Persistent Efficacy Research Articles

Synergy between dinotefuran and fipronil against the cat flea (Ctenocephalides felis): improved onset of action and residual speed of kill in adult cats

BackgroundThe cat flea, Ctenocephalides felis felis (C. felis), is a cosmopolitan hematophagous ectoparasite, and is considered to be the most prevalent flea species in both Europe and the USA. Clinical signs frequently associated with flea bites include pruritus, dermatitis and in severe cases even pyodermatitis and alopecia. Ctenocephalides felis is also a vector for several pathogens and is an intermediate host for the cestode Dipylidium caninum. Treatment of cats with a fast-acting pulicide, that is persistently effective in protecting the animal against re-infestation, is therefore imperative to their health. In addition, a rapid onset of activity (“speed of kill”) may also reduce the risks of disease transmission and flea allergic dermatitis. The aim of this study was to evaluate the in vitro insecticidal activity and potential synergism between dinotefuran and fipronil against C. felis. A further aim was to evaluate the onset of activity and residual speed of kill of the combination in vivo on cats artificially infested with C. felis.MethodsIn the first study, the insecticidal activity of dinotefuran and fipronil separately and dinotefuran/fipronil (DF) in combination, at a fixed ratio (2:1), was evaluated using an in vitro coated-vial bioassay. In the second study, the onset of activity against existing flea infestations and residual speed of kill of DF against artificial flea infestations on cats was assessed in vivo. Onset of activity against existing flea infestations was assessed in terms of knock-down effect within 2 h post-treatment and onset of speed of kill assessed at 3 h, 6 h and 12 h post-treatment. Residual speed of kill was evaluated 6 h and 48 h after infestation, over a period of six weeks post-treatment.ResultsIn vitro results revealed that the DF combination was synergistic and more potent against fleas than either compound alone. The combination also proved effective when tested in vivo. Efficacy was > 97% [geometric mean (GM) and arithmetic mean (AM)] at 3 h after treatment, and ≥ 99.8% (GM and AM) at 6 h and 12 h post-treatment. At 6 h after flea re-infestations, the efficacy of DF remained ≥ 90.8% (GM and AM) for up to 28 days, and at 42 days post-treatment persistent efficacy was still ≥ 54.3% (GM and AM). At 48 h after flea re-infestations, DF remained almost fully effective for up to 28 days, with efficacies ≥ 99.4% (GM and AM) and was persistently ≥ 93.0% (GM and AM) effective for up to 42 days post-treatment.ConclusionsThe combination of dinotefuran and fipronil in a single formulation exhibited strong synergistic insecticidal activity against C. felis in vitro, and also proved effective on artificially infested cats. This activity had a rapid onset that persisted for 6 weeks against re-infestations of C. felis on cats. The rapid curative insecticidal effect was observed as early as 3 h after treatment, and as early as 6 h after re-infestations for up to 6 weeks post-treatment. The insecticidal activity profile of DF makes it an optimal candidate for the protection of cats against flea infestations, and possibly also associated diseases.

Evaluation of the Persistent Preventive Efficacy of 2.5 % Moxidectin/10 % Imidacloprid Spot-on (Advocate\xae, Advantage\xae Multi) in Dogs Experimentally Infected with Angiostrongylus vasorum

Evaluation of the Persistent Preventive Efficacy of 2.5 % Moxidectin/10 % Imidacloprid Spot-on (Advocate\xae, Advantage\xae Multi) in Dogs Experimentally Infected with Angiostrongylus vasorum

Abstract 2807: Developing a variety of primary mouse tumor allograft models for evaluating efficacy of PARP inhibitor

Abstract Recent success of multiple poly (adenosine diphosphate [ADP]) ribose polymerase inhibitors (PARPi) in treating BRCA mutant ovarian cancers has fueled the development of PARPi in several areas, including expanding its use in other BRCA mutant or wildtype cancers; exploring resistant mechanisms and overcoming resistance; seeking for its combination with chemotherapy, radiotherapy and emerging immunotherapy to achieve persistent efficacy. Especially considering the mechanism of action of PARPi, its use can increase the mutational loads in tumors with defects in homologous recombination and DNA double strand break repair, which potentially would enhance the immunogenicity of the tumors. Therefore it would be very interesting to test the effectiveness of combining PARPi with anti-PD1/PD-L1 or anti-CTLA4. However, relevant animal models are lacking for such studies.Syngeneic mouse tumors offer about 30 viable in vivo models for proof of concept studies. However, these models suffer from several limitations: 1) only a few available and responsive to the current checkpoint inhibitors – for given strains of mouse, there are only very few choices of cells/disease types; 2) not mimicking patient tumors since they are in vitro immortalized cell lines; 3) not reflective of patient disease pathways thus unfit for common target agents, either in mono- or combination therapy. We have established allografts of spontaneous mouse tumors (MuPrime®) derived from genetically engineered mouse models (GEMMs) as a new type of immuno-oncology models with following advantages: 1) its primary nature of “stem cell diseases” and relevant tumor microenvironment; 2) its diverse cancer types/strains of mice; 3) engineered oncogenic drivers as seen in human diseases, deriving from a wide range of available GEMMs, suitable for targeted agents. Thus far, we have built a small library of allografts and are testing them to facilitate pharmacological investigation, particularly those of immuno-oncology.We have found a few models, including an APCmin/+ skin squamous cell carcinoma and a P53 null sarcoma responded well to PARPi Niraparib. Continuous treatment with Niraparib led to development of partial or complete resistance. We are now profiling the resistant models to find out their general mutation loads, as well as specific biomarkers render resistant mechanisms. We are also treating the tumors with mouse PD1 antibody to test whether presumably enhanced mutation loads would sensitize these tumors to immunotherapy. The data of these studies will be presented at the meeting. Citation Format: Gavin Jiagui Qu, Davy Xuesong Ouyang, Li Chen, Likun Zhang, Annie Xiaoyu An, Jie Cai, Henry Q. X. Li. Developing a variety of primary mouse tumor allograft models for evaluating efficacy of PARP inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2807. doi:10.1158/1538-7445.AM2017-2807

Pharmacokinetic Analysis and in Vivo Antitumor Efficacy of Taccalonolides AF and AJ.

The taccalonolides are microtubule stabilizers that covalently bind tubulin and circumvent clinically relevant forms of resistance to other drugs of this class. Efforts are under way to identify a taccalonolide with optimal properties for clinical development. The structurally similar taccalonolides AF and AJ have comparable microtubule-stabilizing activities in vitro, but taccalonolide AF has excellent in vivo antitumor efficacy when administered systemically, while taccalonolide AJ does not elicit this activity even at maximum tolerated dose. The hypothesis that pharmacokinetic differences underlie the differential efficacies of taccalonolides AF and AJ was tested. The effects of serum on their in vivo potency, metabolism by human liver microsomes and in vivo pharmacokinetic properties were evaluated. Taccalonolides AF and AJ were found to have elimination half-lives of 44 and 8.1 min, respectively. Furthermore, taccalonolide AJ was found to have excellent and highly persistent antitumor efficacy when administered directly to the tumor, suggesting that the lack of antitumor efficacy seen with systemic administration of AJ is likely due to its short half-life in vivo. These results help define why some, but not all, taccalonolides inhibit the growth of tumors at systemically tolerable doses and prompt studies to further improve their pharmacokinetic profile and antitumor efficacy.

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

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

Anti-hIgE gene therapy of peanut-induced anaphylaxis in a humanized murine model of peanut allergy

Peanuts are the most common food to provoke fatal or near-fatal anaphylactic reactions. Treatment with an anti-hIgE mAb is efficacious but requires frequent parenteral administration. Based on the knowledge that peanut allergy is mediated by peanut-specific IgE, we hypothesized that a single administration of an adeno-associated virus (AAV) gene transfer vector encoding for anti-hIgE would protect against repeated peanut exposure in the host with peanut allergy. We developed a novel humanized murine model of peanut allergy that recapitulates the human anaphylactic response to peanuts in NOD-scid IL2Rgammanull mice transferred with blood mononuclear cells from donors with peanut allergy and then sensitized with peanut extract. As therapy, we constructed an adeno-associated rh.10 serotype vector coding for a full-length, high-affinity, anti-hIgE antibody derived from the Fab fragment of the anti-hIgE mAb omalizumab (AAVrh.10anti-hIgE). In the reconstituted mice peanut-specific IgE was induced by peanut sensitization and hypersensitivity, and reactions were provoked by feeding peanuts to mice with symptoms similar to those of human subjects with peanut allergy. A single administration of AAVrh.10anti-hIgE vector expressed persistent levels of anti-hIgE. The anti-hIgE vector, administered either before sensitization or after peanut sensitization and manifestation of the peanut-induced phenotype, blocked IgE-mediated alterations in peanut-induced histamine release, anaphylaxis scores, locomotor activity, and free IgE levels and protected animals from death caused by anaphylaxis. If this degree of persistent efficacy translates to human subjects, AAVrh.10anti-hIgE could be an effective 1-time preventative therapy for peanut allergy and possibly other severe, IgE-mediated allergies.

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

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

The effect of water and shampooing on the efficacy of fluralaner spot-on solution against Ixodes ricinus and Ctenocephalides felis infestations in dogs.

BackgroundFluralaner spot-on solution provides immediate and persistent efficacy against tick and flea infestations in dogs and cats for 12-weeks following topical administration. The active ingredient fluralaner is distributed systemically following transdermal absorption. Therefore, this study tested the hypothesis whether water-immersion or shampooing of dogs following administration of fluralaner spot-on solution has an impact on subsequent tick and flea efficacy.MethodsThirty-two Beagle dogs were allocated to four study groups of 8 dogs each. On day 0, dogs in the 2 treatment groups received topical administration of fluralaner (Bravecto™ spot-on solution) according to label instructions. Dogs in the 2 corresponding control groups remained untreated. On days 3, 21, 49, and 77 dogs in one treatment group and control group were water-immersed for 2–5 min, while dogs in the other treatment group and control group were shampooed 6–8 min with a commercial foaming micro-emulsion, unscented product. On days 4, 28, 56, and 84 all dogs were co-infested with 50 ± 2 female and 10 ± 2 male Ixodes ricinus and 100 ± 4 Ctenocephalides felis, with tick and flea removal and counts 48 ± 2 h post-infestation. Efficacy against ticks and fleas was calculated for each assessment time point.ResultsNo treatment-related adverse event was observed in any of the 16 dogs treated with fluralaner spot-on solution during the study.Efficacy against ticks at each assessment time point was between 99.7 and 100 % in the water-immersed group and between 99.2 and 100 % in the shampooed group. Efficacy against fleas was 100 % at each assessment time point as well in the water-immersed as the shampooed group. Tick and flea reduction in both treatment groups was significant at all assessment time points (p < 0.0001).ConclusionsNeither water-immersion nor shampooing after single topical administration of fluralaner spot-on solution had an impact on the excellent tick and flea efficacy over the 12-week recommended re-treatment interval.

Plasma disposition and faecal excretion of eprinomectin following topical and subcutaneous administration in non-lactating dairy cattle

AIMS: To investigate the plasma disposition and faecal excretion of eprinomectin (EPM) in non-lactating dairy cattle following topical and S/C administration.METHODS: Holstein dairy cows, 3.5–5 years-old, were selected 20–25 days after being dried off and were randomly allocated to receive EPM either topically (n=5) or S/C (n=5) at dose rates of 0.5 and 0.2 mg/kg bodyweight, respectively. Heparinised blood and faecal samples were collected at various times between 1 hour and 30 days after treatment, and were analysed for concentrations of EPM using high performance liquid chromatography with a fluorescence detector.RESULTS: The maximum concentration of EPM in plasma (Cmax) and the time to reach Cmax were both greater after S/C administration (59.70 (SD 12.90) ng/mL and 1.30 (SD 0.27) days, respectively) than after topical administration (20.73 (SD 4.04) ng/mL and 4.40 (SD 0.89) days, respectively) (p<0.001). In addition, S/C administration resulted in greater plasma availability (area under the curve; AUC), and a shorter terminal half-life and mean residence time (295.9 (SD 61.47) ng.day/mL; 2.95 (SD 0.74) days and 4.69 (SD 1.01) days, respectively) compared with topical administration (168.2 (SD15.67) ng.day/mL; 4.63 (SD 0.32) days, and 8.23 (SD 0.57) days, respectively) (p<0.01). EPM was detected in faeces between 0.80 (SD 0.45) and 13.6 (SD 4.16) days following S/C administration, and between 1 (SD 0.5) and 20.0 (SD 3.54) days following topical administration. Subcutaneous administration resulted in greater faecal excretion than topical administration, expressed as AUC adjusted for dose (1188.9 (SD 491.64) vs. 311.5 (SD 46.90) ng.day/g; p<0.05). Maximum concentration in faeces was also higher following S/C than topical administration (223.0 (SD 63.96) vs. 99.47 (SD 43.24) ng/g; p<0.01).CONCLUSIONS: Subcutaneous administration of EPM generated higher plasma concentrations and greater plasma availability compared with topical administration in non-lactating cattle. Although the S/C route provides higher faecal concentrations, the longer faecal persistence of EPM following topical administration may result in more persistent efficacy preventing establishment of incoming nematode larvae in cattle.

Standardization and Regulation of Allergen Products in the European Union.

Product-specific standardization is of prime importance to ensure persistent quality, safety, and efficacy of allergen products. The regulatory framework in the EU has induced great advancements in the field in the last years although national implementation still remains heterogeneous. Scores of methods for quantification of individual allergen molecules are developed each year and also the challenging characterization of chemically modified allergen products is progressing. However, despite the unquestionable increase in knowledge and the subsequent improvements in control of quality parameters of allergen products, an important aim has not been reached yet, namely cross-product comparability. Still, comparison of allergen product potency, either based on total allergenic activity or individual allergen molecule content, is not possible due to a lack of standard reference preparations in conjunction with validated standard methods. This review aims at presenting the most recent developments in product-specific standardization as well as activities to facilitate cross-product comparability in the EU.

Comparison between Corticosteroid, Platelet Rich Plasma (PRP) and Xylocaine Infiltration for Lateral Epicondylosis (Tennis Elbow): A Prospective Randomized Study

Background: Platelet rich plasma and corticosteroid injection have both been suggested to treat chronic lateral epicondylosis. The aim of this study was to compare the safety and effectiveness of corticosteroid, PRP and xylocaine infiltration for lateral epicondylosis. Materials and Methods: 150 patients with chronic lateral epicondylosis were randomly divided into three groups. Group A was treated with a single injection of 2 ml of corticosteroid mixed with 1 ml of xylocaine, Group B with 2 ml of PRP mixed with 1 ml of xylocaine and Group C with 3 ml of 2% xylocaine through peppering needle technique. Pain and functional improvements were assessed using visual analogue scale (VAS) and Nirschl’s staging at 0,2,6,12,26 and 52 weeks. Results: Baseline evaluation showed no difference between the three groups (p>0.05). Analysis at 2 weeks showed no difference in Nirschl staging but showed significant decrease in VAS score in favour of corticosteroid group. No statistically significant difference was noted between groups at 6 weeks (p>0.05). At 12 weeks VAS score was comparable but Nirschl stage was significantly low in corticosteroid group. Evaluation at 26 and 52 weeks demonstrated a statistically significant difference between groups favouring PRP group (p<0.05). Conclusion: PRP, Corticosteroid and Xylocaine are safe and effective in treatment of lateral epicondylosis. Both steroid and xylocaine are effective on a short term period. However, on long term follow-up, PRP seems to be the more effective treatment with more persistent efficacy than corticosteroid and xylocaine in relieving pain.

Effects of Rispens CVI988 vaccination followed by challenge with Marek’s disease viruses of differing virulence on the replication kinetics and shedding of the vaccine and challenge viruses

Vaccination with “imperfect” vaccines that prevent disease but not infection is strongly implicated in the observed increased virulence of Marek’s disease virus (MDV) over the past six decades. The current “gold standard” vaccine, Rispens CVI988 (Rispens), has maintained efficacy despite use for five decades, raising the question of whether it too favours higher virulence MDVs. To investigate this, we studied the kinetics of Rispens CVI988 (Rispens) and two MDV strains of different virulence in 236 commercial ISA Brown chickens vaccinated with Rispens at hatch and challenged with vMDV isolate MPF57 or vvMDV isolate FT158 on day five. Each treatment was replicated in two isolators and from 7 to 56 days post infection (dpi) peripheral blood leucocytes (PBL), feather and dust samples were collected and subjected to differential quantitative PCR (qPCR). Rispens vaccination significantly reduced challenge MDV viral load in a sample-dependant manner with evidence of a differentially greater inhibitory effect on the less virulent MDV. Similarly, challenge with the more virulent MDV reduced the Rispens viral load in PBL. Rispens virus load displayed a distinctive pattern of viral load that was similar in PBL and feathers, but different in dust. The clear effects of vaccination and challenge evident in PBL and feather samples were less clearly reflected in dust samples. The data are consistent with the Rispens vaccine reducing replication of lesser virulent MDVs to a greater extent like the HVT vaccine. Likely reasons for the persistent efficacy of Rispens vaccine are discussed.

Involvement of normalized NMDA receptor and mTOR-related signaling in rapid antidepressant effects of Yueju and ketamine on chronically stressed mice.

Yueju, a Traditional Chinese Medicine formula, exhibited fast-onset antidepressant responses similar to ketamine. This study focused on assessing the rapid and persistent antidepressant efficacy of Yueju and ketamine in chronically stressed mice and its association with alternations in prefrontal N-methyl-D-aspartate (NMDA) receptor and mammalian target of rapamycin (mTOR)-related activity. Chronic mild stress (CMS) led to deficits in sucrose preference test (SPT), forced swim test, tail suspension test, and novelty-suppressed feeding test, which were improved differently by acute Yueju or ketamine administration. The improvement in SPT started as soon as 2 hours post Yueju and ketamine but lasted for 6 days only by Yueju. Body weight was regained by Yueju more than ketamine at post-drug administration day (PAD) 6. CMS decreased phosphorylation of the mTOR effectors 4E-BP1 and p70S6K, their upstream regulators ERK and Akt, and downstream targets including synaptic protein GluR1. Yueju or ketamine reversed these changes at PAD 2, but only Yueju reversed phosphor-Akt at PAD 6. CMS selectively and lastingly increased NMDA receptor subunit NR1 expression, which was reversed by ketamine or Yueju at PAD 2 but only by Yueju at PAD 6. These findings suggest that NR1 and Akt/mTOR signaling are important therapeutic targets for depression.

Comparing efficacy of insecticides against cabbage maggot (Diptera: Anthomyiidae) in the laboratory

The efficacy of 29 insecticides was determined against cabbage maggot, Delia radicum (L.) through a laboratory bioassay by exposing field collected D. radicum maggots to insecticide-treated soil immediately after application. In an assay, 10 D. radicum maggots were exposed to insecticide treated soil and then efficacy of insecticides was determined using three parameters: (1) proportion of maggots on the soil surface after 24 h, (2) proportion of change in weight of turnip bait, and (3) dead maggots after 72 h. Efficacy index (scale of 0–100) was developed based on the three parameters. Efficacy index of 11 insecticides was ≥70 against D. radicum and they were zeta-cypermethrin, tolfenpyrad, fenpropathrin, clothianidin, bifenthrin, lambda-cyhalothrin, chlorpyrifos, ethoprop, thiamethoxam + lambda-cyhalothrin, pyrethrins, and oxamyl in the order of highest to lowest efficacy. There was a significant positive correlation (R2 > 0.5) among the three parameters. Furthermore, persistence of efficacy was examined on eight insecticides, where D. radicum maggots were exposed to field aged (1, 3, 7, 14, and 30 d) insecticide treated soil. Percentages of D. radicum maggots dead and on the soil surface were significantly greater when field aged soil was treated with bifenthrin, tolfenpyrad and clothianidin than other insecticides for most of the field age interval treatments. Efficacy of clothianidin did not change through field age interval treatments. The implications of these results on D. radicum management in the central coast of California are discussed.

Efficacy of fluralaner flavored chews (Bravecto) administered to dogs against the adult cat flea, Ctenocephalides felis felis and egg production.

BackgroundFluralaner is a potent insecticide and acaricide with rapid and persistent efficacy. This study measured the efficacy of fluralaner flavored chews (Bravecto®, Merck Animal Health) administered to dogs against adult Ctenocephalides felis felis and egg production.MethodsTwelve purpose-bred dogs were randomly allocated to two groups of six dogs each. Dogs in treatment group 1 were administered a single fluralaner flavored chew to achieve a minimum dose of at least 25 mg/kg while treatment group 2 served as untreated controls. On Days −2, 28, 56, 84, 91, 98, 105, 112, and 120 post-treatment, each dog was infested with approximately 200 unfed cat fleas, C. felis felis (KS1 strain). Forty-eight hours after treatment and 48 h after each infestation, eggs were collected over a 3-h period, counted and viability determined. Dogs were combed to remove any remaining fleas.ResultsTreatment of dogs with oral fluralaner provided a 100 % reduction in flea counts 48 h after treatment and within 48 h of every post-treatment infestation through Day122. Egg production from fluralaner treated dogs was reduced by 99.9 % (two eggs from one dog) within 48 h after treatment and not a single egg (100 % efficacy) was thereafter collected from treated dogs. Adult flea counts and egg production from the fluralaner-treated dogs were significantly lower than for non-treated controls at all post-treatment evaluations (P < 0.001). The two eggs collected from the single treated dog 48 h after treatment did not produce any adult fleas. As no additional eggs were collected from treated dogs, no viability assessment was performed.ConclusionsA single oral dose of fluralaner flavored chews provided 100 % efficacy against repeated flea infestations on dogs for 4 months. Fluralaner reduced egg production of activity reproducing female fleas by 99.9 % and then killed every single female flea before any eggs could be produced following each subsequent re-infestation for the entire 122-day evaluation period.

A randomized controlled trial of the efficacy of orally administered fluralaner (Bravecto™) against induced Ixodes holocyclus (Australian paralysis tick) infestations on dogs.

BackgroundIxodes holocyclus ticks are a frequently fatal threat to dogs in eastern Australia. These ticks secrete a neurotoxin that can produce an ascending paralysis after 72 h attachment that can lead to death in affected animals. Fluralaner is a potent systemic acaricide with immediate and persistent efficacy for tick control including evidence of 100% efficacy against Ixodes ricinus ticks within 72 h. This study investigated the potential for oral fluralaner administration to control I. holocyclus infestation and the subsequent risk of host paralysis.MethodsHealthy Foxhound and Foxhound cross dogs immunized against holocyclotoxin were randomly allocated to receive either a single fluralaner (at least 25 mg/kg) dose or no treatment. All dogs were penned individually and infested with 30 adult unfed female I. holocyclus 1 day before treatment and 14, 28, 42, 56, 70, 84, 112 and 140 days following treatment. Ticks were counted and assessed at 24, 48 and 72 h after the initial fluralaner treatment and after each subsequent infestation. Ticks were not removed at the 24 and 48 h assessments, but were removed after the 72 h assessments. On 112 and 140 days post treatment a new group of untreated control dogs was used.ResultsFluralaner treatment efficacy against I. holocyclus was 100% at 72 h post treatment. Following re-infestations the efficacy remained at 100% at the 72 h assessments for 115 days and reached 95.7% at 143 days. The differences between mean live tick counts on treatment and control groups were significant (P < 0.00l) at all assessment time points for 143 days following treatment.ConclusionsOral fluralaner treatment can prevent Australian paralysis tick infestations for at least 115 days.

Ongoing data from the breast cancer prevention trials: opportunity for breast cancer risk reduction.

Selective estrogen receptor modulators (SERMs) reduce the risk of recurrence of invasive breast cancer and the incidence of first breast cancers in women who are at increased risk. Multiple, randomized clinical trials have shown both the efficacy and safety of SERMs in reducing the risk of breast cancer. Long-term follow-up as long as 20 years in the randomized trials shows persistent efficacy with acceptable safety. Hormone replacement therapy given concurrently with tamoxifen abrogates its preventive effect, but women with atypical hyperplasia derive particular benefit from SERM therapy. Aromatase inhibitors also reduce the risk of developing invasive breast cancer, but the experience with them for risk reduction is limited to few trials. National organizations have made recommendations to use SERMs and aromatase inhibitors to reduce the risk of breast cancer in high-risk women and additional efforts should be made to increase their use in clinical practice, where the number of women needed to treat to prevent one case of breast cancer conforms to accepted standards of preventive medicine.

Comparison Among Patients ≥75 Years Having Percutaneous Coronary Angioplasty Using Drug-Eluting Stents Versus Bare Metal Stents

Limited data are available on long-term efficacy and safety of drug-eluting stents (DES) in elderly patients who underwent PCI. A total of 635 consecutive patients aged ≥75 years who underwent PCI were enrolled at 2 European centers. Of these, 170 patients received at least 1 DES, whereas 465 patients received bare metal stent (BMS) only. Primary end point was the incidence of net adverse clinical events (NACE), defined as the occurrence of ischemic events or bleeding events, and was compared at a median follow-up of 31.2 months. Clinical follow-up information was available in 593 patients (93.4%). The duration of dual antiplatelet therapy was 12.3±5.1 months in the DES group and 3.8±7.4 months in the BMS group. The Kaplan-Meier estimate of NACE at 5 years was significantly lower in DES-treated patients (40.5%) than in BMS-treated patients (55.7%; p=0.009). This benefit was driven by a significant reduction in myocardial infarction (8.6% vs 16.6%; p=0.038) and target vessel revascularization rates (7.9% vs 21.9%; p=0.003) in the DES group, with no significant increase in the incidence of bleeding events (13.8% vs 12.2%; p=0.882). These results were confirmed at propensity score-adjusted Cox proportional hazard analysis. In conclusion, in patients≥75 years, the use of DES compared with BMS seems to reduce myocardial infarction and repeat revascularization rates at long-term follow-up, without an increase in bleeding despite longer duration of dual antiplatelet therapy. This net clinical benefit, resulting from persistent efficacy and safety over time, may support the use of DES as a reasonable option in patients≥75 years.

From bench to bedside: bipolar androgen therapy in a pilot clinical study.

Prostate cancer remains a leading cause of cancer death in Europe and the United States and is an emerging problem in Asia despite significant improvements in available treatments over the last few decades. Androgen deprivation therapy (ADT) has been the core treatment of advance-staged disease since the discovery of prostate cancer's androgen dependence in 1941 by Huggins et al.1 Options for initial medical treatment include gonadotropin-releasing hormone analogues such as leuprolide (LHRH agonist) and degarelix (LHRH antagonist) and androgen receptor (AR) binding agents such as bicalutamide. Although most patients will initially respond to either surgical or medical castration, there is almost always progression to castration-resistant prostate cancer (CRPC) necessitating treatment with more novel agents.2 However, even drugs such as abiraterone and enzalutamide, two next-generation agents used commonly in metastatic CRPC, have failed to demonstrate persistent efficacy in most patients.34

A review of feeding supplementary nitrate to ruminant animals: nitrate toxicity, methane emissions, and production performance

Lee, C. and Beauchemin, K. A. 2014. A review of feeding supplementary nitrate to ruminant animals: Nitrate toxicity, methane emissions, and production performance. Can. J. Anim. Sci. 94: 557–570. The purpose of this review is to discuss the risks and benefits of using supplementary nitrate to reduce enteric methane emissions in ruminants based on the results of a meta-analysis. The meta-analysis confirmed possible nitrate poisoning triggered by higher blood methemoglobin levels with increasing nitrate consumption of ruminants: methemoglobin (%)=41.3×nitrate [g kg−1body weight (BW) d−1]+1.2; R2=0.76, P&lt;0.001. However, acclimatizing animals to nitrate reduced the toxicity of nitrate: methemoglobin (%)=4.2×nitrate (g kg−1BW d−1)+0.4, R2=0.76, P=0.002. Animals fed nitrate reduced enteric methane emissions in a dose-response manner: methane [g kg−1dry matter intake (DMI)]=−8.3×nitrate (g kg−1BW d−1)+15.2, R2=0.80, P&lt;0.001. The reduction of enteric methane emissions due to supplementary nitrate was effective and consistent in both in vitro and in vivo studies and also persistent in several long-term studies. Dry matter intake and live weight gain (LWG) of cattle were not affected by nitrate: DMI change, R2=0.007, P=0.65; LWG change, R2=0.03, P=0.31. It is anticipated that supplementary nitrate as a substitute for urea may change urinary nitrogen composition in a manner that increases ammonia and nitrous oxide emissions from manure. Furthermore, supplementary nitrate may have various physiological roles in nitric oxide metabolism in ruminants. In conclusion, supplementary nitrate is a viable means of mitigating enteric methane emissions due to its consistent and persistent efficacy. Risk of toxicity can be lowered by gradual acclimation of animals to nitrate. However, lowered methane production may not re-direct additional metabolizable energy towards animal production.