Synthesis and Pharmacological Evaluation of Triazolopyrimidinone Derivatives as Noncompetitive, Intracellular Antagonists for CC Chemokine Receptors 2 and 5

CC chemokine receptors 2 (CCR2) and 5 (CCR5) are involved in many inflammatory diseases; however, most CCR2 and CCR5 clinical candidates have been unsuccessful. (Pre)clinical evidence suggests that dual CCR2/CCR5 inhibition might be more effective in the treatment of such multifactorial diseases. In this regard, the highly conserved intracellular binding site in chemokine receptors provides a new avenue for the design of multitarget ligands. In this study, we synthesized and evaluated the biological activity of a series of triazolopyrimidinone derivatives in CCR2 and CCR5. Radioligand binding assays first showed that they bind to the intracellular site of CCR2, and in combination with functional assays on CCR5, we explored structure−affinity/activity relationships in both receptors. Although most compounds were CCR2-selective, 39 and 43 inhibited β-arrestin recruitment in CCR5 with high potency. Moreover, these compounds displayed an insurmountable mechanism of inhibition in both receptors, which holds promise for improved efficacy in inflammatory diseases.Medicinal Chemistr

Amastigota forms resembling Leishmania sp. on corneal ulceration in a dog: case report

Relata-se o caso de um cão com leishmaniose visceral apresentando lesões cutâneas, caquexia e úlcera de córnea. Realizou-se o diagnóstico parasitológico e sorológico por meio de exame do material da medula óssea e por imunofluorescência indireta, respectivamente. À citologia da úlcera corneana, visibilizaram-se formas amastigotas compatíveis com Leishmania sp.One dog with visceral leishmaniasis is reported presenting cutaneous lesions, cachexia, and corneal ulceration. Parasitological and serological diagnoses were performed by exam of contents of the aspirative punction of the bone marrow and by immunofluorecence, respectively. Amastigota forms resembling Leishmania sp. were visualized by citology

Uveitis due to anaplasmosis in a newborn Holstein calf

Relata-se o caso de um bovino com, aproximadamente, seis horas de vida, apresentando histórico de febre, apatia, inapetência e desconforto ocular. No exame oftálmico rotineiro, encontraram-se valores do teste da lágrima de Schirmer aumentados, diminuição da pressão intra-ocular, hemorragia conjuntival, uveíte anterior, edema corneal e injeção ciliar em ambos os olhos. Coletou-se amostra de sangue para realização de esfregaço sangüíneo, hemograma e bioquímica sérica. No esfregaço visibilizaram-se corpúsculos de Anaplasma marginale em hemácias parasitadas. Quanto à bioquímica sérica, não foram observadas alterações. Os mesmos exames foram realizados na mãe do animal tendo como resultado a positividade para A. marginale. Para o controle da uveíte foi utilizada uma única aplicação de 0,5ml de betametasona a 5%, por via subconjuntival, em cada um dos olhos. Para o tratamento da anaplasmose, seguiu-se o protocolo a base de 10mg/kg de oxitetraciclina, por via intramuscular profunda, a cada 12 horas. Diante os achados oftálmicos e a presença de corpúsculos de A. marginale em hemácias parasitadas, contatou-se, ser um caso de uveíte crônica secundaria a doença sistêmica, factível com Anaplasmose

Hemangiosarcoma of the nictitant membrane in a Brazilian Fila dog: case report Hemangiosarcoma em membrana nictitante de cão da ração Fila Brasileiro: relato de caso

It was reported a case of a 9-year-old Brazilian Fila male dog that had been affected by a tissular formation of the nictitant membrane of the right eye with four months of evolution. Conjunctival hyperemia and edema, serosanguinolent secretion, and a conjunctival neoformation at the nictitant membrane were observed. Surgical exeresis of the neoformation was performed. Endothelial cells slightly differentiated and pleomorphic, with an intense vascular neoformation compatible to nictitant membrane hemangiosarcoma, were found at the histological exam.<br>Relata-se o caso de um cão, macho, da raça Fila Brasileiro, com nove anos de idade, acometido por neoformação tecidual na membrana nictitante do olho direito, com cerca de quatro meses de evolução. Realizou-se exame oftálmico rotineiro, a partir do qual se notaram hiperemia e edema conjuntivais, secreção ocular serossangüinolenta e neoformação saliente na conjuntiva da membrana nictitante. Realizou-se a exérese cirúrgica da neoformação. À histopatologia, encontraram-se células endoteliais pouco diferenciadas e pleomórficas que originavam intensa neoformação vascular, compatíveis com hemangiossarcoma da membrana nictitante

Effects of the Ottonia martiana Miq. (Piperaceae) extract on dog's ocular surface

The anesthetics effects of aqueous extract of Ottonia martiana leaves were studied on the ocular surface of healthy beagle dogs. The dogs were divided in three groups (n=15): control group (CG), proxymetacaine group (PG) and Ottonia group (OG), which were treated with 0.9% saline, 0.5% proxymetacaine hydrochloride ophthalmic solution and O. martiana extract respectively. An oftalmic evaluation was performed before the treatments. Eye drops were instilled at time 0 (T0) and 3 minutes later (T3). Axial corneal sensitivity was evaluated by esthesiometry 5 and 10 minutes after T0. Tear production and intraocular pressure were evaluated 10 minutes after T0. Slit lamp biomicroscopy was performed 10 and 20 minutes after T0 and the eyes were stained with fluorescein 20 minutes after T0. The STT was reduced in PG. Conjunctival hyperemia was observed in 13 animals from PG and constituted the only ocular alteration observed during the study. Esthesiometry revealed a decreased corneal sensitivity for PG and OG. Those results show that the O. martiana extract acts reducing corneal sensitivity in dogs. Moreover, its use does not decrease the tear production and does not cause any clinical ophthalmic alteration