Pharmacokinetics and metabolism of eprinomectin in cats when administered in a novel topical combination of fipronil, (S)-methoprene, eprinomectin and praziquantel

AbstractFour studies were conducted to determine the pharmacokinetic characteristics and in vitro metabolism of eprinomectin, a semi-synthetic avermectin, in cats. Pharmacokinetic parameters including bioavailability of eprinomectin were determined in a parallel study design comprised of one group of eight cats which were treated once topically at 0.12mL/kg bodyweight with BROADLINE®, a novel combination product (fipronil 8.3% (w/v), (S)-methoprene 10% (w/v), eprinomectin 0.4% (w/v) and praziquantel 8.3% (w/v)), delivering a dose of 0.5mg eprinomectin per kg body weight, and a group of six cats which received 0.4% (w/v) eprinomectin at 0.4mg/kg bodyweight once by intravenous injection. For cats treated by topical application, the average eprinomectin (B1a component) maximum plasma concentration (Cmax) was 20ng/mL. The maximum concentrations were reached 24h after dosing in the majority of the animals (six of eight cats). The average terminal half-life was 114h due to slow absorption (‘flip-flop’ kinetics). Following intravenous administration the average Cmax was 503ng/mL at 5min post-dose, and the mean elimination half-life was 23h. Eprinomectin was widely distributed with a mean volume of distribution of 2390mL/kg, and the clearance rate was 81mL/h/kg. Mean areas under the plasma concentration versus time curves extrapolated to infinity were 2100ngh/mL and 5160ngh/mL for the topical and intravenous doses, respectively. Topical eprinomectin was absorbed with an average absolute bioavailability of 31%. In a second parallel design study, the dose proportionality of eprinomectin after single topical administration of BROADLINE® was studied. Four groups of eight cats each were treated once topically with 0.5, 1, 2 or 5 times the minimum recommended dose of the combination, 0.12mL/kg bodyweight. Based on comparison of areas under the plasma concentration versus time curves from the time of dosing to the last time point at which eprinomectin B1a was quantified, and Cmax, dose proportionality was established. In addition, the metabolic pathway of eprinomectin using cat liver microsomes, and plasma protein binding using cat, rat, and dog plasma were studied in vitro. Results of the analyses of eprinomectin B1a described here showed that it is metabolically stable and highly protein bound (>99%), and thus likely to be, as with other species, excreted mainly as unchanged parent drug in the feces of cats

Treatment and control of bovine hypodermosis with ivermectin long-acting injection (IVOMEC® GOLD)

Background: The studies reported here were conducted to assess the efficacy of ivermectin long-acting injection (IVM LAI; IVOMEC® GOLD, Merial; 3.15 % w/v ivermectin) for the treatment and control of natural infestations of cattle by Hypoderma bovis and Hypoderma lineatum, which are the most economically important oestrid flies of cattle in the northern hemisphere. Methods: Cattle selected from herds with a history of Hypoderma infestation were grouped into blocks of three (Italy, 33 cattle; Germany, 30 cattle) or two (USA, 16 cattle) animals each, on the basis of positivity at the pre-treatment anti-Hypoderma antibody titres. Within each block, animals were randomly allocated to one of the following treatment regimens: saline (control); IVM LAI, administered at the predicted time of occurrence of first-instar larvae (Italy, Germany, USA); IVM LAI, administered at the predicted time of occurrence of second- and/or third-instar larvae (Italy, Germany). All treatments were administered by subcutaneous injection in correspondence of the area anterior to the shoulder at 1 ml/50 kg body weight, which corresponds to 630 mcg IVM/kg for IVM LAI. Results: No Hypoderma larvae emerged from animals treated with IVM LAI, whereas live H. lineatum (Italy) or H. bovis (Germany, USA) larvae were collected from saline-treated animals (P < 0.01). No adverse reactions to treatments were in any of the animals enrolled in the study. Conclusions: The results from this study demonstrate that ivermectin in a long-acting formulation is 100 % efficacious in the treatment of cattle naturally infested by H. bovis and H. lineatum larvae at all stages of development. IVM LAI can, therefore, be used as 'prophylactic' treatment for Hypoderma spp. infestations in absence of external evidence of their presence and thus prior to skin and carcass damage, and as 'therapeutic' treatment, when warbles are already present

Mice as paratenic hosts of Aelurostrongylus abstrusus

Several species of nematodes included in the superfamily Metastrongyloidea are recognized agents of parasitic infections in felines. Aelurostrongylus abstrusus is the most prevalent species affecting the respiratory system of domestic cats. The route of infection in cats is supposed to be through ingestion of gastropod intermediate or paratenic hosts. However, because gastropods are not the preferred preys of cats, rodents were suggested to play an important role as paratenic hosts in the biological cycle of A. abstrusus and in the epidemiology of aelurostrongylosis

Survey of Toxoplasma gondii and Neospora caninum, haemotropic mycoplasmas and other arthropod-borne pathogens in cats from Albania

BACKGROUND: Albania is a country on the western part of the Balkan Peninsula. The Mediterranean climate is favourable for the stable development of many arthropod species, which are incriminated as vectors for various agents. Recently, several papers have reported on epidemiological aspects of parasitic diseases including vector-borne disease agents of dogs with zoonotic characteristics in Albania. However, data on the epidemiology of feline parasitic and bacterial agents in Albania is scarce. METHODS: Serum and EDTA-blood samples collected from 146 domestic cats from Tirana during 2008 through 2010 were examined for exposure to Toxoplasma gondii, Neospora caninum, Leishmania infantum, and Anaplasma spp. with IFAT, for infection with L. infantum, A. phagocytophilum, Bartonella spp. and haemotropic mycoplasmas with conventional PCR and real-time PCR and for Dirofilaria immitis with antigen ELISA. Additionally blood smear microscopy was carried out for detection of blood-borne pathogens. RESULTS: Antibodies to T. gondii (titre ≥1:100) were demonstrated in 91 cats (62.3%). Antibodies to N. caninum (titre ≥1:100), L. infantum (titre ≥1:64) and Anaplasma spp. (titre ≥1:100) were found in the serum of 15 (10.3%), 1 (0.7%) or 3 (2.1%) cats, respectively. DNA of haemotropic mycoplasmas was detected in the blood of 45 cats (30.8%), namely Candidatus Mycoplasma haemominutum (21.9%), Mycoplasma haemofelis (10.3%), and Candidatus Mycoplasma turicensis (5.5%), with ten cats harbouring co-infections of two mycoplasmas each; blood from one cat was PCR positive for Bartonella henselae. No DNA of Leishmania spp. and A. phagocytophilum or circulating D. immitis antigen was detected in any cat sample. The overall prevalence of haemotropic mycoplasmas was significantly higher in male compared to female cats (40.6% vs. 24.1%, p = 0.0444); and age was associated positively with the prevalence of antibodies to T. gondii (p = 0.0008) and the percentage of haemotropic mycoplasma infection (p = 0.0454). CONCLUSIONS: With the broad screening panel including direct and indirect methods applied in the present study, a wide spectrum of exposure to or infection with parasitic or bacterial agents was detected

Efficacy of a novel topical fipronil, (S)-methoprene, eprinomectin and praziquantel combination against naturally acquired intestinal nematode and cestode infections in cats.

The efficacy of a novel topical combination formulation of fipronil, (S)-methoprene, eprinomectin and praziquantel against naturally acquired intestinal nematode and cestode infections in cats was evaluated in seven negative control, blinded studies. Cats were selected based on a pre-treatment faecal examination indicating a patent infection with at least hookworms (two studies), Toxocara ascarids (one study), taeniid cestodes (two studies) or Dipylidium cestodes (two studies). In each study, cats were assigned randomly to blocks of two animals each, based on decreasing pre-treatment body weight and were randomly allocated to one of two groups of six to 12 cats: untreated (control) or treated with topical fipronil (8.3%, w/v), (S)-methoprene (10%, w/v), eprinomectin (0.4%, w/v) and praziquantel (8.3%, w/v) (BROADLINE(®), Merial) at 0.12 mL/kg body weight (providing a minimum of 10mg fipronil+12 mg S-methoprene+0.5mg eprinomectin+10mg praziquantel per kg body weight). The topical treatment was administered directly on the skin in the midline of the neck in a single spot once on Day 0. For parasite recovery and count, cats were euthanized humanely and necropsied seven or ten days after treatment. A single treatment with the novel topical combination product provided 91% efficacy against Ancylostoma braziliense, ≥ 99% efficacy against Ancylostoma tubaeforme, and >97% efficacy against Toxocara cati. Similarly, excellent efficacy was established against Taenia taeniaeformis, Dipylidium caninum and Diplopylidium spp. as demonstrated by >97% and up to 100% reductions of cestode counts in the treated cats when compared to the untreated controls (P<0.01). All cats accepted the treatment well based on health observations post-treatment and daily health observations. No adverse experiences or other health problems were observed throughout the studies. The results of this series of controlled studies demonstrated high efficacy and excellent acceptability of the novel topical combination formulation of fipronil, (S)-methoprene, eprinomectin and praziquantel against a broad range of feline intestinal nematode and cestode infections

Efficacy against nematode and cestode infections and safety of a novel topical fipronil, (S)-methoprene, eprinomectin and praziquantel combination product in domestic cats under field conditions in Europe

AbstractA novel topical combination product (BROADLINE®, Merial) composed of fipronil, (S)-methoprene, eprinomectin and praziquantel was evaluated for safety and efficacy against nematode and cestode infections in domestic cats. The study comprised a multi-centre, positive control, blinded, field study, using a randomized block design based on order of presentation for allocation. In total 196 client-owned cats, confirmed as positive for naturally acquired infections of nematodes and/or cestodes by pre-treatment faecal examination, were studied in seven countries in Europe. Pre-treatment faecal examination revealed the presence of Toxocara, hookworm, Capillaria and/or spirurid nematode infections in 129, 73, 33 or 1 cat(s), respectively; infections with taeniid and Dipylidium cestodes were demonstrated in 39 and 17 cats, respectively. Cats were allocated randomly to one of two treatments in a ratio of 2, topical fipronil (8.3%, w/v), (S)-methoprene (10%, w/v), eprinomectin (0.4%, w/v) and praziquantel (8.3%, w/v) (BROADLINE®, Merial; 130 cats); and 1, topical PROFENDER® Spot-On (Bayer; 66 cats) and treated once on Day 0. For evaluation of efficacy, two faecal samples were collected, one prior to treatment (Day −4±4 days) and one at the end of the study (Day 14±5 days). These were examined for fecal forms of nematode and cestode parasites. For evaluation of safety, cats were examined by a veterinarian before treatment and at the end of the study, and cat owners recorded the health status of their cats daily until the end of the study.For cats treated with Broadline®, the efficacy was >99.9%, 100%, and 99.6% for Toxocara, hookworms, and Capillaria, respectively; and the efficacy was >99.9%, >99.9%, and 98.5%, respectively, for the cats treated with Profender® (p<0.001 for all nematodes and both treatments). Efficacy was 100% for both cestodes for both treatments (p<0.001).No treatment related adverse experiences were observed throughout the study. For both treatments, every cat that completed the study was given a safety score of ‘excellent’ for both local and systemic evaluations. The topical combination product of fipronil, (S)-methoprene, eprinomectin and praziquantel was shown to have an excellent safety profile and demonstrated high levels of efficacy when administered once as topical solution to cats infected with nematodes and cestodes under field conditions

New mitogenome and nuclear evidence on the phylogeny and taxonomy of the highly zoonotic tapeworm Echinococcus granulosus sensu stricto

Cystic echinococcosis, a zoonotic disease caused by Echinococcus granulosus sensu lato (s.l.), is a significant global public health concern. Echinococcus granulosus s. l. is currently divided into numerous genotypes (G1-G8 and G10) of which G1-G3 are the most frequently implicated genotypes in human infections. Although it has been suggested that G1-G3 could be regarded as a distinct species E. granulosus sensu stricto (s. s.), the evidence to support this is inconclusive. Most importantly, data from nuclear DNA that provide means to investigate the exchange of genetic material between G1-G3 is lacking as none of the published nuclear DNA studies have explicitly included G2 or G3. Moreover, the commonly used relatively short mtDNA sequences, including the complete coxl gene, have not allowed unequivocal differentiation of genotypes G1-G3. Therefore, significantly longer mtDNA sequences are required to distinguish these genotypes with confidence. The main aim of this study was to evaluate the phylogenetic relations and taxonomy of genotypes G1-G3 using sequences of nearly complete mitogenomes (11,443 bp) and three nuclear loci (2984 bp). A total of 23 G1-G3 samples were analysed, originating from 5 intermediate host species in 10 countries. The mtDNA data demonstrate that genotypes G1 and G3 are distinct mitochondrial genotypes (separated by 37 mutations), whereas G2 is not a separate genotype or even a monophyletic cluster, but belongs to G3. Nuclear data revealed no genetic separation of G1 and G3, suggesting that these genotypes form a single species due to ongoing gene flow. We conclude that: (a) in the taxonomic sense, genotypes G1 and G3 can be treated as a single species E. granulosus s. s.; (b) genotypes G1 and G3 should be regarded as distinct genotypes only in the context of mitochondrial data; (c) we recommend excluding G2 from the genotype list. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Quantum state preparation and macroscopic entanglement in gravitational-wave detectors

Long-baseline laser-interferometer gravitational-wave detectors are operating at a factor of 10 (in amplitude) above the standard quantum limit (SQL) within a broad frequency band. Such a low classical noise budget has already allowed the creation of a controlled 2.7 kg macroscopic oscillator with an effective eigenfrequency of 150 Hz and an occupation number of 200. This result, along with the prospect for further improvements, heralds the new possibility of experimentally probing macroscopic quantum mechanics (MQM) - quantum mechanical behavior of objects in the realm of everyday experience - using gravitational-wave detectors. In this paper, we provide the mathematical foundation for the first step of a MQM experiment: the preparation of a macroscopic test mass into a nearly minimum-Heisenberg-limited Gaussian quantum state, which is possible if the interferometer's classical noise beats the SQL in a broad frequency band. Our formalism, based on Wiener filtering, allows a straightforward conversion from the classical noise budget of a laser interferometer, in terms of noise spectra, into the strategy for quantum state preparation, and the quality of the prepared state. Using this formalism, we consider how Gaussian entanglement can be built among two macroscopic test masses, and the performance of the planned Advanced LIGO interferometers in quantum-state preparation

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure