RESUMO
Diphosphonates (DP) are synthetic pyrophosphates with a P-C-P backbone and are predominantly used for the treatment of bone diseases. Several DP have also been shown to exert significant antiarthritic effects in the rat adjuvant-induced polyarthritis model; however, there is no direct evidence for the anti-inflammatory effects of these compounds. We therefore tested the effects of dichloromethylene diphosphonate on delayed-type hypersensitivity granuloma elicited by s.c. implantation of antigen-soaked hydroxyapatite disks in antigen-sensitized mice. Dichloromethylene diphosphonate induced a dose-related inhibition of the delayed-type hypersensitivity granuloma response (38-64% at 25-100 mg/kg/day s.c. or p.o.); novel DP analogs, U-81581, U-82579 and U-84849 were also effective in the same dose range. In contrast, all DP failed to suppress 24-hr delayed-type hypersensitivity paw edema in mice. In addition to rat adjuvant-induced polyarthritis, mouse antigen-induced erosive arthritis was also significantly suppressed by s.c. administration of all four DP. Toxicity was minimal for each DP (> 600 mg/kg p.o. or s.c.). We conclude that DP represent a novel class of anti-inflammatory agents with excellent therapeutic potential for chronic inflammatory diseases including rheumatoid arthritis.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Difosfonatos/farmacologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Feminino , Granuloma de Corpo Estranho/tratamento farmacológico , Hipersensibilidade Tardia/tratamento farmacológico , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Ratos , Ratos WistarRESUMO
Recombinant human interleukin-1 alpha (IL-1 alpha) induced a time-dependent (0-72 hours) and concentration-dependent (0.01-10 ng/ml) production of metalloproteinases (collagenase, gelatinase, stromelysin) and prostaglandin E2 (PGE2) in rabbit articular chondrocytes (RAC). Exposure of RAC to recombinant human platelet-derived growth factor homodimer BB (PDGF-BB; 2-200 ng/ml) in the presence of stimulatory and substimulatory concentrations of IL-1 alpha resulted in a marked augmentation of metalloproteinase and PGE2 production. PDGF-BB exerted no agonist effects on RAC responsiveness. PDGF-BB up-regulated the number of IL-1 receptors per chondrocyte but had no effect on receptor affinity. Cycloheximide and actinomycin D caused a concentration-dependent suppression of the PDGF-BB-mediated potentiation of radiolabeled IL-1 alpha binding to RAC and cell responsiveness to IL-1 alpha. Similarly, IL-1 increased the number of PDGF receptors on RAC without changing receptor affinity. These data are discussed within the context of cytokine-growth factor interactions as components of the pathogenesis of arthritic diseases.
Assuntos
Cartilagem Articular/enzimologia , Dinoprostona/biossíntese , Interleucina-1/farmacologia , Metaloendopeptidases/biossíntese , Fator de Crescimento Derivado de Plaquetas/farmacologia , Animais , Cartilagem Articular/citologia , Cicloeximida/farmacologia , Dactinomicina/farmacologia , Sinergismo Farmacológico , Indução Enzimática/efeitos dos fármacos , Coelhos , Proteínas Recombinantes/farmacologia , Fatores de TempoRESUMO
Recombinant human interleukin-1 alpha (rhIL-1 alpha) and recombinant human interleukin 1 beta (rhIL-1 beta) stimulated the time- and concentration-dependent release of glycosaminoglycan (GAG) from bovine nasal cartilage explants. Maximum GAG release occurred during six to eight days of cartilage exposure to either species of rhIL-1; and rhIL-1 alpha was consistently more potent than rhIL-1 beta. In addition to inducing cartilage matrix resorption, rhIL-1 alpha and rhIL-1 beta also inhibited the incorporation of [35SO4]sulfate into cartilage, which is a reflection of the suppression of GAG synthesis. IL-1 had no capacity to stimulate GAG relase from or inhibit GAG synthesis by dead cartilage. Cycloheximide, an inhibitor of protein synthesis, and 1, 10-phenanthroline, a metalloproteinase inhibitor, suppressed rhIL-1-stimulated cartilage matrix resorption. Polyclonal antisera to rhIL-1 alpha and rhIL-1 beta specifically neutralized the respective cytokines.
Assuntos
Cartilagem/metabolismo , Glicosaminoglicanos/biossíntese , Interleucina-1/farmacologia , Animais , Bovinos , Cicloeximida/farmacologia , Relação Dose-Resposta a Droga , Técnicas Imunológicas , Técnicas In Vitro , Fenantrolinas/farmacologia , Polimixina B/farmacologia , Proteínas Recombinantes , Sulfatos/metabolismoRESUMO
In an extensive analysis of the antiviral and interferon-induction structure-activity relationship of 6-arylpyrimidinones we found that modifications at positions 1-4 of the pyrimidine ring resulted in a loss of activity. However, we uncovered interesting hypotensive and antiinflammatory activity with a series of N-substituted analogues, the results of which we report herein.
Assuntos
Anti-Inflamatórios/síntese química , Diurese/efeitos dos fármacos , Hipotensão/induzido quimicamente , Fenilacetatos/metabolismo , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Estilbenos/metabolismo , Tamoxifeno/análogos & derivados , Animais , Anti-Inflamatórios/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Artrite/tratamento farmacológico , Relação Dose-Resposta a Droga , Feminino , Furosemida/farmacologia , Guanetidina/farmacologia , Coração/efeitos dos fármacos , Hidroclorotiazida/farmacologia , Masculino , Metilação , Natriurese/efeitos dos fármacos , Fenilacetatos/síntese química , Fenilacetatos/farmacologia , Potássio/urina , Ratos , Ratos Endogâmicos , Estilbenos/síntese química , Estilbenos/farmacologia , Relação Estrutura-Atividade , Tamoxifeno/síntese química , Tamoxifeno/metabolismo , Tamoxifeno/farmacologiaRESUMO
A reversed passive Arthus reaction was elicited in the rat pleural cavity. The kinetics of this inflammatory response indicate that exudate volume (cells and fluid) reaches a maximum level approximately 2 to 4 hr postantibody challenge. The neutrophil is the major cellular constituent of the pleural exudate during the first 12 hr of this reaction, reaching peak values at 4 hr; whereas, the monocyte predominates between 15 and 24 hr. Lymphocytes, eosinophils, and mast cells were also identified in the pleural exudates. The serotonin antagonists, cyproheptadine and methylsergide, and the antihistamine, chlorpheniramine, demonstrated marginal activity in the Arthus pleurisy model. The histamine antagonist, metiamide, was inactive. The nonsteroidal anti-inflammatory agents, flurbiprofen, ibuprofen, indomethacin, and benoxaprofen caused a modest suppression of exudate volume (18-32%) and cell accumulation (28-34%). The fluid and cellular components of the Arthus reaction were significantly inhibited by dexamethasone, triamcinolone, paramethasone, and prednisolone. The oral gold preparation, auranofin, had a pronounced effect on exudate volume; whereas, other antirheumatic agents such as D-penicillamine, azathioprine, and chloroquine had no effect on the Arthus pleurisy reaction. The immunomodulator, levamisole, suppressed exudate volume, but had no effect on cell accumulation in the pleural cavity.
Assuntos
Reação de Arthus/complicações , Pleurisia/etiologia , Corticosteroides/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Reação de Arthus/prevenção & controle , Movimento Celular/efeitos dos fármacos , Ciclofosfamida/uso terapêutico , Modelos Animais de Doenças , Antagonistas dos Receptores Histamínicos/uso terapêutico , Levamisol/uso terapêutico , Masculino , Monócitos/imunologia , Neutrófilos/imunologia , Derrame Pleural/citologia , Ratos , Antagonistas da Serotonina/uso terapêutico , Soroalbumina Bovina/imunologia , Fatores de TempoRESUMO
While some salicylates (salicyclic acid and salicylaldehyde, especially) are as potent as aspirin as acute, orally-active anti-flammatory drugs in the rat, they are either inactive or far less potent as PG synthesis inhibitors when added directly to isolated platelets or when given orally. Although PGE1 and PGE2 produce anti-ulcerogenic effects when given to rats in the presence of selected non-steroidal anti-flammatory drugs, they fail to inhibit the acute anti-flammatory and anti-nociceptive effects of these drugs. They are anti-flammatory and anti-nociceptive under certain experimental conditions. PGE1 and PGE2 can also behave as hypothermic agents when given subcutaneously. Related studies, using PG synthesis stimulators in vivo and in vitro (substituted phenylureas), also cause anti-nociception and hypothermia. All of these indirect studies, when taken together, infer that PG synthesis inhibition per se fails to explain, entirely, the pharmacologic effects of non-steroidal anti-inflammatory drugs. They also suggest that the precise role of certain PGs in toxicopharmacology is far from simple and straightforward.
Assuntos
Prostaglandinas/farmacologia , Salicilatos/farmacologia , Analgésicos , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Temperatura Corporal/efeitos dos fármacos , Carragenina , Edema/fisiopatologia , Técnicas In Vitro , Inflamação/fisiopatologia , Masculino , Prostaglandinas/biossíntese , Prostaglandinas E/farmacologia , Ratos , Úlcera Gástrica/induzido quimicamenteAssuntos
Anti-Inflamatórios/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Inflamação/induzido quimicamente , Administração Tópica , Animais , Anti-Inflamatórios/administração & dosagem , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/farmacologia , Óleo de Cróton/administração & dosagem , Óleo de Cróton/farmacologia , Combinação de Medicamentos , Inflamação/tratamento farmacológico , Masculino , Ratos , Ácidos Sulfúricos/administração & dosagem , Ácidos Sulfúricos/farmacologiaRESUMO
Although acetaminophen and phenacetin do not inhibit PG synthesis when added directly to isolated rat platelets and when given orally, both drugs inhibit carrageenan-induced hindpaw edema--a widely used inflammatory assay method. It does not appear that the anti-inflammatory effects of these non-steroidal drugs (unlike other well-known non-steroidal drugs) can be explained on the basis of PG-synthetase inhibition.