL-1β), and IL-6 levels as well as the erythrocyte sedimentation rate (ESR) in peripheral venous blood samples were measured, along with the Visual Analogue Scale (VAS) score with activity and Harris hip score preoperation at 1, 2, 4, 7, and 14 days as well as 1 and 3 months post-operation., Results: The 2 groups were comparable in sex and age, and no significant differences were observed in the preoperative CRP, IL-1β, and IL-6 levels, ESR, VAS score, or Harris hip score between the 2 groups (all P > .05). However, during the postoperative period, the PAI group exhibited significantly lower levels of CRP, IL-1β, and IL-6 as well as a lower ERS and VAS score compared with the control group (P < .05), while the Harris hip score was significantly higher postoperatively in the PAI group (P < .05)., Conclusion: Multimodal drug PAI can alleviate the inflammatory response and enhance hip function recovery after hip arthroplasty in elderly patients with osteoporotic femoral neck fractures., Competing Interests: The authors have no conflicts of interest to disclosure., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

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.

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.

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.

Background: The Australian paralysis tick, Ixodes holocyclus, causes tick paralysis in dogs and cats in the eastern coastal regions of Australia. Prevention is the best option to protect dogs against this potentially fatal disease and sarolaner provides rapid and sustained efficacy against I. holocyclus. In this laboratory study, the efficacy of two combination endectocides containing sarolaner + moxidectin + pyrantel (Simparica Trio™) and afoxolaner + milbemycin (NexGard Spectra ® ) was evaluated against an artificial infestation of I. holocyclus., Methods: Twenty-four (n =24) foxhounds were randomly allocated to three treatment groups and artificially infested with 30 adult female viable ticks on Days - 1, 7, 14, 21, 28 and 35. On Day 0, dogs in each treatment group were treated with either Drontal ® (control group), Simparica Trio™ at the label dose to provide minimum doses of sarolaner (1.2 mg/kg), moxidectin (24 µg/kg) and pyrantel (5 mg/kg) or NexGard Spectra ® to provide minimum doses of afoxolaner (2.5 mg/kg) and milbemycin (0.5 mg/kg). Live tick counts were performed at 48 and 72 hours after treatment and after each re-infestation on Days 7, 14, 21, 28 and 35. Efficacy was determined at each time point relative to counts for control dogs based on geometric means., Results: Against an existing infestation, efficacy of both Simparica Trio™ and NexGard Spectra ® was 99.6% and 100% at 48 and 72 h time points, respectively (P = 1.000). Against subsequent weekly infestations, treatment with Simparica Trio™ and NexGard Spectra ® resulted in efficacy of ≥ 97.7% and ≥ 95.5% (P ≥ 0.0911), respectively at the 48 h time point and at the 72 h time point, Simparica Trio™ and NexGard Spectra ® resulted in efficacy of ≥ 99.0% and ≥ 98.4% (P ≥ 0.0511), respectively. There were no treatment-related adverse events in the study., Conclusions: Single doses of Simparica Trio™ and NexGard Spectra ® were highly efficacious and provided comparable efficacy against the Australian paralysis tick, I. holocyclus for up to 35 days.

Background: Lysophosphatidic acid (LPA) is a small glycerophospholipid that acts as a potent extracellular signal in various biological processes and diseases. Our previous work demonstrated that the expression of the LPA receptors LPA 1 and LPA 3 is elevated in the early postnatal heart. However, the role of this stage-specific expression of LPA 1 and LPA 3 in the heart is unknown. Methods and Results: By using LPA 3 and LPA 1 knockout mice, and neonatal SD rats treated with Ki16425 (LPA 1 /LPA 3 inhibitor), we found that the number of proliferating cardiomyocytes, detected by coimmunostaining pH3, Ki67 or BrdU with cardiac troponin T, was significantly decreased in the LPA 3 knockout mice and the Ki16425-treated rats but not in the LPA 1 knockout mice during the first week of postnatal life. Using a myocardial infarction (MI) model, we found that cardiac function and the number of proliferating cardiomyocytes were decreased in the neonatal LPA 3 KO mice and increased in the AAV9-mediated cardiac-specific LPA 3 overexpression mice. By using lineage tracing and AAV9-LPA 3 , we further found that LPA 3 overexpression in adult mice enhances cardiac function and heart regeneration as assessed by pH3-, Ki67-, and Aurora B-positive cardiomyocytes and clonal cardiomyocytes after MI. Genome-wide transcriptional profiling and additional mechanistic studies showed that LPA induces cardiomyocyte proliferation through the PI3K/AKT, BMP-Smad1/5, Hippo/YAP and MAPK/ERK pathways in vitro , whereas only ERK was confirmed to be activated by LPA-LPA 3 signaling in vivo . Conclusion: Our study reports that LPA 3 -mediated LPA signaling is a crucial factor for cardiomyocyte proliferation in the early postnatal heart. Cardiac-specific LPA 3 overexpression improved cardiac function and promoted cardiac regeneration after myocardial injury induced by MI. This finding suggested that activation of LPA 3 potentially through AAV-mediated gene therapy might be a therapeutic strategy to improve the outcome after MI., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

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.

Objective: Breast cancer is one of the most prevalent malignancies and leading causes of females' mortality worldwide. Because of resistance to various treatment options, new treatments based on molecular targeting has introduced as noticeable strategies in cancer treatment. In this regard, heat shock protein 90 (Hsp90) inhibitors are proposed as effective anticancer drugs. The goal of the study was to utilize a combination of the doxorubicin (DOX) and NVP-AUY 922 on the MCF-7 breast cancer model to investigate the possible cytotoxic mechanisms., Methods: MCF-7 breast cancer cell line was prepared and treated with various concentrations of DOX and NVP-AUY922 in single-drug treatments. We investigated the growth-inhibitory pattern by MTT assay after continuous exposure to NVP-AUY922 and DOX in order to determine dose-response. Then the combinatorial effects were evaluated in concentrations of 0.5 × IC50, 0.2 × IC50, 1 × IC50 and, 2 × IC50 of each drugs. Based on MTT results of double combinations, low effective doses were selected for Real-time PCR [caspase3 and vascular endothelial growth factor(VEGF)] and caspase 3 enzyme activity., Results: A dose-dependent inhibitory effects were presented with increasing the doses of both drugs in single treatments. The upregulation of caspase 3 and downregulation of VEGF mRNA were observed in double combinations of NVP-AUY922 and DOX versus single treatments. Also, in these combinations in low doses of examined drugs (0.5 × IC50, 0.2 × IC50), higher caspase 3 activity were presented in comparison to single treatments (p<0.05)., Conclusions: Our findings indicate an effective action of NVP-AUY922 in combined with DOX in this cell line. These results can predict the treatment outcome in this model.

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.)

A method for the simultaneous determination of parecoxib and its metabolite valdecoxib in beagle plasma by UPLC-MS/MS was developed and validated. After the plasma was extracted by acetonitrile precipitation, the analytes were separated on an Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) using acetonitrile-formic acid as the mobile phase in gradient mode. The analytes were monitored by multiple reaction monitoring (MRM) in electrospray negative ion mode. The mass transfer pairs were m/z 368.97→119.01 for parecoxib, m/z 312.89→118.02 for valdecoxib, and m/z 379.98→316.02 for celecoxib (internal standard, IS). The correlation coefficients of parecoxib and valdecoxib ranged from 5 to 4000 ng/mL were greater than 0.9998. The recovery of parecoxib and valdecoxib was greater than 82.54%. The inter- and intra-day precision RSD values were 1.36~3.65% and 2.28~5.91%, respectively. The accuracy of RE values were -1.38%~1.96%. Finally, the matrix effect (ME) and stability were also within acceptable criteria. This method had been successfully applied to the pharmacokinetics of parecoxib and valdecoxib in beagle plasma after injection of parecoxib (1.33 mg/kg, intramuscular injection)., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Li et al.)

Background: One randomized, controlled clinical field study was conducted in 18 general veterinary practices throughout the USA to evaluate the safety and efficacy of a novel oral chewable combination tablet, Simparica Trio™, containing sarolaner, moxidectin and pyrantel for the treatment and prevention of fleas on dogs., Methods: Client-owned dogs, from households of three or fewer dogs were eligible for enrollment. Four hundred and twenty-two dogs from 251 households were enrolled. Households were randomly assigned in a 2:1 ratio to treatment with either Simparica Trio™ at the minimum label dose of 1.2 mg/kg sarolaner, 24 µg/kg moxidectin and 5 mg/kg pyrantel (as pamoate salt) or afoxolaner (NexGard ® , Boehringer-Ingelheim) at the label dose. One dog per household was selected as the primary dog for efficacy evaluations. Treatments were dispensed and dogs were dosed in their home environment on Day 0 and on approximately Day 30. Flea counts and examination for clinical signs of flea allergy dermatitis (FAD) were performed at the initial visit the day before or on Day 0 prior to treatment and on Days 30 and 60. Additionally, all dogs were examined for general health at each visit and blood and urine were collected for clinical pathology at screening and Day 60., Results: Simparica Trio™ reduced geometric mean live flea counts by 99.0% by Day 30 and by 99.7% by Day 60. As a result of the rapid reduction in flea infestations, clinical signs associated with FAD substantially improved following treatment. Simparica Trio™ was well-tolerated and a diverse range of concomitant medications were administered to dogs during the course of the study. Simparica Trio™ chewable tablets were well-accepted by dogs, with the majority of flavored chewable tablets (91.9%) voluntarily consumed by free choice without, or when offered in food., Conclusions: Simparica Trio™ administered orally once monthly for two consecutive treatments was safe and effective against natural flea infestations and substantially improved clinical signs associated with FAD in client-owned dogs in a field study conducted in the USA.

Background: Lyme disease (LD) is an increasing public health threat in temperate zones of the northern hemisphere, yet relatively few methods exist for reducing LD risk in endemic areas. Disrupting the LD transmission cycle in nature is a promising avenue for risk reduction. This experimental study evaluated the efficacy of fluralaner, a recent oral acaricide with a long duration of effect in dogs, for killing Ixodes scapularis ticks in Peromyscus maniculatus mice, a known wildlife reservoir for Borrelia burgdorferi in nature., Methods: We assigned 87 mice to 3 fluralaner treatment groups (50 mg/kg, 12.5 mg/kg and untreated control) administered as a single oral treatment. Mice were then infested with 20 Ixodes scapularis larvae at 2, 28 and 45 days post-treatment and we measured efficacy as the proportion of infesting larvae that died within 48 h. At each infestation, blood from 3 mice in each treatment group was tested to obtain fluralaner plasma concentrations (C p )., Results: Treatment with 50 mg/kg and 12.5 mg/kg fluralaner killed 97% and 94% of infesting larvae 2 days post-treatment, but no significant effect of treatment on feeding larvae was observed 28 and 45 days post-treatment. Mouse C p did not differ significantly between the two tested doses. Mean C p decreased from 13,000 ng/ml in the 50 mg/kg group and 4000 ng/ml in the 12.5 mg/kg group at Day 2 to < 100 ng/ml in both groups at Day 45., Conclusions: We provide the first evidence that fluralaner is effective for killing immature ticks in Peromyscus mice, a first step in evaluating its potential for treating wild rodents as a public health intervention to reduce LD risk in endemic areas.

Objectives: To evaluate the morphine-sparing effects of the sequential treatment versus placebo in subjects undergoing total knee arthroplasty (TKA), the effects on pain relief, inflammation control and functional rehabilitation after TKA and safety., Design: Double-blind, pragmatic, randomised, placebo-controlled trial., Setting: Four tertiary hospitals in China., Participants: 246 consecutive patients who underwent elective unilateral TKA because of osteoarthritis (OA)., Interventions: Patients were randomised 1:1 to the parecoxib/celecoxib group or the control group. The patients in the parecoxib/celecoxib group were supplied sequential treatment with intravenous parecoxib 40 mg (every 12 hours) for the first 3 days after surgery, followed by oral celecoxib 200 mg (every 12 hours) for up to 6 weeks. The patients in the control group were supplied with the corresponding placebo under the same instructions., Primary and Secondary Outcome Measures: The primary endpoint was the cumulative opioid consumption at 2 weeks post operation (intention-to-treat analysis). Secondary endpoints included the Knee Society Score, patient-reported outcomes and the cumulative opioid consumption., Results: The cumulative opioid consumption at 2 weeks was significantly smaller in the parecoxib/celecoxib group than in the control group (median difference, 57.31 (95% CI 34.66 to 110.33)). The parecoxib/celecoxib group achieving superior Knee Society Scores and EQ-5D scores and greater Visual Analogue Scale score reduction during 6 weeks. Interleukin 6, erythrocyte sedation rate and C-reactive protein levels were reduced at 72 hours, 2 weeks and 4 weeks and prostaglandin E2 levels were reduced at 48 hours and 72 hours in the parecoxib/celecoxib group compared with the placebo group. The occurrence of adverse events (AEs) was significantly lower in the parecoxib/celecoxib group., Conclusions: The sequential intravenous parecoxib followed by oral celecoxib regimen reduces morphine consumption, achieves better pain control and functional recovery and leads to less AEs than placebo after TKA for OA., Trial Registration Number: ClinicalTrials.gov (ID: NCT02198924)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To investigate efficacy of combined use of parecoxib and dexmedetomidine on postoperative pain and early cognitive dysfunction after laparoscopic cholecystectomy for elderly patients., Methods: The present prospective randomized controlled study included a total of 80 patients who underwent laparoscopic cholecystectomy surgery during January 2016 to November 2017 in our hospital. All patients were randomly divided into 4 groups, the parecoxib group, the dexmedetomidine group, the parecoxib and dexmedetomidine combined group, and the control group. Demographic data and clinical data were collected. Indexes of heart rate (HR), mean arterial pressure (MAP), levels of jugular venous oxygen saturation (SjvO2) and jugular venous oxygen pressure (PjvO2) were recorded at different time points before and during the surgery. The mini-mental state examination (MMSE) score, Ramsay score and Visual Analogue Score (VAS) were measured., Results: Levels of both SjvO2 and PjvO2 were significantly higher in parecoxib group, dexmedetomidine group and the combined group than the control group. Meanwhile, levels of both SjvO2 and PjvO2 in the combined group were the highest. VAS scores were significantly lower in the combined group than all other groups, and total patient controlled intravenous analgesia (PCIA) pressing times within 48 h after surgery were the lowest in the combined group. Both Ramsay and MMSE scores were the highest in the combined group compared with other groups, while were the lowest in the control group., Conclusion: The combined use of parecoxib and dexmedetomidine could reduce the postoperative pain and improve the postoperative sedation and cognitive conditions of patients after laparoscopic cholecystectomy.

Background: Flea bite is considered to be the main cause of allergic dermatitis in cats. There is a need for treatments able to control clinical signs of allergic dermatitis associated with flea bite in cats. This was an open pre-treatment versus post-treatment clinical field study. All cats included in the study presented pruritus, skin lesions or other evidence compatible with flea infestation. Skin lesions were assessed (using SCORFAD) at days 0, 28, 56 and 84 whereas pruritus severity was assessed (using PVAS) at days 0, 15, 28, 56 and 84. On day 0, The fluralaner (280 mg/ml) product (Bravecto® spot-on for cats) was supplied in pipettes containing 0.4, 0.89 and 1.79 ml for cats of 1.2-2.8 kg, > 2.8-6.25 kg and > 6.25-12.5 kg body weight, respectively. The other animals living in the same household also received fluralaner. Based on cytological examination at day 0, oral amoxicillin and clavulanic acid was prescribed for 21 days if indicated. For cats presenting intense pruritus and discomfort at day 0, oral prednisolone at 0.5 mg/kg was prescribed for 3 days., Results: During the study all cats, except for one (cat number 10), improved significantly. Post-treatment median SCORFAD scores at all evaluations were significantly different from the pre-treatment score on day 0 (P values < 0.002 for all three post treatment examination days) with a score reduction of 49% on day 28, 79% on day 56 and 87% on day 84. The PVAS score decreased significantly over the study period for all cats but one (cat number 10). Post-treatment median PVAS scores at all evaluations were significantly different from the pre-treatment PVAS score on day 0 (P value < 0.002 for all four post-treatment days) with a reduction of 46% on day 15, 67% on day 28, 82% on day 56 and 92% on day 84. No adverse reaction or other health issue was reported during the study., Conclusions: A single topical treatment with fluralaner results in a significant reduction of flea bite allergic dermatitis clinical signs in cats over the subsequent 12 weeks without any additional environmental treatment.

The aim of this study was to evaluate the efficacy of a single dose of oral afoxolaner in controlling fleas in cats. Fourteen cats were used. The cats were given identification numbers, housed individually, artificially infested with Ctenocephalides felis felis, and treated (or not) with afoxolaner. Were divided into a treatment group and a control group (n = 7/group), on the basis of the fleas count hours after an infestation applied on Day (one-by-one allocation after ordering by count). At the start of the experimental protocol (designated day 0), the treated group received afoxolaner in a single dose of 2.5 mg/kg and the control group animals received a placebo. All animals were infested with 100 C. felis felis fleas two days before day 0, as well as on days 5, 12, 19, 26, 33, 40, 47, 54, and 63, parasite loads being evaluated at 48 h after each infestation. The efficacy of afoxolaner was 100% on day 2 and remained above 98% until day 42, decreasing to 95.3% by day 63. The findings confirm that a single dose of oral afoxolaner was effective in controlling C. felis felis in cats, and there were no observed adverse events.

Aims: Despite terizidone being part of the second-line recommended drugs for treatment of drug-resistant tuberculosis (DR-TB), information on its pharmacokinetics is scarce. The aim of this study was to describe the steady-state population pharmacokinetics (PPK) of terizidone and its primary metabolite cycloserine in patients with DR-TB and determine the effect of patient characteristics., Methods: This clinical study involved 39 adult DR-TB patients admitted to Brewelskloof Hospital in Cape Town, South Africa for intensive treatment phase. Blood samples were collected at predose and 0.5, 1, 2, 3, 3.5, 4, 8, 16 and 24 hours after drug administration. The estimation of PPK parameters was performed using nonlinear mixed-effects modelling software Monolix 2018R1. Free-fat mass was used to perform allometric scaling on disposition parameters., Results: A 1-compartment model best described the pharmacokinetics of terizidone and cycloserine. A modified transit compartment model described the absorption of terizidone. The parameters of terizidone model were mean transit time (1.7 h), absorption rate constant (2.97 h -1 ), apparent volume of distribution (Vp/F: 13.4 L) and apparent total clearance (0.51 L h -1 ). In the joint model, apparent fraction of terizidone converted to cycloserine was 0.29 while apparent clearance of terizidone via other routes and apparent cycloserine clearance was 0.1 L h -1 and 2.94 L h -1 , respectively. Serum albumin had significant effect on Vp/F., Conclusions: The developed PPK model described well the concentration-time profile for terizidone and cycloserine in DR-TB patients. High albumin concentration was associated with low Vp/F., (© 2019 The British Pharmacological Society.)

O 6 -methylguanine-DNA methyltransferase (MGMT) is an enzyme that removes alkyl groups at the O 6 -position of guanine in DNA. MGMT expression is reduced or absent in many tumor types derived from a diverse range of tissues, most notably in glioma. Low MGMT expression confers significant sensitivity to DNA alkylating agents such as temozolomide, providing a natural therapeutic index over normal tissue. In this study, we sought to identify novel approaches that could maximally exploit the therapeutic index between tumor cells and normal tissues based on MGMT expression, as a means to enhance selective tumor cell killing. Temozolomide, unlike other alkylators, activated the ataxia telangiectasia and Rad3-related (ATR)-checkpoint kinase 1 (Chk1) axis in a manner that was highly dependent on MGMT status. Temozolomide induced growth delay, DNA double-strand breaks, and G 2 -M cell-cycle arrest, which led to ATR-dependent phosphorylation of Chk1; this effect was dependent on reduced MGMT expression. Treatment of MGMT-deficient cells with temozolomide increased sensitivity to ATR inhibitors both in vitro and in vivo across numerous tumor cell types. Taken together, this study reveals a novel approach for selectively targeting MGMT-deficient cells with ATR inhibitors and temozolomide. As ATR inhibitors are currently being tested in clinical trials, and temozolomide is a commonly used chemotherapeutic, this approach is clinically actionable. Furthermore, this interaction potently exploits a DNA-repair defect found in many cancers. SIGNIFICANCE: Monofunctional alkylating agents sensitize MGMT-deficient tumor cells to ATR inhibitors., (©2019 American Association for Cancer Research.)

A research centre with 30,568 laying hens, kept in enriched cages and in aviaries, had become naturally infested with poultry red mites (PRM) in 32 of its 48 bird units. Therefore, at the age of 52 weeks all hens were treated with fluralaner through the drinking water. After this treatment, PRM were no longer observed. As all birds were of the same age, and since production figures were measured daily in all 48 units, this offered a unique opportunity to examine how PRM had affected performance. Statistical analyses were done to compare the evolution of production data from the pre-treatment to the post-treatment period in units that were visually free of PRM or infested with PRM to different levels. Production standards provided by the breeding organizations were used as a reference. The results demonstrated significant posttreatment increases of laying percentage, egg weight, egg mass, percentage first choice eggs, feed intake and body weight in heavily infested hens of one or both housing systems, as compared to the non-infested controls. These data confirm that PRM infestations can impact the main performance traits related to profitability of laying hen farms as well as the hens' general condition.

Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children and causes chronic diarrhea in AIDS patients, but the only approved treatment is ineffective in malnourished children and immunocompromised people. We here use a drug repositioning strategy and identify a promising anticryptosporidial drug candidate. Screening a library of benzoxaboroles comprised of analogs to four antiprotozoal chemical scaffolds under pre-clinical development for neglected tropical diseases for Cryptosporidium growth inhibitors identifies the 6-carboxamide benzoxaborole AN7973. AN7973 blocks intracellular parasite development, appears to be parasiticidal, and potently inhibits the two Cryptosporidium species most relevant to human health, C. parvum and C. hominis. It is efficacious in murine models of both acute and established infection, and in a neonatal dairy calf model of cryptosporidiosis. AN7973 also possesses favorable safety, stability, and PK parameters, and therefore, is an exciting drug candidate for treating cryptosporidiosis.