RESUMO
A 44-year-old woman presented to the rheumatology clinic with a 5-month history of stiffness and tightness of the skin of the distal fingers, together with pruritus and skin changes throughout the limbs and chest. She had also developed Raynaud's phenomenon (during the summer months), fatigue and abdominal discomfort with early satiety. She had a history of adenocarcinoma of the left breast and had undergone a wide local excision and axillary node clearance 11 years earlier with adjuvant chemotherapy and hormone therapy to which she had responded well. She was found to have sclerodactyly with skin thickening over the knees, upper arms, face and chest wall together with nodularity at the scar site and distortion of the left breast. Subsequent investigations revealed recurrent metastatic breast cancer with paraneoplastic scleroderma. We explore this interesting case and review our current understanding of paraneoplastic scleroderma.
Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/secundário , Neoplasias Hepáticas/secundário , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/secundário , Síndromes Paraneoplásicas/etiologia , Esclerodermia Localizada/etiologia , Adulto , Neoplasias da Mama/complicações , Carcinoma Ductal de Mama/complicações , Feminino , Humanos , Neoplasias Hepáticas/complicações , Recidiva Local de Neoplasia/complicações , Neoplasias Ovarianas/complicaçõesRESUMO
Vanilloid receptor 1 (VR1, TRPV1) is a cation-selective ion channel that is expressed on primary afferent neurons and is upregulated following inflammation and nerve damage. Blockers of this channel may have utility in the treatment of chronic nociceptive and neuropathic pain. Here, we describe the optimization from a high throughput screening hit, of a series of 6-aryl-7-isopropylquinazolinones that are TRPV1 antagonists in vitro. We also demonstrate that one compound is active in vivo against capsaicin-induced hyperalgesia and in models of neuropathic and nociceptive pain in the rat.
Assuntos
Dor/tratamento farmacológico , Quinazolinas/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Barreira Hematoencefálica/metabolismo , Células CHO , Células CACO-2 , Permeabilidade da Membrana Celular , Doença Crônica , Cricetinae , Cricetulus , Modelos Animais de Doenças , Humanos , Técnicas In Vitro , Camundongos , Testes para Micronúcleos , Microssomos Hepáticos/metabolismo , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Canais de Cátion TRPV/genéticaRESUMO
The ability of 2'-alpha-C-carboxyalkyl nucleosides to undergo an unusual two-step stereocontrolled nucleobase exchange process has been investigated. Upon silylation a protected 2'-deoxy-2'-alpha-C-(carboxymethyl)uridine derivative can undergo intramolecular displacement of the uracil base, by the 2'-carboxylic acid group, to form a pentofuranosyl gamma-lactone. Under identical conditions the homologous 2'-deoxy-2'-alpha-C-(carboxyethyl)uridine derivative does not yield the corresponding delta-lactone, but undergoes elimination of uracil to give the corresponding glycal. The pentofuranosyl gamma-lactone is a good substrate for nucleoside synthesis by the Vorbrüggen procedures and undergoes completely stereoselective ring opening with either pyrimidine or purine silylated nucleobases to give novel 2'-C-carboxymethyl beta-nucleosides in moderate to high yield.
