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2.
Clin Drug Investig ; 40(8): 755-764, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32583295

RESUMO

BACKGROUND AND OBJECTIVE: Opioid-induced respiratory depression (OIRD) is a potentially fatal complication associated with conventional opioids. Currently, there is a paucity of validated endpoints available to measure respiratory safety. Oliceridine, an investigational intravenous (IV) opioid, is a G-protein selective µ-agonist with limited activity on ß-arrestin2, a signaling pathway associated with adverse events including OIRD. In controlled phase III trials, oliceridine 0.35 mg and 0.5 mg demand doses demonstrated comparable analgesia to morphine 1 mg with favorable improvements in respiratory safety. In this exploratory analysis, we report dosing interruption (DI) and average cumulative duration of DI (CDDI) for both oliceridine and morphine. METHODS: Patients requiring analgesia after bunionectomy or abdominoplasty were randomized to IV demand doses of placebo, oliceridine (0.1 mg, 0.35 mg, or 0.5 mg), or morphine (1 mg), administered via patient-controlled analgesia (PCA), following a loading dose (oliceridine 1.5 mg, morphine 4 mg, volume-matched placebo) with a 6-min lockout interval. Certified nurse anesthetists monitored each patient and withheld study medication according to the patient's respiratory status. For each patient, the duration of all DIs was summed and reported as CDDI. A zero-inflated gamma mixture model was used to compute the mean CDDI for each treatment. RESULTS: Proportion of patients with DI was lower with oliceridine (0.1 mg: 3.2%, 0.35 mg: 13.9%, 0.5 mg: 15.1%) versus morphine (22%). The CDDI was also lower across all demand doses of oliceridine versus morphine. CONCLUSION: Using DI as a surrogate for OIRD indicates improved respiratory safety with oliceridine versus morphine that merits further investigation.


Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos Opioides/efeitos adversos , Morfina/efeitos adversos , Dor Pós-Operatória/tratamento farmacológico , Insuficiência Respiratória/induzido quimicamente , Compostos de Espiro/efeitos adversos , Tiofenos/efeitos adversos , Adulto , Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Manejo da Dor , Medição da Dor , Insuficiência Respiratória/tratamento farmacológico , Compostos de Espiro/administração & dosagem , Tiofenos/administração & dosagem
3.
Psychopharmacology (Berl) ; 237(8): 2405-2418, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32435819

RESUMO

RATIONALE: Agonists of the kappa opioid receptor (KOR) have been shown to block the rewarding effects of drugs of abuse, but with negative side effects. The antipruritic drug nalfurafine, approved in Japan in 2009, is a potent, selective KOR agonist that does not cause significant side effects in humans. Nalfurafine has not been extensively tested for its effect on drug reward and reinforcement in preclinical models. OBJECTIVES: The goal of this study was to compare the effects of nalfurafine and a reference KOR agonist for a variety of KOR-mediated endpoints in male C57BL6 mice. Specifically, we aimed to evaluate the "therapeutic window"-doses of agonists lower than those eliciting negative side effects, while still effective for desired therapeutic effects. METHODS: In this study, several low doses of nalfurafine and U50,488 were tested for serum prolactin release, rotarod-mediated sedation, and place-conditioning in male C57BL6 mice. These agonists were also tested for effects on intravenous cocaine self-administration, both on an FR1 schedule and on a progressive ratio schedule for 0.5 mg/kg/infusion cocaine. RESULTS: Serum prolactin levels increased following doses of both nalfurafine (3 µg/kg and 10 µg/kg) and U50,488 (3 mg/kg). These doses did not cause sedation in the rotarod assay or aversion in a place-conditioning assay, but blocked conditioned place preference for cocaine. Immediate pretreatment of mice with 10 µg/kg nalfurafine and 3 mg/kg U50,488, however, potentiated cocaine self-administration. Further 10 µg/kg nalfurafine was also observed to potentiate cocaine-seeking behavior as demonstrated by increased progressive ratio break point. CONCLUSIONS: Both nalfurafine and U50,488 showed a separation of negative side effects and the modulation of cocaine reward, suggesting this effect of KOR agonists at low doses may be characteristic of the KOR system in general. At higher doses, nalfurafine had similar effects to traditional KOR agonists like U50,488, indicating that its relative potency, rather than differences in KOR signaling, may be responsible for its unique effects in humans.


Assuntos
Comportamento Aditivo/tratamento farmacológico , Cocaína/administração & dosagem , Morfinanos/administração & dosagem , Receptores Opioides kappa/agonistas , Recompensa , Compostos de Espiro/administração & dosagem , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Comportamento Aditivo/psicologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Opioides kappa/fisiologia , Autoadministração , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
4.
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
5.
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
6.
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
7.
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
8.
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
9.
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
10.
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
11.
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
12.
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
13.
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
14.
Psychopharmacology (Berl) ; 237(5): 1471-1480, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32006048

RESUMO

RATIONALE: Combinations of mu and kappa opioid receptor (KOR) agonists have been proposed as potential analgesic formulations with reduced abuse liability. The current studies extend previous work by investigating the typical KOR agonist, salvinorin A, and the atypical KOR agonist, nalfurafine, as deterrents of oxycodone self-administration using a progressive ratio (PR) schedule of reinforcement. METHODS: In separate experiments, adult male rhesus monkeys (N = 4/experiment) were trained under a PR schedule of reinforcement to self-administer cocaine (0.1 mg/kg/injection) and saline on alternating days. Oxycodone (0.01-0.1 mg/kg/injection) alone and combined with salvinorin A (experiment 1; 0.006, 0.012 mg/kg/injection) or nalfurafine (experiment 2; 0.0001-0.00032 mg/kg/injection) were tested within the alternating cocaine and saline baseline. The mechanism of nalfurafine's effects on oxycodone self-administration was investigated via pretreatment with the KOR antagonist, nor-binaltorphimine (nor-BNI; 10 mg/kg; i.m.). RESULTS: All subjects self-administered oxycodone alone above saline levels at sufficiently large doses, and combining salvinorin A or nalfurafine with oxycodone reduced the mean number of injections per session to saline levels (experiment 1) or to levels that were significantly lower than oxycodone alone (experiment 2). The ability of nalfurafine to reduce oxycodone self-administration was reversed by pretreatment with nor-BNI. CONCLUSIONS: These results demonstrate that KOR agonists, including the clinically used KOR agonist, nalfurafine, can punish self-administration of a prescription opioid analgesic, oxycodone, in rhesus monkeys and that nalfurafine's punishing effect is KOR-dependent. Combinations of KOR agonists with prescription opioids may have reduced abuse liability.


Assuntos
Analgésicos Opioides/administração & dosagem , Comportamento Aditivo/tratamento farmacológico , Diterpenos Clerodânicos/administração & dosagem , Morfinanos/administração & dosagem , Oxicodona/administração & dosagem , Receptores Opioides kappa/agonistas , Compostos de Espiro/administração & dosagem , Animais , Comportamento Aditivo/psicologia , Cocaína/administração & dosagem , Relação Dose-Resposta a Droga , Macaca mulatta , Masculino , Naltrexona/administração & dosagem , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/administração & dosagem , Reforço Psicológico , Autoadministração
15.
J Med Chem ; 63(10): 5089-5099, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32022560

RESUMO

We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and orally active PTHR1 agonist 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (PCO371, 16c). This compound is currently being evaluated in a phase 1 clinical study for the treatment of hypoparathyroidism.


Assuntos
Imidazolidinas/administração & dosagem , Imidazolidinas/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/agonistas , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Compostos de Espiro/administração & dosagem , Compostos de Espiro/metabolismo , Administração Oral , Animais , Feminino , Humanos , Hipoparatireoidismo/tratamento farmacológico , Hipoparatireoidismo/metabolismo , Imidazolidinas/química , Células LLC-PK1 , Ratos , Ratos Sprague-Dawley , Compostos de Espiro/química , Suínos
16.
J Antibiot (Tokyo) ; 73(5): 290-298, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31992865

RESUMO

The emergence of antibiotic resistance necessitates not only the identification of new compounds with antimicrobial properties, but also new strategies and combination therapies to circumvent this growing problem. Here, we report synergistic activity against methicillin-resistant Staphylococcus aureus (MRSA) of the ß-lactam antibiotic oxacillin combined with 7,8-dideoxygriseorhodin C in vitro. Ongoing efforts to identify antibiotics from marine mollusk-associated bacteria resulted in the isolation of 7,8-dideoxygriseorhodin C from a Streptomyces sp. strain cultivated from a marine gastropod tissue homogenate. Despite the long history of 7,8-dideoxygriseorhodin C in the literature, the absolute configuration has never been previously reported. A comparison of measured and calculated ECD spectra resolved the configuration of the spiroketal carbon C6, and 2D ROESY NMR spectroscopy established the absolute configuration as 6s,6aS. The compound is selective against Gram-positive bacteria including MRSA and Enterococcus faecium with an MIC range of 0.125-0.5 µg ml-1. Moreover, the compound synergizes with oxacillin against MRSA as observed in the antimicrobial microdilution and time-kill assays. Simultaneous treatment of the compound with oxacillin resulted in an approximately tenfold decrease in MIC with a combination index of <0.5, indicating synergistic anti-MRSA activity.


Assuntos
Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Oxacilina/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/isolamento & purificação , Sinergismo Farmacológico , Enterococcus faecium/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Naftoquinonas/administração & dosagem , Naftoquinonas/química , Naftoquinonas/isolamento & purificação , Naftoquinonas/farmacologia , Oxacilina/administração & dosagem , Compostos de Espiro/administração & dosagem , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/farmacologia , Streptomyces/metabolismo
17.
Parasit Vectors ; 12(1): 509, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666109

RESUMO

BACKGROUND: Haemaphysalis longicornis is the major tick affecting dogs in most of the East Asia/Pacific region and has recently been detected in a number of areas of the USA. This tick is a vector for a number of pathogens of dogs, other mammals and humans. In this study, the efficacy of a single oral administration of sarolaner (Simparica®, Zoetis) at the minimum label dosage (2 mg/kg) was evaluated against an existing infestation of H. longicornis and subsequent weekly reinfestations for 5 weeks after treatment. METHODS: Sixteen dogs were ranked on pretreatment tick counts and randomly allocated to treatment on Day 0 with sarolaner at 2 mg/kg or a placebo. The dogs were infested with H. longicornis nymphs on Days - 2, 5, 12, 19, 26 and 33. Efficacy was determined at 48 hours after treatment and subsequent re-infestations based on live tick counts relative to placebo-treated dogs. RESULTS: There were no adverse reactions to treatment. A single dose of sarolaner provided 100% efficacy on Days 2, 7, 14 and 21; and ≥ 97.4% efficacy on Days 28 and 35. Considering only attached, live ticks, efficacy was 100% for the entire 35 days of the study. Geometric mean live tick counts for sarolaner were significantly lower than those for placebo on all days (11.62 ≤ t(df) ≤ 59.99, where 13.0 ≤ df ≤ 14.1, P < 0.0001). CONCLUSIONS: In this study, a single oral administration of sarolaner at 2 mg/kg provided 100% efficacy against an existing infestation of H. longicornis nymphs and ≥ 97.4% efficacy (100% against attached ticks) against weekly reinfestation for at least 35 days after treatment.


Assuntos
Antiparasitários/uso terapêutico , Vetores Aracnídeos , Azetidinas/uso terapêutico , Doenças do Cão/tratamento farmacológico , Ixodidae , Compostos de Espiro/uso terapêutico , Infestações por Carrapato/veterinária , Administração Oral , Animais , Antiparasitários/administração & dosagem , Azetidinas/administração & dosagem , Doenças do Cão/parasitologia , Doenças do Cão/prevenção & controle , Cães , Compostos de Espiro/administração & dosagem , Infestações por Carrapato/tratamento farmacológico , Infestações por Carrapato/prevenção & controle
18.
Environ Sci Pollut Res Int ; 26(36): 36615-36622, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31734837

RESUMO

Spirotetramat is a toxic commercially known as Movento used to control pistachio psylla pests. In the present study, the effects of Movento on passive avoidance learning of rats and their ability to explore the novel object in the novel object recognition test were investigated. The changes in the concentration of hippocampal brain-derived neurotrophic factor (BDNF) proteins were evaluated, too. Male Wistar rats were gavaged at different dosages of the Movento (50, 100, 250, 500, 1000, 1250, and 1500 mg/kg) or saline for 7 days (administered every 2 days). We showed that Movento caused 50 and 100% mortality at the dose of 1250 and 1500 mg/kg, respectively. At the dose of 1000 mg/kg, Movento significantly decreased locomotor activity (P < 0.05). These rats also displayed a significant decrease in the number of training trials in the shuttle box and the ability to recognize a novel object compared with the control group (P < 0.01). The BDNF protein level of hippocampus also showed a significant decrease in the Movento (1000 mg/kg) compared with the control group (P < 0.01) while the number of pancellular necrosis pyramidal CA1 cells increased significantly in the Movento group (P < 0.001). We concluded that exposure to Movento can decline sensory, motor, and learning in rats.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Compostos Aza/toxicidade , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/efeitos dos fármacos , Inseticidas/toxicidade , Compostos de Espiro/toxicidade , Animais , Compostos Aza/administração & dosagem , Hipocampo/metabolismo , Hipocampo/patologia , Inseticidas/administração & dosagem , Dose Letal Mediana , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Compostos de Espiro/administração & dosagem
19.
Expert Opin Drug Saf ; 18(12): 1127-1132, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31622113

RESUMO

Introduction: Chemotherapy-induced nausea and vomiting is a significant clinical issue that affects patients' quality of life as well as treatment decisions. Significant improvements in the control of chemotherapy-induced nausea and vomiting have occurred in the past 15 years with the introduction of new antiemetic agents 5-HT3, receptor antagonists, neurokinin-1 receptor antagonists, and olanzapine. Oral (aprepitant, 2003; netupitant, 2014; rolapitant, 2015) neurokinin-1 receptor antagonists have been developed along with intravenous formulations (fosaprepitant, NEPA, rolapitant, HTX-019) for the prevention of chemotherapy-induced nausea and vomiting.Areas covered: This review presents a description of the safety and efficacy of rolapitant along with a comparison to the other oral and intravenous formulations of the neurokinin-1 receptor antagonists.Expert opinion: Oral rolapitant has been demonstrated in clinical trials to be safe and effective in controlling chemotherapy-induced nausea and vomiting in patients receiving moderately and highly emetogenic chemotherapy. Rolapitant has a longer half-life (180 h) than other commercially available NK-1 receptor antagonists and does not induce or inhibit CYP34A, unlike the other NK-1 receptor antagonists. Future studies may determine if these may be important clinical issues.


Assuntos
Antieméticos/administração & dosagem , Antagonistas do Receptor de Neuroquinina-1/administração & dosagem , Compostos de Espiro/administração & dosagem , Animais , Antieméticos/efeitos adversos , Antieméticos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Humanos , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Antagonistas do Receptor de Neuroquinina-1/efeitos adversos , Antagonistas do Receptor de Neuroquinina-1/farmacocinética , Qualidade de Vida , Compostos de Espiro/efeitos adversos , Compostos de Espiro/farmacocinética , Vômito/induzido quimicamente , Vômito/tratamento farmacológico
20.
J Pharmacol Exp Ther ; 371(2): 487-499, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31492823

RESUMO

Mu opioid receptor (MOR)-targeting analgesics are efficacious pain treatments, but notorious for their abuse potential. In preclinical animal models, coadministration of traditional kappa opioid receptor (KOR)-targeting agonists with MOR-targeting analgesics can decrease reward and potentiate analgesia. However, traditional KOR-targeting agonists are well known for inducing antitherapeutic side effects (psychotomimesis, depression, anxiety, dysphoria). Recent data suggest that some functionally selective, or biased, KOR-targeting agonists might retain the therapeutic effects of KOR activation without inducing undesirable side effects. Nalfurafine, used safely in Japan since 2009 for uremic pruritus, is one such functionally selective KOR-targeting agonist. Here, we quantify the bias of nalfurafine and several other KOR agonists relative to an unbiased reference standard (U50,488) and show that nalfurafine and EOM-salvinorin-B demonstrate marked G protein-signaling bias. While nalfurafine (0.015 mg/kg) and EOM-salvinorin-B (1 mg/kg) produced spinal antinociception equivalent to 5 mg/kg U50,488, only nalfurafine significantly enhanced the supraspinal analgesic effect of 5 mg/kg morphine. In addition, 0.015 mg/kg nalfurafine did not produce significant conditioned place aversion, yet retained the ability to reduce morphine-induced conditioned place preference in C57BL/6J mice. Nalfurafine and EOM-salvinorin-B each produced robust inhibition of both spontaneous and morphine-stimulated locomotor behavior, suggesting a persistence of sedative effects when coadministered with morphine. Taken together, these findings suggest that nalfurafine produces analgesic augmentation, while also reducing opioid-induced reward with less risk of dysphoria. Thus, adjuvant administration of G protein-biased KOR agonists like nalfurafine may be beneficial in enhancing the therapeutic potential of MOR-targeting analgesics, such as morphine.


Assuntos
Analgesia/métodos , Sistemas de Liberação de Medicamentos/métodos , Morfinanos/administração & dosagem , Morfina/administração & dosagem , Medição da Dor/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Compostos de Espiro/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Sinergismo Farmacológico , Feminino , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Medição da Dor/métodos , Distribuição Aleatória , Receptores Opioides kappa/administração & dosagem , Receptores Opioides mu/agonistas
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