RESUMO
Evaluation of a wide range of avermectin derivatives for flea activity in an in vitro feeding screen using the cat flea, Ctenocephalides felis, revealed a narrow structure-activity relationship (SAR) with activity surprisingly associated with monosaccharides and especially their C-5-oximes. We discovered commercially exploitable flea activity in a single compound, selamectin 33, which also possessed the necessary antiparasitic spectrum and margin of safety for development as a broad-spectrum companion animal endectocide.
Assuntos
Inseticidas/química , Inseticidas/farmacologia , Ivermectina/análogos & derivados , Ivermectina/química , Ivermectina/farmacologia , Sifonápteros , Animais , Gatos , Cães , Feminino , Inseticidas/síntese química , Ivermectina/síntese química , Espectroscopia de Ressonância Magnética , Masculino , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
Selamectin, 25-cyclohexyl-25-de(1-methylpropyl)-5-deoxy-22, 23-dihydro-5-(hydroxyimino)-avermectin B1 monosaccharide, is a novel endectocide with a unique combination of efficacy and safety in dogs and cats following both oral and topical administration. The compound is active against fleas and ticks, intestinal hookworms and ascarids, and immature heartworms. Also it is well tolerated at higher dosages than 22,23-dihydroavermectin B1a (DHAVM) or milbemycin oxime in Collies, which is a breed known to exhibit idiosyncratic sensitivity to avermectins.
Assuntos
Antiparasitários/administração & dosagem , Antiparasitários/uso terapêutico , Doenças do Gato/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Ectoparasitoses/veterinária , Ivermectina/análogos & derivados , Sifonápteros/efeitos dos fármacos , Administração Tópica , Animais , Gatos , Cães , Relação Dose-Resposta a Droga , Esquema de Medicação , Ectoparasitoses/tratamento farmacológico , Feminino , Ivermectina/uso terapêutico , MasculinoRESUMO
Doramectin, 25-cyclohexyl-5-O-demethyl-25-de(l-methylpropyl)avermectin A1a, was selected as the best of a series of novel avermectins prepared by mutational biosynthesis. The primary evaluation of its in vivo antiparasitic activity was carried out using a rat Trichostrongylus colubriformis model and a rabbit Psoroptes cuniculi model. In each case the new avermectin performed favourably relative to dihydroavermectin B1a (DHAVM), the major component of ivermectin. Doramectin was extensively evaluated in cattle using an experimental micelle formulation, proving highly effective in cattle infected with Ostertagia ostertagi, Cooperia oncophora and Dictyocaulus viviparus when administered subcutaneously at 200 micrograms kg-1. The plasma pharmacokinetic characteristics of doramectin in cattle following intravenous administration revealed a plasma half-life of approximately 89 h. In the micelle formulation, doramectin administered subcutaneously at 400 micrograms kg-1 provided persistent activity against infection of cattle with C. oncophora and O. ostertagi for at least 8 and 12 days respectively.
Assuntos
Anti-Helmínticos/uso terapêutico , Doenças dos Bovinos/tratamento farmacológico , Inseticidas/uso terapêutico , Ivermectina/análogos & derivados , Infestações por Ácaros/veterinária , Infecções por Nematoides/veterinária , Administração Oral , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/farmacocinética , Bovinos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Feminino , Injeções Subcutâneas/veterinária , Inseticidas/administração & dosagem , Inseticidas/farmacocinética , Enteropatias Parasitárias/tratamento farmacológico , Enteropatias Parasitárias/veterinária , Ivermectina/administração & dosagem , Ivermectina/farmacocinética , Ivermectina/uso terapêutico , Masculino , Micelas , Infestações por Ácaros/tratamento farmacológico , Ácaros , Infecções por Nematoides/tratamento farmacológico , Coelhos , Distribuição Aleatória , Ratos , Ratos Wistar , Tricostrongilose/tratamento farmacológico , Tricostrongilose/veterináriaRESUMO
Avermectins with a wide range of novel C-25 substituents have been prepared by feeding carboxylic acids or their biosynthetic precursors to a Streptomyces avermitilis mutant strain ATCC 53568. This organism lacks the ability to form isobutyric and S-2-methylbutyric acids from their 2-oxo acid precursors and thus is unable to produce natural avermectins unless supplied with these acids. The novel avermectins produced by mutational biosynthesis possess broad-spectrum antiparasitic activity.
Assuntos
Anti-Helmínticos/metabolismo , Ivermectina/análogos & derivados , Streptomyces/metabolismo , Animais , Anti-Helmínticos/química , Anti-Helmínticos/farmacologia , Caenorhabditis/efeitos dos fármacos , Ácidos Carboxílicos/metabolismo , Cromatografia Líquida de Alta Pressão , Dípteros , Fermentação , Ivermectina/química , Ivermectina/metabolismo , Ivermectina/farmacologia , Estrutura Molecular , Mutação , Streptomyces/genéticaRESUMO
A series of compounds related to 4-(6-methoxy-2-naphthyl)butan-2-one has been prepared and tested for antiinflammatory activity by the cotton pellet granuloma method. Compounds possessing a small lipophilic group such as methoxyl, methyl, or chloro in the 6 position in conjunction with a butan-2-one side chain in the 2 position of the naphthalene ring were most active. The indtroduction of a methyl group along the side chain was invariably deleterious. Good activity was generally retained by forming esters of a butan-2-ol side chain.
Assuntos
Anti-Inflamatórios/síntese química , Naftalenos/síntese química , Animais , Feminino , Gossypium , Granuloma/etiologia , Granuloma/fisiopatologia , Naftalenos/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The ability of several non-steroidal acidic anti-inflammatory drugs to cause ulceration when given as copper complexes has been examined. The damage caused by clopirac, niflumic acid and aspirin was virtually abolished when they were given as copper complexes whereas the damage caused by indomethacin, ketoprofen and (+)-naproxen was unaltered. The lack of ulceration with three of these preparations appeared to be correlated with a much reduced ability to inhibit prostaglandin synthesis as determined using an in vitro enzyme system.