RESUMO
Robenacoxib is a member of the coxib class of nonsteroidal anti-inflammatory drugs (NSAID), with high selectivity for the cyclooxygenase (COX)-2 isoform of COX. In this study, the efficacy and tolerability of robenacoxib were compared with those of carprofen in canine osteoarthritis in a multi-centre, prospective, randomized, blinded, positive-controlled noninferiority clinical trial. Both drugs were administered orally once daily at recommended dosages: robenacoxib at 1-2 mg/kg (n = 125 dogs) and racemic carprofen at 2-4 mg/kg (n = 63 dogs) for a total of 12 weeks. The efficacy of the test compounds was assessed by veterinary investigators and owners using numerical rating scales at baseline and days 7, 14, 28, 56 and 84. In both groups, all scores were significantly (P < 0.0001) improved compared with baseline at all time points (days 7-84). Robenacoxib had noninferior efficacy to carprofen for the primary endpoint, the global functional disability, both for all dogs and for the subgroup of dogs in which robenacoxib was not administered during meals. Noninferiority was also demonstrated for three of six veterinary investigator secondary endpoints and four of six owner efficacy endpoints. For haematology and clinical chemistry variables, there were some significant differences from baseline levels but no differences between groups. There were no differences between groups in the frequencies of adverse events, which were reported in 46% dogs with robenacoxib and 52% with carprofen (P = 0.44), which were most frequently mild events affecting the gastrointestinal tract. In conclusion, noninferior efficacy and tolerability of robenacoxib compared with carprofen was demonstrated in dogs with osteoarthritis.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Carbazóis/uso terapêutico , Difenilamina/análogos & derivados , Doenças do Cão/tratamento farmacológico , Osteoartrite/veterinária , Fenilacetatos/uso terapêutico , Animais , Difenilamina/uso terapêutico , Cães , Feminino , Masculino , Osteoartrite/tratamento farmacológicoRESUMO
During 2007, a large-scale controlled, multicentre, blinded and randomised field study was conducted in Scotland, England and France to assess the efficacy and safety of monepantel, the first molecule to be developed from the recently discovered amino-acetonitrile derivatives class of anthelmintics, in sheep. Monepantel was administered orally, at a minimum dose of 2.5 mg/kg bodyweight, for the control of gastrointestinal nematodes in sheep maintained at pasture in a range of commercial production systems. Efficacy was measured by faecal egg count (FEC) reduction tests seven days after treatment and was demonstrated to be over 98 per cent against mixed-genus infections. The reduction in FEC of monepantel-treated sheep was statistically significantly greater than in untreated control sheep (P<0.0001). The efficacy of monepantel against mixed-genus natural field infections of the major gastrointestinal nematodes was in agreement with similar studies conducted in Australia and New Zealand. There were no treatment-related adverse events during the study, which included the use of a range of concomitant treatments.
Assuntos
Aminoacetonitrila/análogos & derivados , Anti-Helmínticos/uso terapêutico , Gastroenteropatias/veterinária , Helmintíase Animal/tratamento farmacológico , Infecções por Nematoides/veterinária , Doenças dos Ovinos/tratamento farmacológico , Administração Oral , Aminoacetonitrila/efeitos adversos , Aminoacetonitrila/uso terapêutico , Animais , Anti-Helmínticos/efeitos adversos , Método Duplo-Cego , Inglaterra , França , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/parasitologia , Infecções por Nematoides/tratamento farmacológico , Contagem de Ovos de Parasitas/veterinária , Escócia , Ovinos , Resultado do TratamentoRESUMO
Nectins are adhesion molecules that participate in the organization of epithelial and endothelial junctions and serve as receptors for herpes simplex virus entry. They belong to the immunoglobulin superfamily, are homologues of the poliovirus receptor (PVR/CD155), and were also named poliovirus receptor-related (PRR) proteins. We identify a new member of the nectin family named nectin4. Peptide sequences of human and murine nectin4 share 92% identity, and as for other members, the ectodomain is made of three immunoglobulin-like domains of V, C, C types. In contrast to other nectin molecules, detection of nectin4 transcripts is mainly restricted to placenta in human tissues. Expression is broader in mouse, and interestingly nectin4 is detected at days 11, 15, and 17 during murine embryogenesis. Nectin4 interacts with afadin, a F-actin-associated molecule, via its carboxyl-terminal cytoplasmic sequence. Both molecules co-localize at cadherin-based adherens junctions in the MDCKII epithelial cell line. Nectins are homophilic adhesion molecules, and recently heterophilic interactions have been described between nectin3/nectin1 and nectin3/nectin2. We confirmed these trans-interactions and also described nectin3 as the PVR/CD155 ligand. By means of several approaches, we report on the identification of nectin4 as a new ligand for nectin1. First, a soluble chimeric recombinant nectin4 ectodomain (nectin4-Fc) trans-interacts with cells expressing nectin1 but not with cells expressing nectin2, nectin3, or PVR/CD155. Conversely, nectin1-Fc binds to cells expressing nectin4. Second, nectin1-Fc precipitates nectin4 expressed in COS cells. Third, reciprocal in vitro physical interactions were detected between nectin4-Fc and nectin1-Fc. The nectin4-Fc/nectin4-Fc interaction was detected suggesting that nectin4 exhibits both homophilic and heterophilic properties. Using the same approaches we demonstrate, for the first time, that the V domain of nectin1 acts as a major functional region involved in trans-heterointeraction with nectin4 and also nectin3.
Assuntos
Moléculas de Adesão Celular/biossíntese , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/fisiologia , Proteínas de Membrana , Actinas/química , Sequência de Aminoácidos , Animais , Northern Blotting , Células COS , Cálcio/metabolismo , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Clonagem Molecular , DNA Complementar/metabolismo , Cães , Ensaio de Imunoadsorção Enzimática , Células Epiteliais , Éxons , Humanos , Immunoblotting , Imuno-Histoquímica , Cinesinas , Ligantes , Camundongos , Proteínas dos Microfilamentos/metabolismo , Modelos Biológicos , Dados de Sequência Molecular , Miosinas , Nectinas , Peptídeos/química , Placenta/metabolismo , Testes de Precipitina , Ligação Proteica , Estrutura Terciária de Proteína , Receptores Virais/química , Homologia de Sequência de Aminoácidos , Fatores de Tempo , Distribuição Tecidual , TransfecçãoRESUMO
We have isolated nectin3/PRR3, the fourth human member of the nectin/PRR family, also described as the alpha herpes virus receptor family. Nectin/PRR members are adhesion molecules expressed at intercellular junctions. Nectin3/PRR3 is a transmembrane protein, whose extracellular region contains three Ig-like domains (V, C and C) and shares approximately 30% identity with the other members. It is mainly expressed in testis and placental tissues. SDS-PAGE analyses demonstrate that nectin3/PRR3 has a molecular weight of 83kDa. Nectin1/PRR1L and nectin2/PRR2S and L were found to be specifically expressed at the intercellular junctions. This localization is in part due to the interaction of the C-terminal part of these receptors (ended by the consensus sequence A/EXYV) and the PDZ domain of afadin. In this report we demonstrate that the nectin3/PRR3 receptor carries the A/EXYV consensus sequence and interacts in vivo with both long and short isoforms of afadin. These results suggest that the human nectin3/PRR3 is a new afadin-associated molecule.