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1.
Eur J Pharmacol ; 898: 173986, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33640406

RESUMO

The high-affinity choline transporter CHT1 mediates choline uptake, the rate-limiting and regulatory step in acetylcholine synthesis at cholinergic presynaptic terminals. CHT1-medated choline uptake is specifically inhibited by hemicholinium-3, which is a type of choline analog that acts as a competitive inhibitor. Although the substrate choline and the inhibitor hemicholinium-3 are well-established ligands of CHT1, few potent ligands other than choline analogs have been reported. Here we show that tetrahydropyrimidine anthelmintics, known as nicotinic acetylcholine receptor agonists, act as competitive inhibitors of CHT1. A ligand-dependent trafficking assay in cell lines expressing human CHT1 was designed to search for CHT1 ligands from a collection of biologically active compounds. We found that morantel as well as other tetrahydropyrimidines, pyrantel and oxantel, potently inhibits the high-affinity choline uptake activity of CHT1 in a competitive manner similar to the inhibitor hemicholinium-3. They also inhibit the high-affinity choline transporter from the nematode Caenorhabditis elegans. Finally, tetrahydropyrimidines potently inhibit the high-affinity choline uptake in rat brain synaptosomes at a low micromolar level, resulting in the inhibition of acetylcholine synthesis. The rank order of potency in synaptosomes is as follows: morantel > pyarantel > oxantel (Ki = 1.3, 5.7, and 8.3 µM, respectively). Our results reveal that tetrahydropyrimidine anthelmintics are novel CHT1 ligands that inhibit the high-affinity choline uptake for acetylcholine synthesis in cholinergic neurons.


Assuntos
Anti-Helmínticos/farmacologia , Encéfalo/efeitos dos fármacos , Proteínas de Transporte de Cátions/antagonistas & inibidores , Colina/metabolismo , Pirimidinas/farmacologia , Simportadores/antagonistas & inibidores , Animais , Anti-Helmínticos/metabolismo , Ligação Competitiva , Transporte Biológico , Encéfalo/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Feminino , Células HEK293 , Humanos , Ligantes , Camundongos , Morantel/metabolismo , Morantel/farmacologia , Ligação Proteica , Transporte Proteico , Pirantel/análogos & derivados , Pirantel/metabolismo , Pirantel/farmacologia , Pirimidinas/metabolismo , Simportadores/genética , Simportadores/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo
2.
PLoS Pathog ; 17(2): e1008982, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33544769

RESUMO

In the absence of efficient alternative strategies, the control of parasitic nematodes, impacting human and animal health, mainly relies on the use of broad-spectrum anthelmintic compounds. Unfortunately, most of these drugs have a limited single-dose efficacy against infections caused by the whipworm, Trichuris. These infections are of both human and veterinary importance. However, in contrast to a wide range of parasitic nematode species, the narrow-spectrum anthelmintic oxantel has a high efficacy on Trichuris spp. Despite this knowledge, the molecular target(s) of oxantel within Trichuris is still unknown. In the distantly related pig roundworm, Ascaris suum, oxantel has a small, but significant effect on the recombinant homomeric Nicotine-sensitive ionotropic acetylcholine receptor (N-AChR) made up of five ACR-16 subunits. Therefore, we hypothesized that in whipworms, a putative homolog of an ACR-16 subunit, can form a functional oxantel-sensitive receptor. Using the pig whipworm T. suis as a model, we identified and cloned a novel ACR-16-like subunit and successfully expressed the corresponding homomeric channel in Xenopus laevis oocytes. Electrophysiological experiments revealed this receptor to have distinctive pharmacological properties with oxantel acting as a full agonist, hence we refer to the receptor as an O-AChR subtype. Pyrantel activated this novel O-AChR subtype moderately, whereas classic nicotinic agonists surprisingly resulted in only minor responses. We observed that the expression of the ACR-16-like subunit in the free-living nematode Caenorhabditis elegans conferred an increased sensitivity to oxantel of recombinant worms. We demonstrated that the novel Tsu-ACR-16-like receptor is indeed a target for oxantel, although other receptors may be involved. These finding brings new insight into the understanding of the high sensitivity of whipworms to oxantel, and highlights the importance of the discovery of additional distinct receptor subunit types within Trichuris that can be used as screening tools to evaluate the effect of new synthetic or natural anthelmintic compounds.


Assuntos
Antinematódeos/farmacologia , Proteínas de Helminto/antagonistas & inibidores , Pirantel/análogos & derivados , Receptores Colinérgicos/química , Tricuríase/tratamento farmacológico , Trichuris/efeitos dos fármacos , Animais , Caenorhabditis elegans/efeitos dos fármacos , Feminino , Proteínas de Helminto/classificação , Proteínas de Helminto/metabolismo , Masculino , Pirantel/farmacologia , Receptores Colinérgicos/classificação , Receptores Colinérgicos/metabolismo , Suínos , Tricuríase/metabolismo , Tricuríase/parasitologia , Xenopus laevis/metabolismo
3.
Acta Vet Scand ; 63(1): 5, 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33494770

RESUMO

BACKGROUND: With intensive use of anthelmintic drugs in recent decades, anthelmintic resistance (AR) in horse nematodes is becoming a growing issue in many countries. However, there is little available information about the parasites, treatment practices or AR in the horse population in Lithuania. The aim of this study was to assess the current situation of AR on horse farms in Lithuania. The study was conducted in 25 stables on horses with a strongyle faecal egg count (FEC) of ≥ 200 eggs per gram. A faecal egg count reduction test (FECRT) was performed on each farm after administration of ivermectin (IVM) or pyrantel (PYR). RESULTS: The efficacy of IVM was comparatively high, with 98.8% of 250 horses having a zero egg count 14 days after treatment. Two conditions were used to interpret the FECRT results for PYR: firstly, resistance was determined when FECR was < 90% and the lower 95% confidence interval (LCL) was < 80%, and secondly when in addition the upper confidence level (UCL) was < 95%. Under the first condition, resistance against PYR was found in five stables (25% of all tested herds), while when considering the UCL as well, resistance was only detected in two stables (8%). The FEC showed a significant (P < 0.01) difference between the treatment and control groups. Only cyathostomin larvae were detected in larval cultures derived from strongyle-positive faecal samples collected 14 days after treatment of a test group with PYR. CONCLUSIONS: This in vivo study showed that PYR resistance is prevalent on horse farms in Lithuania, while the efficacy of IVM still appears to be unaffected. However, further studies of ivermectin resistance are needed. These findings should guide the implementation of more sustainable management of strongyle infections in horses in Lithuania.


Assuntos
Anti-Helmínticos/uso terapêutico , Doenças dos Cavalos/tratamento farmacológico , Infecções por Nematoides/veterinária , Animais , Anti-Helmínticos/farmacologia , Resistência a Medicamentos , Fezes/parasitologia , Feminino , Doenças dos Cavalos/parasitologia , Cavalos , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Lituânia , Masculino , Nematoides/efeitos dos fármacos , Infecções por Nematoides/tratamento farmacológico , Contagem de Ovos de Parasitas/veterinária , Pirantel/farmacologia , Pirantel/uso terapêutico
4.
Parasit Vectors ; 13(1): 448, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32891172

RESUMO

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.


Assuntos
Doenças do Cão/tratamento farmacológico , Cães/parasitologia , Ixodes/efeitos dos fármacos , Infestações por Carrapato/veterinária , Acaricidas/administração & dosagem , Acaricidas/uso terapêutico , Administração Oral , Animais , Austrália , Azetidinas/administração & dosagem , Azetidinas/uso terapêutico , Combinação de Medicamentos , Isoxazóis/administração & dosagem , Isoxazóis/uso terapêutico , Macrolídeos/administração & dosagem , Macrolídeos/uso terapêutico , Naftalenos/administração & dosagem , Naftalenos/uso terapêutico , Carga Parasitária , Pirantel/administração & dosagem , Pirantel/uso terapêutico , Compostos de Espiro/administração & dosagem , Compostos de Espiro/uso terapêutico , Infestações por Carrapato/tratamento farmacológico , Resultado do Tratamento
5.
Parasit Vectors ; 13(1): 339, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32660542

RESUMO

BACKGROUND: Recent reports indicated that increasing the monthly oral dosage and the number of consecutive monthly doses of moxidectin improved the efficacy against macrocyclic lactone (ML)-resistant Dirofilaria immitis. The two laboratory studies reported here evaluated the efficacy of four or six monthly oral doses of 24 µg/kg moxidectin compared to six monthly doses of either Heartgard® Plus (ivermectin/pyrantel) or Interceptor® Plus (milbemycin oxime/praziquantel) against ML-resistant D. immitis strains. METHODS: Dogs were inoculated 30 days prior to first treatment with 50 third-stage (L3) larvae of a ML-resistant strain of D. immitis, ZoeLA or JYD-34. In each study, dogs (six per group) were randomized to treatment with six monthly doses of placebo, four or six monthly doses of 24 µg/kg moxidectin, or six monthly doses of Heartgard® Plus or Interceptor® Plus at their label dose rates. Efficacy was evaluated by adult heartworm counts approximately nine months after L3 inoculation. RESULTS: All negative-control dogs were infected with adult heartworms (geometric mean, 35.6; range, 24-41) for ZoeLA and (geometric mean, 32.9; range, 30-37) for JYD-34. Efficacies against ZoeLA for moxidectin, Heartgard® Plus and Interceptor® Plus were ≥ 96.1%, 18.7% and 21.2%, respectively. Adult counts for both moxidectin-treated groups were significantly lower than negative control (P < 0.0001), significantly lower than Heartgard® Plus and Interceptor® Plus (P < 0.0001), but not significantly different from each other (P = 0.5876). Counts for Heartgard® Plus and Interceptor® Plus were not significantly different than negative control (P ≥ 0.2471). Efficacies against JYD-34 were ≥ 95.9%, 63.9% and 54.6% for moxidectin, Heartgard® Plus and Interceptor® Plus, respectively. Counts for all groups were significantly lower than negative control (P ≤ 0.0001). Counts for six monthly doses of moxidectin were significantly lower than those for four monthly doses (P = 0.0470), and the counts for both moxidectin-treated groups were significantly lower than Heartgard® Plus and Interceptor® Plus (P ≤ 0.0002). CONCLUSIONS: Moxidectin administered orally at 24 µg/kg to dogs for four or six consecutive months was ≥ 95.9% effective in preventing the development of two ML-resistant heartworm strains and resulted in significantly fewer adult D. immitis than in dogs treated with Heartgard® Plus or Interceptor® Plus when administered for six consecutive months at their approved label dosages in two laboratory efficacy studies.


Assuntos
Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/tratamento farmacológico , Doenças do Cão/parasitologia , Macrolídeos/administração & dosagem , Animais , Cães , Combinação de Medicamentos , Resistência a Medicamentos , Ivermectina/administração & dosagem , Ivermectina/uso terapêutico , Lactonas/uso terapêutico , Macrolídeos/uso terapêutico , Praziquantel/administração & dosagem , Praziquantel/uso terapêutico , Pirantel/administração & dosagem , Pirantel/uso terapêutico
6.
Parasit Vectors ; 13(1): 342, 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32646465

RESUMO

BACKGROUND: Parascaris univalens is a pathogenic parasite of foals and yearlings worldwide. In recent years, Parascaris spp. worms have developed resistance to several of the commonly used anthelmintics, though currently the mechanisms behind this development are unknown. The aim of this study was to investigate the transcriptional responses in adult P. univalens worms after in vitro exposure to different concentrations of three anthelmintic drugs, focusing on drug targets and drug metabolising pathways. METHODS: Adult worms were collected from the intestines of two foals at slaughter. The foals were naturally infected and had never been treated with anthelmintics. Worms were incubated in cell culture media containing different concentrations of either ivermectin (10-9 M, 10-11 M, 10-13 M), pyrantel citrate (10-6 M, 10-8 M, 10-10 M), thiabendazole (10-5 M, 10-7 M, 10-9 M) or without anthelmintics (control) at 37 °C for 24 h. After incubation, the viability of the worms was assessed and RNA extracted from the anterior region of 36 worms and sequenced on an Illumina NovaSeq 6000 system. RESULTS: All worms were alive at the end of the incubation but showed varying degrees of viability depending on the drug and concentration used. Differential expression (Padj < 0.05 and log2 fold change ≥ 1 or ≤ - 1) analysis showed similarities and differences in the transcriptional response after exposure to the different drug classes. Candidate genes upregulated or downregulated in drug exposed worms include members of the phase I metabolic pathway short-chain dehydrogenase/reductase superfamily (SDR), flavin containing monooxygenase superfamily (FMO) and cytochrome P450-family (CYP), as well as members of the membrane transporters major facilitator superfamily (MFS) and solute carrier superfamily (SLC). Generally, different targets of the anthelmintics used were found to be upregulated and downregulated in an unspecific pattern after drug exposure, apart from the GABA receptor subunit lgc-37, which was upregulated only in worms exposed to 10-9 M of ivermectin. CONCLUSIONS: To our knowledge, this is the first time the expression of lgc-37 and members of the FMO, SDR, MFS and SLC superfamilies have been described in P. univalens and future work should be focused on characterising these candidate genes to further explore their potential involvement in drug metabolism and anthelmintic resistance.


Assuntos
Anti-Helmínticos/farmacologia , Ascaridoidea , Transcriptoma/efeitos dos fármacos , Animais , Anti-Helmínticos/metabolismo , Infecções por Ascaridida/metabolismo , Infecções por Ascaridida/veterinária , Ascaridoidea/efeitos dos fármacos , Ascaridoidea/metabolismo , Resistência a Medicamentos , Doenças dos Cavalos/metabolismo , Doenças dos Cavalos/parasitologia , Cavalos , Ivermectina/metabolismo , Ivermectina/farmacologia , Pirantel/análogos & derivados , Pirantel/metabolismo , Pirantel/farmacologia , Tiabendazol/metabolismo , Tiabendazol/farmacologia
7.
Parasit Vectors ; 13(1): 385, 2020 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-32727548

RESUMO

BACKGROUND: Infection with the cardiopulmonary nematode Angiostrongylus vasorum may cause severe disease in dogs, therefore prophylactic treatments are necessary to prevent infection in dogs at risk. A clinical field study was conducted to demonstrate the efficacy and safety of an oral combination of sarolaner, moxidectin and pyrantel (Simparica Trio®) for the prevention of A. vasorum infection in dogs (prevention study). A survey study was conducted concurrently to determine the infection pressure in the same areas. METHODS: Prevention and survey studies were both conducted at the same veterinary clinics in endemic hot spots for A. vasorum in Denmark and Italy. The prevention study was a randomized, placebo controlled, double masked study where 622 client-owned dogs were treated and tested at 30 days intervals for 10 months. In the survey study 1628 dogs that were at risk of infection and/or were suspected to be infected were tested by fecal and/or serological methods, and the percent of dogs positive for A. vasorum was calculated. RESULTS: In the prevention study, there were no adverse events related to treatment with Simparica Trio®. Two placebo-treated animals became infected with A. vasorum during the 10-month study period, while none of the dogs in the combination product-treated group became infected. In the survey study, 12.2% of the study dogs were found positive to A. vasorum, indicating high exposure to the parasite during the period of the prevention study. CONCLUSIONS: Monthly oral treatment with the combination of sarolaner, moxidectin and pyrantel (Simparica Trio®) was 100% effective in the prevention of natural infection with A. vasorum in dogs in highly endemic areas. In endemic areas, A. vasorum occurrence in dogs at risk is considerable.


Assuntos
Antinematódeos/uso terapêutico , Infecções por Strongylida/veterinária , Administração Oral , Angiostrongylus/efeitos dos fármacos , Animais , Antinematódeos/administração & dosagem , Azetidinas/administração & dosagem , Azetidinas/farmacologia , Dinamarca , Doenças do Cão/tratamento farmacológico , Doenças do Cão/parasitologia , Doenças do Cão/prevenção & controle , Cães , Combinação de Medicamentos , Hospitais Veterinários , Itália , Macrolídeos/administração & dosagem , Macrolídeos/farmacologia , Carga Parasitária , Pirantel/administração & dosagem , Pirantel/farmacologia , Compostos de Espiro/administração & dosagem , Compostos de Espiro/farmacologia , Infecções por Strongylida/tratamento farmacológico , Infecções por Strongylida/prevenção & controle , Inquéritos e Questionários
8.
Artigo em Inglês | MEDLINE | ID: mdl-32403053

RESUMO

Ancylostoma caninum is the most prevalent intestinal nematode of dogs, and has a zoonotic potential. Multiple-drug resistance (MDR) has been confirmed in a number of A. caninum isolates, including isolate Worthy 4.1F3P, against all anthelmintic drug classes approved for hookworm treatment in dogs in the United States (US). The cyclooctadepsipeptide emodepside is not registered to use in dogs in the US, but in a number of other countries/regions. The objective of this study was to evaluate the efficacy of emodepside + praziquantel, as well as three commercial products that are commonly used in the US for treatment of hookworms, against a suspected (subsequently confirmed) MDR A. caninum isolate Worthy 4.1F3P. 40 dogs infected on study day (SD) 0 with 300 third-stage larvae, were randomly allocated to one of five treatment groups with eight dogs each: pyrantel pamoate (Nemex®-2), fenbendazole (Panacur® C), milbemycin oxime (Interceptor®), emodepside + praziquantel tablets and non-treated control. Fecal egg counts (FEC) were performed on SDs 19, 20, 22, 27, 31 and 34. All treatments were administered as per label requirements on SD 24 to dogs in Groups 1 through 4. Two additional treatments were administered on SDs 25 and 26 to dogs in Group 2 as per label requirements. Dogs were necropsied on SD 34 and the digestive tract was removed/processed for worm recovery and enumeration. The geometric mean (GM) worm counts for the control group was 97.4, and for the pyrantel pamoate, fenbendazole, milbemycin oxime, and emodepside + praziquantel groups were 74.8, 72.0, 88.9, and 0.4, respectively. These yielded efficacies of 23.2%, 26.1%, and 8.8%, and 99.6%, respectively. These data support previous findings of the MDR status of Worthy 4.1F3P as treatments with pyrantel pamoate, fenbendazole and milbemycin oxime lacked efficacy. In sharp contrast, Worthy 4.1F3P was highly susceptible to treatment with emodepside + praziquantel.


Assuntos
Ancylostomatoidea , Ancilostomíase/veterinária , Anti-Helmínticos/uso terapêutico , Doenças do Cão/parasitologia , Ancylostomatoidea/isolamento & purificação , Ancylostomatoidea/patogenicidade , Ancilostomíase/tratamento farmacológico , Animais , Anti-Helmínticos/administração & dosagem , Depsipeptídeos/administração & dosagem , Depsipeptídeos/uso terapêutico , Doenças do Cão/tratamento farmacológico , Cães , Combinação de Medicamentos , Resistência a Múltiplos Medicamentos , Infecções por Uncinaria/tratamento farmacológico , Infecções por Uncinaria/veterinária , Intestinos/parasitologia , Macrolídeos/administração & dosagem , Macrolídeos/uso terapêutico , Praziquantel/administração & dosagem , Praziquantel/uso terapêutico , Pirantel/administração & dosagem , Pirantel/uso terapêutico , Resultado do Tratamento
9.
Parasit Vectors ; 13(1): 57, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113466

RESUMO

BACKGROUND: Five studies were conducted to evaluate a novel oral combination tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio™), for efficacy against induced flea infestations, speed of kill and effects on flea reproduction on dogs. METHODS: Based on pre-treatment flea counts, dogs were randomly allocated to treatment with a single, oral dose of either placebo or 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) on Day 0. All dogs were infested with approximately 100 unfed, adult fleas (C. felis or C. canis) prior to treatment and weekly for 5 weeks post-treatment. In Studies 1, 2 and 3, the number of viable fleas were comb-counted at 24 h after treatment and after each weekly infestation; Study 2 also included groups treated with tablets containing sarolaner-alone (1.2 mg/kg), moxidectin-alone (24 µg/kg) or pyrantel-alone (5 mg/kg). In Study 4, flea counts were conducted at 3, 4, 8 and 12 h after treatment and subsequent weekly infestations to establish speed of kill. In Study 5 (flea reproduction), dogs were housed in an enclosure designed to facilitate collection of flea eggs. RESULTS: Efficacy of Simparica Trio™ against C. felis was ≥ 99.7% and against C. canis was 100% at 24 h after treatment and after subsequent infestations for at least 35 days. Treatment with sarolaner-alone had similar efficacy to Simparica Trio™, while moxidectin-alone and pyrantel-alone were no different from placebo at most time points. In Study 4, significant flea killing started at 4 h after treatment; by 8 h after treatment, all treated dogs were free of fleas. Following weekly re-infestation, the combination product reduced fleas by ≥ 97.8% within 12 h for 28 days. Simparica Trio™ reduced flea egg-laying by 100% for 35 days. No treatment-related adverse reactions occurred in any study. CONCLUSIONS: A single dose of Simparica Trio™ at the recommended minimum dose provided highly efficacious and rapid treatment within 4 h of existing flea infestations and persistent control of fleas on dogs for 5 weeks. The efficacy against fleas resulted in 100% prevention of flea reproduction for over a month following a single oral dose.


Assuntos
Acaricidas/administração & dosagem , Doenças do Cão/tratamento farmacológico , Infestações por Pulgas/veterinária , Administração Oral , Animais , Azetidinas/administração & dosagem , Ctenocephalides/fisiologia , Doenças do Cão/prevenção & controle , Cães , Combinação de Medicamentos , Feminino , Infestações por Pulgas/tratamento farmacológico , Infestações por Pulgas/prevenção & controle , Macrolídeos/administração & dosagem , Masculino , Carga Parasitária , Pirantel/administração & dosagem , Reprodução/efeitos dos fármacos , Compostos de Espiro/administração & dosagem , Fatores de Tempo , Resultado do Tratamento
10.
Parasit Vectors ; 13(1): 100, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113468

RESUMO

BACKGROUND: Tick infestations can cause direct deleterious effects to dogs as a result of tick blood-feeding, and indirectly ticks can transmit disease agents that can be detrimental to the health of both dogs and humans. Six laboratory studies were conducted to support dosage selection and efficacy confirmation of a novel combination of sarolaner, moxidectin and pyrantel against four tick species that commonly infest dogs in Europe. METHODS: Two studies were conducted against Dermacentor reticulatus (one of which was a dose determination study), two against Ixodes ricinus, and one each against Ixodes hexagonus and Rhipicephalus sanguineus (sensu lato). In each study, eight purpose-bred Beagle or mix-breed dogs were randomly allocated to each treatment group and infested with 50 unfed adult ticks on Days-2, 5, 12, 19, 26 and 33. On Day 0 dogs were treated orally with placebo or the combination product. In the dose determination study, dogs received sarolaner at point dosages of 0.6 mg/kg, 1.2 mg/kg or 2.4 mg/kg in combination with moxidectin and pyrantel, and in all other studies dogs received Simparica Trio™ to provide minimum dosages of 1.2 mg/kg sarolaner, 24 µg/kg moxidectin and 5 mg/kg pyrantel (as pamoate salt). Efficacy was assessed based on live tick counts conducted 48 hours after treatment and each weekly infestation. RESULTS: There were no treatment-related adverse events in any study. In the dose determination study, 1.2 mg/kg sarolaner was the lowest dosage evaluated that provided > 90% efficacy for at least 28 days and therefore was selected as the dosage to provide tick control for at least one month following a single oral treatment. In the dose confirmation studies, a single oral dose of Simparica Trio™ provided ≥ 99.2% efficacy against existing infestations of all tick species, and against re-infestations efficacy was ≥ 97.2% against D. reticulatus for 28 days and against all other species for 35 days. CONCLUSIONS: These studies support the sarolaner dose selected and confirm the efficacy of a single oral dose of Simparica Trio™ against existing infestations and re-infestations of the common tick species infesting dogs in Europe for at least one month.


Assuntos
Acaricidas/administração & dosagem , Doenças do Cão/tratamento farmacológico , Infestações por Carrapato/veterinária , Administração Oral , Animais , Azetidinas/administração & dosagem , Doenças do Cão/parasitologia , Doenças do Cão/prevenção & controle , Cães , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Europa (Continente) , Feminino , Ixodidae/classificação , Macrolídeos/administração & dosagem , Masculino , Pirantel/administração & dosagem , Compostos de Espiro/administração & dosagem , Comprimidos , Infestações por Carrapato/tratamento farmacológico , Infestações por Carrapato/parasitologia , Infestações por Carrapato/prevenção & controle , Fatores de Tempo , Resultado do Tratamento
11.
Parasit Vectors ; 13(1): 70, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113470

RESUMO

BACKGROUND: Gastrointestinal nematodes are parasites that commonly infect dogs, and infections can be subclinical or may cause considerable clinical disease. Some species are zoonotic and may also cause clinical disease in humans. Year-round treatment of dogs is recommended to eliminate existing infections, which also indirectly reduces the potential for subsequent human exposure to zoonotic species. Here we present two studies that evaluated the safety and efficacy of a novel chewable oral tablet containing sarolaner, moxidectin and pyrantel against gastrointestinal nematode infections in dogs presented as veterinary patients in Europe and the USA. METHODS: Dogs naturally infected with Toxocara canis, Toxascaris leonina, Ancylostoma caninum and/or Uncinaria stenocephala were enrolled in the European study, and dogs naturally infected with T. canis were enrolled in the USA study. The animals were treated once orally with Simparica Trio™ tablets to provide 1.2-2.4 mg/kg sarolaner, 24-48 µg/kg moxidectin and 5-10 mg/kg pyrantel (as pamoate salt) or with a commercially available product according to the label directions as positive control. Efficacy was based on the post-treatment reduction in geometric mean egg counts (per gram feces) 7 or 10 days after treatment compared to pre-treatment egg counts. RESULTS: Simparica Trio™ was well tolerated in both studies. In the European study, geometric mean egg counts for T. canis, T. leonina, A. caninum and U. stenocephala were reduced by ≥ 98.3% in the Simparica Trio™ group and by ≥ 97.4% in the afoxolaner + milbemycin oxime group. In the USA study, geometric mean egg counts for T. canis were reduced by 99.2% in the Simparica Trio™ group and by 98.6% in the ivermectin + pyrantel group. In the USA study, 48 and 10 dogs in the Simparica Trio™ and the ivermectin + pyrantel group, respectively, were co-infected with A. caninum and the reduction in the post-treatment mean fecal egg counts were 98.6% and 74.7%, respectively. CONCLUSIONS: A single oral administration of Simparica Trio™ chewable tablets was well tolerated and was effective in the treatment of dogs with naturally occurring gastrointestinal nematode infections presented as veterinary patients in Europe and the USA.


Assuntos
Antinematódeos/administração & dosagem , Doenças do Cão/tratamento farmacológico , Enteropatias Parasitárias/veterinária , Nematoides/efeitos dos fármacos , Infecções por Nematoides/veterinária , Administração Oral , Animais , Azetidinas/administração & dosagem , Cães , Combinação de Medicamentos , Europa (Continente) , Feminino , Enteropatias Parasitárias/tratamento farmacológico , Macrolídeos/administração & dosagem , Masculino , Nematoides/classificação , Infecções por Nematoides/tratamento farmacológico , Contagem de Ovos de Parasitas , Pirantel/administração & dosagem , Compostos de Espiro/administração & dosagem , Resultado do Tratamento , Estados Unidos
12.
Parasit Vectors ; 13(1): 99, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113471

RESUMO

BACKGROUND: Ancylostomatids ('hookworms') are among the most important zoonotic nematode parasites infecting dogs worldwide. Ancylostoma caninum and Uncinaria stenocephala are two of the most common hookworm species that infect dogs. Both immature and adult stages of hookworms are voracious blood feeders and can cause death in young dogs before infection can be detected by routine fecal examination. Hence, treatment of both immature and adult stages of hookworms will decrease the risk of important clinical disease in the dog as well as the environmental contamination caused by egg-laying adults, which should reduce the risk of infection for both dogs and humans. The studies presented here were conducted to evaluate the efficacy of a novel, oral chewable tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio™), against induced larval (L4), immature adult (L5) and adult A. caninum, and adult U. stenocephala infections in dogs. METHODS: Eight negative-controlled, masked, randomized laboratory studies were conducted. Two separate studies were conducted against each of the target parasites and stages. Sixteen or 18 purpose bred dogs, 8 or 9 in each of the two treatment groups, were included in each study. Dogs experimentally infected with the target parasite were dosed once on Day 0 with either placebo tablets or Simparica Trio™ tablets to provide minimum dosages of 1.2 mg/kg sarolaner, 24 µg/kg moxidectin and 5.0 mg/kg pyrantel (as pamoate salt). Timing of dosing relative to parasite inoculation allowed for efficacy to be evaluated primarily against the target parasite stage. Worm counts were conducted 7 or 8 days after treatments during necropsy. Efficacy was based on the number of worms recovered at necropsy compared to placebo control. RESULTS: Based on geometric mean worm counts, efficacy of Simparica Trio™ was ≥ 98.4% against L4 larval stage of A. caninum, ≥ 99.8% against immature adult (L5) A. caninum, and 100% against adult A. caninum and adult U. stenocephala. CONCLUSIONS: These studies confirm the efficacy of a single oral dose of a novel, chewable tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio™) against L4 larval and immature adult (L5) A. caninum, and adult A. caninum and U. stenocephala infections in dogs.


Assuntos
Antinematódeos/administração & dosagem , Doenças do Cão/tratamento farmacológico , Infecções por Uncinaria/veterinária , Administração Oral , Ancylostomatoidea/crescimento & desenvolvimento , Animais , Azetidinas/administração & dosagem , Doenças do Cão/parasitologia , Cães , Combinação de Medicamentos , Infecções por Uncinaria/tratamento farmacológico , Infecções por Uncinaria/parasitologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Macrolídeos/administração & dosagem , Carga Parasitária , Pirantel/administração & dosagem , Compostos de Espiro/administração & dosagem , Comprimidos , Resultado do Tratamento
13.
Parasit Vectors ; 13(1): 98, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113472

RESUMO

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.


Assuntos
Acaricidas/administração & dosagem , Doenças do Cão/tratamento farmacológico , Infestações por Pulgas/veterinária , Administração Oral , Animais , Azetidinas/administração & dosagem , Dermatite/tratamento farmacológico , Dermatite/veterinária , Cães , Combinação de Medicamentos , Feminino , Infestações por Pulgas/tratamento farmacológico , Hospitais Veterinários , Isoxazóis/administração & dosagem , Macrolídeos/administração & dosagem , Masculino , Naftalenos/administração & dosagem , Carga Parasitária , Pirantel/administração & dosagem , Sifonápteros , Compostos de Espiro/administração & dosagem , Comprimidos , Resultado do Tratamento , Estados Unidos
14.
Parasit Vectors ; 13(1): 76, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113473

RESUMO

BACKGROUND: The black-legged (or deer) tick, Ixodes scapularis, commonly infests dogs in the USA and is the vector of important zoonotic pathogens, including Borrelia burgdorferi, the causative agent of Lyme disease. Rapid onset of activity is important in reducing the feeding activity of ticks, thereby reducing the possibility of transmission of infections. The speed of kill of a novel oral combination product, Simparica Trio™ containing sarolaner, moxidectin and pyrantel was evaluated in a well-controlled laboratory study against an existing infestation and subsequent weekly induced infestations of I. scapularis ticks on dogs. METHODS: Dogs were allocated randomly based on host suitability tick counts to treatment with a single dose of either placebo or 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). All dogs were infested with approximately 50 unfed adult I. scapularis ticks at a 1:1 sex ratio on Days -2, 7, 14, 21, 28 and 35. Tick counts were conducted at 8, 12 and 24 h after treatment on Day 0 and after each subsequent infestation. RESULTS: No treatment-related adverse events occurred during the study. Dogs in the placebo-treated group maintained adequate tick infestations for the duration of the study. Day 0 tick counts at 8 h after treatment with Simparica Trio™ were reduced relative to placebo against an existing infestation with efficacy of 67.5%, demonstrating that Simparica Trio™ started killing ticks soon after treatment. Efficacy was 98.4 % at 12 h and 99.4% at 24 h. Rapid speed of kill was maintained throughout the month, with efficacy of ≥ 94.2% at 24 h after re-infestation through Day 28. CONCLUSIONS: A single dose of Simparica Trio™ administered orally to dogs at the minimum label dose of 1.2 mg/kg sarolaner, 24 µg/kg moxidectin and 5 mg/kg pyrantel (as pamoate salt) was safe and began to kill existing I. scapularis ticks within 8 h after treatment and resulted in ≥ 94.2% efficacy within 24 h against re-infestations for a month.


Assuntos
Acaricidas/administração & dosagem , Doenças do Cão/tratamento farmacológico , Infestações por Carrapato/veterinária , Administração Oral , Animais , Vetores Aracnídeos , Azetidinas/administração & dosagem , Cães , Combinação de Medicamentos , Feminino , Ixodes , Macrolídeos/administração & dosagem , Masculino , Carga Parasitária , Pirantel/administração & dosagem , Compostos de Espiro/administração & dosagem , Infestações por Carrapato/tratamento farmacológico , Fatores de Tempo , Resultado do Tratamento
15.
Parasit Vectors ; 13(1): 77, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113476

RESUMO

BACKGROUND: The efficacy of a novel oral combination product, Simparica Trio™, containing sarolaner, moxidectin and pyrantel was evaluated against five tick species that commonly infest dogs in the USA, Amblyomma americanum, Amblyomma maculatum, Dermacentor variabilis, Ixodes scapularis and Rhipicephalus sanguineus. METHODS: Laboratory studies were conducted against two different strains of each tick species. In each study, 10 purpose-bred Beagle or mixed-breed dogs were randomly allocated to one of two treatment groups based on pre-treatment host-suitability tick counts. Dogs were infested with approximately 50 (45-55) unfed adult ticks on Days -2, 5, 12, 19, 26 and 33. On Day 0, dogs received either a single oral dose of 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 placebo. Tick counts were conducted at 48 h post-treatment and after each subsequent weekly re-infestation for A. maculatum, D. variabilis, I. scapularis and R. sanguineus studies and at 48 hours or at 72 h post-treatment and after weekly re-infestation in the first and second A. americanum studies, respectively. RESULTS: No treatment-related adverse reactions occurred in any study. In all studies, placebo-treated dogs maintained infestations throughout the entire study duration, and dogs treated with Simparica Trio™ had significantly lower (P ≤ 0.0010) mean live tick counts than placebo-treated dogs at all time-points. Against A. maculatum, D. variabilis, I. scapularis and R. sanguineus, a single oral dose of Simparica Trio™ evaluated at 48 h post-treatment provided ≥ 98.9% efficacy against existing infestations, and within 48 h of re-infestation efficacy was ≥ 90.4% through at least Day 28 (except for R. sanguineus on Day 14 in a single study with an efficacy of 89.7%). Against A. americanum, Simparica Trio™ provided ≥ 99.4% efficacy at ≤ 72 h after treatment of existing infestations and maintained ≥ 98.4% efficacy at ≤ 72 h after re-infestation through at least Day 35. CONCLUSIONS: A single dose of Simparica Trio™ administered orally at the minimum label dosage of 1.2 mg/kg sarolaner, 24 µg/kg moxidectin and 5 mg/kg pyrantel provided treatment and control of the common tick species infesting dogs in the USA for at least one month.


Assuntos
Acaricidas/administração & dosagem , Doenças do Cão/tratamento farmacológico , Infestações por Carrapato/veterinária , Administração Oral , Animais , Azetidinas/administração & dosagem , Doenças do Cão/parasitologia , Doenças do Cão/prevenção & controle , Cães , Combinação de Medicamentos , Ixodidae/classificação , Macrolídeos/administração & dosagem , Carga Parasitária , Pirantel/administração & dosagem , Compostos de Espiro/administração & dosagem , Infestações por Carrapato/tratamento farmacológico , Infestações por Carrapato/parasitologia , Infestações por Carrapato/prevenção & controle , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
16.
Parasit Vectors ; 13(1): 71, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113482

RESUMO

BACKGROUND: Ascarid infections are among the most prevalent intestinal parasitic infections occurring in dogs around the world, with Toxocara canis and Toxascaris leonina commonly observed. Toxocara canis can cause considerable disease in dogs and humans, and year-round prophylactic treatment and control in dogs is recommended. Elimination of immature stages of these parasites before egg-laying will reduce environmental contamination and the risk of infection for both dogs and humans. Studies were conducted to evaluate the efficacy of a novel, oral chewable tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio™) against induced immature adult (L5) and adult T. canis, and adult T. leonina infections in dogs. METHODS: Six negative-controlled, masked, randomized laboratory studies were conducted. Two studies each evaluated efficacy against immature adult (L5) T. canis, adult T. canis, and adult T. leonina. Sixteen to 40 dogs were included in each study. Dogs experimentally infected with the target parasite were dosed once on Day 0 with either placebo tablets or Simparica Trio™ tablets to provide minimum dosages of 1.2 mg/kg sarolaner, 24 µg/kg moxidectin and 5.0 mg/kg pyrantel (as pamoate salt). Efficacy was based on the number of worms recovered at necropsy 7-10 days after treatment compared to placebo control. RESULTS: Based on geometric mean worm counts, efficacy of the sarolaner + moxidectin + pyrantel combination was ≥ 95.2% against immature adult T. canis, ≥ 97.3% against adult T. canis, and ≥ 89.7% against adult T. leonina. There were no treatment-related adverse events in any study. CONCLUSIONS: These studies confirm the efficacy of a single dose of a new oral chewable tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio™) against immature adult and adult T. canis, and adult T. leonina infections in dogs.


Assuntos
Antinematódeos/administração & dosagem , Infecções por Ascaridida/veterinária , Doenças do Cão/tratamento farmacológico , Enteropatias Parasitárias/veterinária , Administração Oral , Animais , Infecções por Ascaridida/tratamento farmacológico , Azetidinas/administração & dosagem , Cães , Combinação de Medicamentos , Feminino , Enteropatias Parasitárias/tratamento farmacológico , Macrolídeos/administração & dosagem , Masculino , Contagem de Ovos de Parasitas , Pirantel/administração & dosagem , Compostos de Espiro/administração & dosagem , Comprimidos , Toxascaris/efeitos dos fármacos , Toxascaris/fisiologia , Toxocara canis/efeitos dos fármacos , Toxocara canis/fisiologia , Resultado do Tratamento
17.
Parasit Vectors ; 13(1): 64, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113483

RESUMO

BACKGROUND: Infection with Angiostrongylus vasorum may cause severe clinical disease, even death in dogs, however, due to the often non-specific clinical signs, diagnosis is not always straightforward. Regular prophylactic treatment may offer a safe means to protect dogs against infection. The efficacy of a novel oral endectocide containing moxidectin, sarolaner and pyrantel was investigated for the prevention of angiostrongylosis in dogs in three placebo-controlled, randomized, masked studies. The initial study (Study 1) determined the efficacious dosage of moxidectin in the combination product by evaluating three different dose levels, and two follow-up studies (Studies 2 and 3) confirmed the efficacy of the selected moxidectin dose. METHODS: Animals were infected orally with 200 infective third-stage larvae (L3) of A. vasorum and were treated 28 days later with the combination product or with placebo. Timing of dosing relative to infection allowed for efficacy to be evaluated against the immature adult (L5) stage. Dogs in Study 1 received treatments with oral tablets to deliver 3, 12 or 24 µg/kg moxidectin in combination with 2 mg/kg sarolaner and 5.0 mg/kg pyrantel (as pamoate salt) or placebo. In Studies 2 and 3, Simparica Trio™ tablets were administered to provide minimum dosages of 1.2 mg/kg sarolaner, 24 µg/kg moxidectin and 5.0 mg/kg pyrantel (as pamoate salt). Efficacy of the combination product was calculated as the percent reduction in adult worm counts at necropsy relative to placebo. RESULTS: In Study 1, the 3, 12 and 24 µg/kg moxidectin dosage in the combination product provided 7.2%, 54.5% and 94.7% efficacy against the immature adult stages of A. vasorum, respectively. Studies 2 and 3 confirmed that the efficacy of 24 µg/kg moxidectin combined with 1.2 mg/kg sarolaner and 5 mg/kg pyrantel in Simparica Trio™ was ≥ 92.9%. All three studies established that a single oral administration of 24 µg/kg moxidectin in the combination product provided effective prophylactic treatment for angiostrongylosis, reduced L1 production and fecal excretion and minimized the tissue damage to the lungs. CONCLUSIONS: A single oral treatment of dogs with Simparica Trio™ providing moxidectin at a minimum dose of 24 µg/kg was efficacious in the prevention of angiostrongylosis.


Assuntos
Angiostrongylus/efeitos dos fármacos , Antinematódeos/administração & dosagem , Doenças do Cão/prevenção & controle , Infecções por Strongylida/veterinária , Administração Oral , Animais , Azetidinas/administração & dosagem , Cães , Combinação de Medicamentos , Feminino , Macrolídeos/administração & dosagem , Masculino , Pirantel/administração & dosagem , Compostos de Espiro/administração & dosagem , Infecções por Strongylida/prevenção & controle , Resultado do Tratamento
18.
Parasit Vectors ; 13(1): 72, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113486

RESUMO

BACKGROUND: A novel chewable oral tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio™) has recently been developed to provide persistent protection against flea and tick infections for a month, treatment of hookworm and roundworm infections and prevention of heartworm and lungworm disease in dogs. Two field studies were conducted to evaluate the safety and efficacy of Simparica Trio™ against natural flea and tick infestations on dogs in Europe. METHODS: Dogs with natural flea or tick infestations were allocated randomly to treatment on Day 0 with either Simparica Trio™ tablets (flea study: n = 297; tick study: n = 189) to provide 1.2-2.4 mg/kg sarolaner, 24-48 µg/kg moxidectin and 5-10 mg/kg pyrantel (as pamoate salt) or with NexGard® Spectra (afoxolaner + milbemycin oxime) according to the label instructions (flea study: n = 164; tick study: n = 91). Efficacy was calculated based on the mean percent reduction in live parasite counts compared to the respective pre-treatment counts on Days 14 and 30 in the flea study and on Days 7, 14, 21 and 30 in the tick study. To count the fleas, the dog's entire coat was systematically combed using an extra fine-tooth flea comb until all fleas were removed. For the tick counts, the dog's entire coat was searched manually. Resolution of the clinical signs of flea allergy dermatitis (FAD) was assessed in flea allergic dogs in the flea study. Palatability was assessed in both studies. RESULTS: Simparica Trio™ was well tolerated in both studies. Efficacy against fleas was ≥ 97.9% in the Simparica Trio™ group and ≥ 96.1% in the NexGard® Spectra group. Efficacy against ticks was ≥ 94.8% in the Simparica Trio™ group and ≥ 94.4% in the NexGard® Spectra group. Clinical signs of flea allergy dermatitis improved following treatment with Simparica Trio™. Simparica Trio™ tablets were voluntarily and fully consumed on ≥ 78% of the 485 occasions they were offered. CONCLUSIONS: A single oral dose of Simparica Trio™ was safe and highly efficacious against naturally occurring flea and tick infestations for 1 month on dogs. Clinical signs of FAD improved following treatment. Simparica Trio™ was voluntarily and readily consumed by most dogs.


Assuntos
Acaricidas/administração & dosagem , Doenças do Cão/tratamento farmacológico , Infestações por Pulgas/veterinária , Infestações por Carrapato/veterinária , Administração Oral , Animais , Azetidinas/administração & dosagem , Dermatite/tratamento farmacológico , Dermatite/veterinária , Cães , Combinação de Medicamentos , Feminino , Infestações por Pulgas/tratamento farmacológico , Macrolídeos/administração & dosagem , Masculino , Carga Parasitária , Pirantel/administração & dosagem , Compostos de Espiro/administração & dosagem , Comprimidos , Infestações por Carrapato/tratamento farmacológico , Fatores de Tempo , Resultado do Tratamento
19.
Parasit Vectors ; 12(1): 576, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31818311

RESUMO

BACKGROUND: The canine hookworm, Ancylostoma caninum is the most prevalent and important intestinal nematode parasite of dogs in the USA. Hookworms are typically well controlled by treatment with all commonly used anthelmintics that are approved for this use in dogs. However, in the past few years, cases of recurrent/persistent canine hookworm infections appear to have dramatically increased, suggesting that anthelmintic resistance (AR) may have evolved in this parasite. These cases are highly overrepresented by greyhounds, but multiple other breeds are also represented. The aim of this study was to characterize several of these suspected resistant isolates using in vitro, genetic and clinical testing to determine if these cases represent true anthelmintic resistance in A. caninum. METHODS: Fecal samples containing hookworm eggs from three cases of persistent hookworm infections; one from a greyhound, one from a miniature schnauzer and one from a hound-mix, were received by our laboratory. These were then used to establish infections in laboratory dogs and to perform egg hatch assays (EHA) and larval development assays (LDA) for detecting resistance to benzimidazoles and macrocyclic lactones, respectively. Additional EHA and LDA were performed on eggs recovered from the laboratory-induced infections. Fecal egg count reduction tests were performed to detect resistance to pyrantel. Deep amplicon sequencing assays were developed to measure the frequency of non-synonymous single nucleotide polymorphisms (SNP) at codons 167, 198 and 200 of the A. caninum isotype-1 ß-tubulin gene. RESULTS: Resistance ratios for the three A. caninum isolates tested ranged from 6.0 to > 100 and 5.5 to 69.8 for the EHA and LDA, respectively. Following treatment with pyrantel, reduction in faecal egg counts was negative or 0%. Deep amplicon sequencing of the isotype-1 ß-tubulin gene identified a high frequency of resistance-associated SNPs at codon 167 in all three resistant isolates and in two additional clinical cases. CONCLUSIONS: These data conclusively demonstrate multiple anthelmintic resistance in multiple independent isolates of A. caninum, strongly suggesting that this is an emerging problem in the USA. Furthermore, evidence suggest that these resistant hookworms originate from racing greyhound farms and kennels, though additional research is needed to confirm this.


Assuntos
Ancylostoma/efeitos dos fármacos , Ancylostoma/genética , Ancilostomíase/veterinária , Anti-Helmínticos/farmacologia , Resistência a Múltiplos Medicamentos/genética , Contagem de Ovos de Parasitas/veterinária , Ancilostomíase/parasitologia , Animais , Cruzamento , Doenças do Cão , Cães , Fezes/parasitologia , Polimorfismo de Nucleotídeo Único , Pirantel/farmacologia , Estados Unidos
20.
Parasit Vectors ; 12(1): 445, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31506094

RESUMO

BACKGROUND: Dirofilaria immitis is a filarial parasite of dogs that can cause serious or fatal cardiopulmonary disease. Three studies were conducted to evaluate the efficacy and safety of monthly treatment with moxidectin in a chewable tablet product in combination with sarolaner and pyrantel to prevent heartworm disease in dogs after experimental challenge and in a clinical field study in the USA. METHODS: In two laboratory studies, dogs (8 per group) that had been inoculated 30 days prior with 50 third-stage D. immitis larvae were randomized to treatment on Day 0 with placebo or combination product, at the minimum dose of 24 µg/kg moxidectin, 2 mg/kg sarolaner and 5 mg/kg pyrantel (as pamoate salt). Study 2 also included groups treated with tablets containing moxidectin-alone (24 µg/kg) or sarolaner-alone (2 mg/kg). Efficacy was evaluated ~ 5 months after inoculation by adult heartworm counts at necropsy. In the field study, 410 dogs ≥ 8 weeks-old from 23 USA veterinary clinics were treated for 11 months with either combination product at 24-48 µg/kg moxidectin, 2-4 mg/kg sarolaner and 5-10 mg/kg pyrantel (n = 272) or Heartgard® Plus (ivermectin/pyrantel) at the label recommended dose rate (n = 138). Efficacy was evaluated on Day 330 using antigen and microfilaria testing to assess adult heartworm infection. RESULTS: In the laboratory studies, there were no heartworms recovered from any dog treated with the combination product or moxidectin alone and all dogs treated with placebo or sarolaner-alone were infected with 20-44 adult heartworms. In the field study, all dogs treated with the combination product tested negative for heartworm infection on Day 330, whereas two dogs treated with Heartgard® Plus tested positive. The Heartgard® Plus-treated dogs that tested heartworm positive were from the lower Mississippi River Valley region, where heartworm resistance has been confirmed to occur. The combination product was well tolerated in all studies. CONCLUSIONS: In laboratory studies, no heartworms were recovered from dogs treated with a single dose of the novel combination product containing moxidectin, sarolaner and pyrantel. Additionally, in the field study no dog tested positive for adult heartworm infection when dosed with the combination product monthly for 11 months, while two dogs treated with Heartgard® Plus tested positive.


Assuntos
Antinematódeos/administração & dosagem , Azetidinas/administração & dosagem , Quimioprevenção/métodos , Dirofilariose/prevenção & controle , Doenças do Cão/prevenção & controle , Macrolídeos/administração & dosagem , Pirantel/administração & dosagem , Compostos de Espiro/administração & dosagem , Administração Oral , Animais , Dirofilaria immitis/efeitos dos fármacos , Cães , Quimioterapia Combinada/métodos , Placebos/administração & dosagem , Resultado do Tratamento , Estados Unidos
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