RESUMO
OBJECTIVE: The purpose of this study was to compare measurements of glucose obtained via iontophoretic extraction with the GlucoWatch automatic glucose biographer (Cygnus, Inc., Redwood City, CA) with capillary blood glucose values that were determined 1) in a controlled outpatient clinic setting and 2) in a home setting. RESEARCH DESIGN AND METHODS: There were 76 GlucoWatch biographers used on 28 different young adults (21 women and 7 men) with type 1 diabetes (age 30.9 +/- 6.9 years and duration of diabetes 18.4 +/- 8.1 years [mean +/- SD]) in a controlled outpatient clinic setting. Some subjects participated on multiple days. Subjects wore two GlucoWatch biographers, each on the forearm (ventral aspect). Comparisons were made to HemoCue blood glucose analyzer (Aktiebolgat Leo, Helsingborg, Sweden) capillary blood glucose measurements. In addition, GlucoWatch biographers (one each day for 3 consecutive days) were used by 12 subjects (8 women, 4 men) in a home setting. Comparisons were made to capillary blood glucose values determined using the One Touch Profile meter (Johnson & Johnson, New Brunswick, NJ). RESULTS: GlucoWatch biographer glucose values correlated well with capillary blood glucose values determined using the HemoCue analyzer in the clinic setting (r = 0.90, 1,554 paired data points) and using the One Touch Profile meter in the home setting (r = 0.85, 204 paired data points). When 36 subjects wore two biographers simultaneously, the correlation between the two biographers was r = 0.94. The error grid analysis demonstrated that > 96% of biographer glucose values determined in the clinic or home setting were in the clinically acceptable A and B regions. CONCLUSIONS: This study confirms the accuracy and precision of glucose values as determined using the GlucoWatch biographer in clinic and home settings.
Assuntos
Automonitorização da Glicemia/instrumentação , Automonitorização da Glicemia/métodos , Diabetes Mellitus Tipo 1/sangue , Adulto , Capilares , Desenho de Equipamento , Feminino , Dedos/irrigação sanguínea , Humanos , Masculino , Análise de Regressão , Reprodutibilidade dos TestesRESUMO
Series of 5-phenoxy-2(1H)-pyrimidinones, 5-phenoxy-4(3H)-pyrimidinones, and related compounds were prepared in a follow-up of a lead prepared as a potential cyclic nucleotide regulating agent. Compounds were evaluated for bronchodilator activity in histamine-challenged guinea pigs and for anticulcer activity in a cold-restraint, stressed rat ulcer model. Bronchodilator activity comparable to, or greater than, that of theophylline was found in both the 2(1H)- and 4(3H)-pyrimidinone series and was most prominent in analogues containing either an electron-withdrawing or -donating substituent in the para position of the phenoxy ring. Significant antiulcer activity was observed only in the 2(1H)-pyrimidinone series among three closely related analogues. One of these, 5-(m-methylphenoxy)-2(1H)-pyrimidinone (3), exhibited more potent antiulcer effects than the clinically useful antiulcer agent carbenoxolone, without demonstrating bronchodilator activity.
Assuntos
Antiulcerosos/síntese química , Broncodilatadores/síntese química , Pirimidinonas/síntese química , Animais , Feminino , Mucosa Gástrica/efeitos dos fármacos , Cobaias , Muco/metabolismo , Pirimidinonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Improved glycemic control significantly reduces long-term microvascular complications of diabetes mellitus associated with chronic hyperglycemia. The GlucoWatch biographer is designed to facilitate intensive diabetes management by providing automatic, frequent, and noninvasive glucose readings up to three times per hour for as long as 12 hours. METHODS: The device extracts glucose through intact skin using reverse iontophoresis and measures the extracted glucose with an electrochemical biosensor. A clinical trial was performed to assess the effect of acetaminophen, a potential interference for traditional blood glucose meters, on the accuracy of the GlucoWatch biographer in adult subjects with diabetes (n = 18). One thousand milligram doses of acetaminophen were administered to subjects in two groups: one to achieve Cmax (peak acetominophen concentration) at the time of biographer calibration and the other to achieve Cmax during the measurement period. The biographer readings were compared to serial fingerstick blood glucose measurements. RESULTS: Time profiles over 9 hours show close tracking of the biographer glucose results with fingerstick blood glucose measurements for all groups. The mean difference between the two measurements is between 8 and 12 mg/dL for all groups. The mean absolute value of the relative difference is less than 20%, and more than 93% of the points were in the clinically acceptable (A+B) region of the Clarke Error Grid. No statistically significant differences were found for any accuracy measurement across all groups. CONCLUSIONS: The GlucoWatch Biographer provides frequent measurements of glucose over a 12-hour period with high accuracy. No effect of therapeutic dosage of acetaminophen on the accuracy of the glucose readings was found.
Assuntos
Acetaminofen/farmacologia , Automonitorização da Glicemia/métodos , Glicemia/análise , Monitorização Ambulatorial/instrumentação , Monitorização Ambulatorial/métodos , Adulto , Análise de Variância , Automação , Técnicas Biossensoriais , Automonitorização da Glicemia/instrumentação , Calibragem , Eletroquímica , Desenho de Equipamento , Humanos , Reprodutibilidade dos Testes , Fatores de Tempo , Estados Unidos , População BrancaRESUMO
In an effort to determine the mechanism of papain action in causing an emphysema-like lesion in hamsters, the number and types of cells and the activities of two lysosomal enzymes in the lung were determined after papain exposure. Three and four weeks after a 3-h exposure to an aerosol of 3% papain the following alterations in lung structure and function were observed: (1) the mean linear intercept, or average distance between adjacent alveoli, was increased; (2) the internal surface area declined; (3) the dynamic compliance was elevated at low breathing frequencies. The numbers of cells present free in the lung increased from a control value of 2.0 +/- 0.2 x 10 (6) to 6.6 +/- 0.5 x 10 (6) 5 days after exposure. The free beta-glucuronidase, alysosomal enzyme, likewise increased over threefold during the first 3 days after exposure. These results are consistent with the hypothesis that papain induces an inflammatory-type responses, and this may be in part responsible for inducing the lesion.
Assuntos
Pulmão/efeitos dos fármacos , Papaína/efeitos adversos , Enfisema Pulmonar/etiologia , Animais , Cricetinae , Glucuronidase/análise , Contagem de Leucócitos , Pulmão/enzimologia , Pulmão/patologia , Masculino , Mesocricetus , Neutrófilos , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/enzimologia , Enfisema Pulmonar/patologia , Enfisema Pulmonar/fisiopatologiaAssuntos
Anti-Inflamatórios/farmacologia , Cartilagem/enzimologia , Endopeptidases/isolamento & purificação , Macrófagos/enzimologia , Metaloendopeptidases , Proteoglicanas/metabolismo , Doenças Reumáticas/tratamento farmacológico , Animais , Catepsina D , Catepsinas/análise , Feminino , Glucocorticoides/farmacologia , Glucuronidase/análise , Técnicas In Vitro , Masculino , Camundongos , Elastase Pancreática/análise , Proteoglicanas/isolamento & purificaçãoAssuntos
Glucuronidase/metabolismo , Monócitos/enzimologia , Muramidase/metabolismo , Elastase Pancreática/metabolismo , Alvéolos Pulmonares/enzimologia , Animais , Bioensaio , Glucuronidase/análise , Cobaias , Histocitoquímica , L-Lactato Desidrogenase/análise , Masculino , Métodos , Micrococcus/metabolismo , Muramidase/análise , Elastase Pancreática/análise , Fagocitose , Alvéolos Pulmonares/citologia , Enfisema Pulmonar/fisiopatologiaAssuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Desenho de Fármacos , Avaliação de Medicamentos , Imunossupressores/uso terapêutico , Ensaios Clínicos como Assunto , Simulação por Computador , Humanos , Estados Unidos , United States Food and Drug AdministrationRESUMO
Several pharmacologic agents were tested for inhibition of phagocyte-induced release of lysosomal enzymes from guinea-pig alveolar mononuclear cells and peritoneal leukocytes. The activities of the lysosomal enzyme beta-glucuronidase and the cytoplasmic enzyme lactate dehydrogenase were determined in the cells and media following a 2-hour incubation period of cells and zymosan particles. Adrenergic and cholinergic agents, the 3,'5'-adenosine and guanosine cyclic nucleotides, and theophylline had no effect on phagocytosis or release of beta-glucuronidase or lactate dehydrogenase from alveolar cells. Cytochalasin B stimulated lysosomal but not cytoplasmic enzyme release from these cells in the absence of zymosan. Colchicine and hydrocortisone inhibited phagocytosis and beta-glucuronidase extrusion, and phenylbutazone inhibited only beta-glucuronidase release. Colchicine and phenylbutazone also inhibited enzyme release stimulated by cytochalasin B indicating that they were affecting postphagocytic events. The cyclic nucleotides and theophylline were without effect on the peritoneal leukocytes; dexamethasone and phenylbutazone inhibited enzyme release with only the former antagonizing phagocytosis.
Assuntos
Leucócitos/ultraestrutura , Lisossomos/enzimologia , Macrófagos/ultraestrutura , Alvéolos Pulmonares/ultraestrutura , Acetilcolina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Bucladesina/farmacologia , Colchicina/farmacologia , AMP Cíclico/farmacologia , GMP Cíclico/farmacologia , Citocalasina B/farmacologia , Dimetil Sulfóxido/farmacologia , Cobaias , Técnicas In Vitro , Isoproterenol/farmacologia , Lisossomos/efeitos dos fármacos , Microtúbulos/enzimologia , Prostaglandinas E/farmacologia , Prostaglandinas F/farmacologia , Alvéolos Pulmonares/enzimologia , Teofilina/farmacologiaRESUMO
Cells lavaged from guinea pig lungs selectively release the lysosomal enzymes beta-glucuronidase and lysozyme during the process of phagocytosis. The total enzymatic activity of beta-glucuronidase was elevated in zymosan-exposed compared with non-exposed cells. The divalent cation carrying ionophore A23187 did not stimulate lysosomal enzyme release. Transmission and scanning electron micrographs demonstrate particle uptake and are consistent with enzyme release.
Assuntos
Glucuronidase/metabolismo , Muramidase/metabolismo , Neutrófilos/enzimologia , Alvéolos Pulmonares/enzimologia , Animais , Calcimicina/farmacologia , Cálcio/fisiologia , Citocalasina B/farmacologia , Feminino , Cobaias , L-Lactato Desidrogenase/metabolismo , Lisossomos/enzimologia , Masculino , Fagocitose , Alvéolos Pulmonares/ultraestruturaRESUMO
Naproxen was evaluated for possible disease modifying effects in the Freund's adjuvant injected rat (AIR). Oral administration of the clinical dose, 7 mg/kg/day, lead to an almost complete inhibition of hindpaw swelling and cartilage and bone erosion. This was noted in animals maintained on drug as well as those in which therapy was discontinued. AIR, comparable to arthritic patients, demonstrate a reduced lymphocytic response to T cell mitogens. This response was normalized in naproxen-treated rats. These results suggest that naproxen has a disease modifying effect in the AIR.
Assuntos
Artrite Experimental/tratamento farmacológico , Artrite/tratamento farmacológico , Naproxeno/uso terapêutico , Animais , Concanavalina A/farmacologia , Feminino , Ativação Linfocitária/efeitos dos fármacos , Mitógenos/farmacologia , Fito-Hemaglutininas/farmacologia , Ratos , Linfócitos T/efeitos dos fármacosRESUMO
OBJECTIVE: To evaluate the effect of the antioxidant-like anti-inflammatory agent, ebselen, on cartilage proteoglycan degradation and to determine whether its cartilage protectant activity is related to its antioxidant activity. MATERIALS AND METHODS: Cartilage in organ culture was stimulated with interleukin-1 (IL-1), and proteoglycan degradation was assessed by measuring the amount of sulfated glycosaminoglycan released into the media, proteoglycan synthesis evaluated by [35S]-sulfate incorporation, and prostaglandin E2 (PGE2) release determined by radioimmunoassay (RIA). Glutathione peroxidase (GSH-Px) activity was evaluated in a coupled test system using NADPH/GSSG reductase as an indicator and cyclooxygenase activity was evaluated using sheep seminal vesicle prostaglandin synthase. RESULTS: Ebselen caused a concentration-dependent inhibition of IL-1-stimulated proteoglycan degradation with an IC50 of 4.7 microM. Cartilage PGE2 release was also reduced in the presence of ebselen (IC50 = 6.2 microM). However, at concentrations up to 100 microM, ebselen had no effect on the inhibition of proteoglycan synthesis by IL-1. Induction of proteoglycan breakdown was also inhibited by a sulfur analog of ebselen. This analog was devoid of GSH-Px activity and was 50-fold less potent in cyclooxygenase inhibitory activity, but was equipotent to ebselen in inhibiting cartilage degradation. CONCLUSIONS: Ebselen, unlike other NSAIDs, blocks cartilage proteoglycan breakdown without inhibiting proteoglycan synthesis. This effect is independent of its GSH-Px activity and its ability to inhibit cyclooxygenase and PGE2 production. Therefore, this compound may provide a new mechanism for protecting cartilage matrix from degradative factors in arthritic joints.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Azóis/farmacologia , Cartilagem/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Inflamação/tratamento farmacológico , Interleucina-1/farmacologia , Compostos Organosselênicos/farmacologia , Proteoglicanas/metabolismo , Animais , Artrite/tratamento farmacológico , Cartilagem/metabolismo , Bovinos , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Dissulfeto de Glutationa/análise , Glutationa Peroxidase/metabolismo , Glicosaminoglicanos/metabolismo , Inflamação/induzido quimicamente , Isoindóis , NADP/análise , Técnicas de Cultura de ÓrgãosRESUMO
Oxygen free radicals have the potential to mediate cell injury. Defenses against such radicals include the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX). The purposes of this study were (1) to develop an in vitro model using human cells in which to investigate a potential pharmacologic agent as an inducer of these antioxidant enzymes; (2) to investigate the phenylurea derivative N-[2-(2-oxo-1-imidazolindinyl)ethyl]-N-phenylurea (EDU) in this model with paraquat (PQ) serving as the positive control; and (3) to determine if induction of the antioxidant enzymes by EDU occurs in vivo. Human gingival fibroblasts (Gin-1) were used as the target cell in vitro; PQ and EDU, an inducer of SOD and CAT activities in plants, were evaluated as antioxidant enzyme inducers. Total SOD activity in Gin-1 cells increased 2-fold (p less than 0.05) in the presence of 1.0 mM PQ for 18-48 hr compared with untreated controls. Gin-1 cells incubated with 0.25-2.0 mM PQ for 24 hr had significantly increased total SOD (1.5 to 2.0-fold; p less than 0.05). CAT activity increased with 1.0 and 2.0 mM PQ (p less than 0.05). In the presence of PQ, GSH-PX activity decreased (p less than 0.05) in a concentration-dependent manner, indicating inactivation of this enzyme. No toxicity, indicated by lactate dehydrogenase released into the incubation medium, was noted at PQ concentrations below 5.0 mM. In the presence of 0.125-2.0 mM EDU, total SOD activity in Gin-1 cells significantly increased (1.5 to 2.0-fold; p less than 0.05). CAT activity significantly increased in a dose-dependent manner (p less than 0.05), while GSH-PX activity remained constant following exposure to 0.125-2.0 mM EDU. Intraperitoneal administration of EDU to rats twice a day for 2 days at 100 mg/kg induced SOD activity in heart, liver, and lung compared to controls (p less than 0.05). CAT activity increased in the liver 56% and in the lung 36% (p less than 0.05). GSH-PX activity remained constant. Our findings indicate that Gin-1 cells are a useful model in which to study inducers of antioxidant enzymes in vitro and that the phenylurea compound EDU induces SOD and CAT activities both in vitro and in vivo.
Assuntos
Antioxidantes/metabolismo , Compostos de Fenilureia/farmacologia , Catalase/biossíntese , Linhagem Celular , Cloranfenicol/farmacologia , Cicloeximida/farmacologia , Dactinomicina/farmacologia , Indução Enzimática , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Radicais Livres , Glutationa Peroxidase/biossíntese , Humanos , Paraquat/farmacologia , Superóxido Dismutase/biossínteseRESUMO
Nordihydroguaiaretic acid (NDGA) was investigated for its ability to interact with leukotriene B4 receptors on human polymorphonuclear leukocytes (hPMNs). 3H-LTB4 binding to specific receptors was reduced in a dose-dependent manner with maximal reduction at 100 microM NDGA and an IC50 of about 50 microM. Binding of another inflammatory stimulus. N-formyl-norleucyl-leucyl-phenylalanine (FNLP) was not affected by similar treatment. Chemotaxis and enzyme release stimulated by LTB4 and oligopeptide were inhibited by NDGA. In addition, LTB4-triggered inflammation in vivo in mice was inhibited by systemic administration of NDGA. These data suggest that LTB4 receptor antagonism may contribute to inhibition of inflammation by NDGA.
Assuntos
Catecóis/farmacologia , Leucotrieno B4/metabolismo , Masoprocol/farmacologia , Neutrófilos/efeitos dos fármacos , Animais , Humanos , Técnicas In Vitro , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Leucotrieno B4/farmacologia , Camundongos , Neutrófilos/metabolismo , Receptores Imunológicos/efeitos dos fármacos , Receptores do Leucotrieno B4RESUMO
Recent work suggests that one of the common biochemical characteristics of skin inflammatory diseases such as psoriasis is altered arachidonic acid metabolism with elevated levels of prostaglandins and leukotrienes. DuP 654, a 2-substituted 1-naphthol, is an exceptionally potent inhibitor of 5-lipoxygenase. DuP 654 was tested in various models of skin inflammation and was found to be potent at inhibiting edema induced by the topical application of arachidonic acid, tetradecanoyl phorbol acetate or the calcium ionophore A23187. DuP 654 was also effective in a murine model of contact sensitivity. DuP 654 was effective at reducing the numbers of infiltrating polymorphonuclear leukocytes in AA and TPA induced edema. These data, taken together, suggest that DuP 654 may be effective in treating human skin diseases.
Assuntos
Anti-Inflamatórios/farmacologia , Administração Tópica , Animais , Dermatite/tratamento farmacológico , Dermatite/enzimologia , Dermatite/fisiopatologia , Modelos Animais de Doenças , Camundongos , Naftóis/farmacologia , Peroxidase/metabolismoRESUMO
Proteinases are thought to be responsible for cartilage and bone erosion noted in chronic inflammatory conditions. Suramin [8-(3-benzamindo-4-meta-1-benzamindo)naphthalene-1,3,5-trisulfonic acid], 10(-5) and 10(-4) M, inhibited the release of a mouse macrophage-derived cartilage proteoglycan-degrading enzyme. At 10(-5) M it antagonized the activity of beta-glucuronidase and cathepsin D derived from the mouse macrophage, as well as similar enzymes secreted by rat macrophages in vivo. When cultured at 10(-4) M with rabbit knee cartilage, it antagonized the autolytic release of proteoglycan, indicating an inhibitory activity against a chondrocyte-derived neutral proteinase. After in vivo treatment at 10 mg/kg/day s.c., it was ineffective in preventing the cartilage and bone erosion noted in the adjuvant arthritic rat.
Assuntos
Cartilagem Articular/metabolismo , Suramina/farmacologia , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Ácido Aspártico Endopeptidases , Reabsorção Óssea/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Depressão Química , Endopeptidases/metabolismo , Feminino , Ativação de Macrófagos , Macrófagos/enzimologia , Masculino , Camundongos , Proteoglicanas/metabolismo , Coelhos , Ratos , Ratos EndogâmicosRESUMO
The Freund's adjuvant-injected rat shares a number of features with the arthritis patient, viz the presence of a proliferative synovitis, joint swelling, and cartilage and bone erosion. Naproxen, a prostaglandin synthetase inhibitor which is an effective antiinflammatory agent in laboratory animals and humans, was evaluated as an inhibitor of connective tissue destruction in this model by use of radiologic and histopathologic analyses. Sixteen days after rats were injected with Freund's complete adjuvant, marked joint swelling was noted. On day 17, vehicle or naproxen, 7 mg/kg/day, was administered orally. Twenty-eight days later vehicle-treated animals demonstrated the following pathologic changes in their hindpaws; swelling, cartilage loss, large amounts of pannus within the joint spaces, osteoporosis, bone erosions, periosteal new bone formation, heterotopic ossification, and bony ankylosis. Rats treated 28 days with naproxen had significantly milder disease than the vehicle controls. The incidence of severe juxtaarticular bone destruction was 10/10 in the vehicle controls versus 2/10 of the drug-treated group (P less than 0.01). A comparable reduction in cartilage erosion, incidence of pannus, and new bone formation was noted in the drug-treated group. These effects may relate to an inhibition of prostaglandin biosynthesis; prostaglandins have been shown to: 1) stimulate collagenase secretion from macrophages, 2) stimulate bone resorption in vivo and in vitro, and 3) diminish proteoglycan synthesis in cartilage.
Assuntos
Artrite Experimental/tratamento farmacológico , Artrite/tratamento farmacológico , Tecido Conjuntivo/efeitos dos fármacos , Naproxeno/uso terapêutico , Animais , Anquilose/patologia , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/patologia , Cartilagem/patologia , Tecido Conjuntivo/patologia , Feminino , Naproxeno/farmacologia , Osteoporose/patologia , Prostaglandinas/biossíntese , Radiografia , RatosRESUMO
Intratracheal administration of PMA produces acute lung injury in part due to the generation of O2-derived free radicals. This study evaluated the role of the antioxidant enzyme superoxide dismutase (SOD) in PMA-induced lung injury in the rat. PMA was instilled into rats intratracheally (20-60 micrograms/kg), and the lungs were lavaged 4 hr later. Total number of cells recovered from lavage after PMA treatment was not different from the total number recovered from controls; lavagable PMNs increased in a dose-dependent manner. Albumin in lavage fluid (an index of lung vascular permeability) was significantly increased at 60 micrograms/kg PMA. SOD (10,000 U) + PMA (60 micrograms/kg) reduced the albumin level but significantly increased both total number of cells and number of PMNs recovered from lavage fluid. To investigate the possibility that SOD decreases the ability of PMNs to adhere, PMN aggregation was measured in vitro. The results indicated that 10,000 U SOD can inhibit PMA-induced aggregation by 50%. In contrast, aggregation to other stimuli (e.g., fMet-Leu-Phe, A23187) was unaffected by SOD. We conclude SOD prevents PMA-induced lung permeability and diminishes PMN adherence.
Assuntos
Pneumonia/induzido quimicamente , Acetato de Tetradecanoilforbol/toxicidade , Animais , Agregação Celular/efeitos dos fármacos , Técnicas In Vitro , Masculino , Neutrófilos/efeitos dos fármacos , Pneumonia/prevenção & controle , Ratos , Ratos Endogâmicos Lew , Superóxido Dismutase/farmacologiaRESUMO
Human monocyte IL-1 stimulated the release of proteoglycans from cartilage in organ culture in a concentration-related manner. This stimulation required protein synthesis as shown by inhibition with cycloheximide. The metal chelator, 1,10-phenanthroline, inhibited breakdown, suggesting the involvement of a metalloproteinase. Various nonsteroidal anti-inflammatory drugs (100 microM), and the corticosteroids, dexamethasone and hydrocortisone (1-10 microM), were not effective in blocking proteoglycan release. Of the disease modifying agents tested, levamisole was ineffective while the antimalarials, chloroquine (100 microM) and hydroxychloroquine (100 microM), inhibited the action of IL-1. The free-radical inhibitor SOD (5000 U/ml but not 1000 U/ml) was effective while catalase (8000 U/ml) was not. The protective effects of SOD and the antimalarials suggest that oxygen reactive species may play a role, while lack of inhibition with NSAIDs and corticosteroids indicate that arachidonic acid metabolites may not be important in this degradative process.
Assuntos
Anti-Inflamatórios/farmacologia , Cartilagem/efeitos dos fármacos , Animais , Cartilagem/metabolismo , Bovinos , Técnicas In Vitro , Interleucina-1/farmacologia , Metaloendopeptidases/metabolismo , Proteoglicanas/metabolismoRESUMO
The purpose of this study was to investigate the effects of cyclosporine A (CSA) and methotrexate (MTX) as potential immunomodulators in a nonestablished adjuvant arthritis (AA) model. Non-injected hind paw volumes were reduced when AA rats were treated for 18 days with CSA (100% at 10 mg/kg) or MTX (100% at 0.1 mg/kg). Body weights of drug treated AA rats were increased above untreated AA rats and were similar to non-arthritic controls. AA rats show elevated T helper (W3/25+)/T suppressor (OX 8+) cell ratios (2.0 vs. 3.1, p less than 0.01). The immunomodulators tested all returned these elevated ratios to control non-arthritic levels. Similarly, these drugs returned the reduced mitogen responses and elevated blood granulocyte numbers toward normal non-arthritic control values.
Assuntos
Artrite Experimental/tratamento farmacológico , Imunossupressores/uso terapêutico , Animais , Artrite , Artrite Experimental/patologia , Artrite Experimental/fisiopatologia , Ciclosporinas/uso terapêutico , Pé/patologia , Indometacina/uso terapêutico , Masculino , Metotrexato/uso terapêutico , Ratos , Ratos Endogâmicos , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismoRESUMO
The possible utility of DuP 654, a potent 5-lipoxygenase inhibitor, for treating human inflammatory skin disease was investigated in murine skin treated with 1.0 mg arachidonic acid (AA). When DuP 654 was applied to murine skin treated with AA, it inhibited the resulting inflammation and influx of cells. High performance liquid chromatography and radioimmunoassay analysis of lipid extracts from AA-treated ears indicated that the influx of polymorphonuclear leukocytes (PMN) was temporally preceded by an appearance of significant amounts of 5-HETE (6.7 +/- 1.4 ng/ear) and Leukotriene B4 LTB4 0.92 +/- 0.2 ng/ear) when compared with extracts of untreated ears (5-HETE, 02 +/- 0.3 ng/ear; LTB4, less than 0.1 ng/ear). The levels of the 5-lipoxygenase products were reduced by treatment with 10 micrograms/ear DUP 654. Lipid extracts from AA-treated ears contain chemotactic activity for human PMN and this chemotactic activity in the AA-treated ears could be reduced but not eliminated by immunosorption with anti-LTB4 antibodies coupled to protein A-agarose. The appearance of the chemotactic activity was inhibited by DuP 654. Taken together, these data suggest that DuP 654 may have utility in human inflammatory skin disease.