RESUMEN
Intestinal toxicity exerted by indomethacin was compared to that induced by copper-indomethacinate, free or associated to zwitterionic phospholipids. A single high dose of indomethacin (15 or 20 mg/kg), copper-indomethacinate (15 or 20 mg/kg), or copper-indomethacinate liposomes or nanocapsules (15 mg/kg) was orally administered. Then 24 hr later jejunoileal tissue was taken for macroscopic observation, ex vivo nitrite production, and determination of myeloperoxydase and iNOS activities. Antiinflammatory activity of the drugs was investigated using the carrageenan-induced paw edema model. Indomethacin induced penetrating ulcerations of the intestine that were maximal at hour 24. Copper-indomethacinate induced significantly less ulceration than indomethacin with no significant difference in MPO and iNOS activities. The injurious action of indomethacin on the small intestine was further reduced when copper-indomethacinate was administered as the phospholipid-associated state while similar anti-inflammatory action was observed on rat paw edema. The antiulcerogen effect of copper-indomethacinate seems to be linked to its free radical scavenging effect without any modification of nitric oxide release.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Cobre/farmacología , Indometacina/farmacología , Intestino Delgado/efectos de los fármacos , Óxido Nítrico Sintasa/metabolismo , Compuestos Organometálicos/farmacología , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Indometacina/efectos adversos , Yeyuno/efectos de los fármacos , Yeyuno/metabolismo , Liposomas , Masculino , Óxido Nítrico Sintasa de Tipo II , Peroxidasa/metabolismo , Fosfolípidos , Ratas , Ratas Sprague-Dawley , Úlcera/inducido químicamenteRESUMEN
LDL peroxidation represents one of the first event in the atherogenesis process. Inhibiting LDL oxidation may impede this process and offers a new mechanism to retard atherogenesis. 21-Aminosteroids, derived from methylprednisolone, have recently excited much interest by virtue of their ability to inhibit lipid peroxidation. The aim of our work was to investigate the effect of a novel 21-aminosteroid, U-74389G, in the LDL peroxidation initiated in a metal- and cell-free system by oxygen free radicals, .OH and O2-., generated by water gamma-radiolysis. In a concentration dependent manner, U-74389G increased the resistance of LDL to oxidation measured by the length of the lag phase, reduced the formation of conjugated dienes and thiobarbituric acid-reactive substances (TBARS), and also reduced the alpha-tocopherol disappearance by about 47% at the concentration 20 microM. U-74389G was also able to reduce the chemotactic activity of oxidized LDL towards monocytes, as well as the cholesterol accumulation in macrophages. These observations suggest that the U-74389G is a potent antioxidant by decreasing LDL peroxidation and this should be evaluated in in vivo models as a potential therapy to retard atherogenesis.
Asunto(s)
Antioxidantes/farmacología , Peroxidación de Lípido/efectos de los fármacos , Lipoproteínas LDL/metabolismo , Oxígeno/metabolismo , Pregnatrienos/farmacología , Adulto , Quimiotaxis/efectos de los fármacos , Colesterol/metabolismo , Radicales Libres/metabolismo , Humanos , Hidróxidos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Monocitos/efectos de los fármacos , Monocitos/fisiología , Oxidación-Reducción/efectos de los fármacosRESUMEN
An animal (rat) model of gingival injury ("impaction") induced a gingival inflammatory reaction, which was characterized by a breakdown of gingival collagen and the elastic network, as well as a significant increase of gingival elastase. The present study was conducted to investigate whether ceramides, sphingolipids composed of sphingosine N-acyl-linked to fatty acids, a chemical structure with antielastase properties, could counteract the development of such an inflammatory process. The ceramides used in these experimental series were extracted from wheat and characterized. The main fatty acids were 16:0, 18:1, 18:2, and the sphingoid moiety was phytosphingosine. Inhibition of elastase by ceramides was demonstrated in vitro and the concentration necessary to inhibit 50% of elastase activity was 41 mg/l using the synthetic substrate methoxysuccinyl-alanine-alanine-proline-valine-p-nitroanilide (MeOSuc-AlaAlaProValpNA). However, this anti-elastase activity was not observed in vivo in our animal model of gingival inflammation. A glycosaminoglycan (Heparin), recognized as a potent inhibitor of elastase, was entrapped in ceramides. A local treatment of impacted gingivae by encapsulated heparin led to a dose-related decrease of the elastase level in gingival extracts. Encapsulation in ceramides potentiated the effect exerted by heparin alone. This inhibitory effect of encapsulated heparin on elastase suggested a vector effect of these amphipathic molecules.
Asunto(s)
Ceramidas/farmacología , Inhibidores Enzimáticos/farmacología , Gingivitis/tratamiento farmacológico , Elastasa Pancreática/antagonistas & inhibidores , Animales , Cápsulas , Gingivitis/enzimología , Heparina/farmacología , Masculino , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-Dawley , Solubilidad , Triticum/químicaRESUMEN
An impairment of polymorphonuclear leukocyte (PMN) functions has been described following burn trauma. It was thus of interest to investigate the effect of RU 41740, an agent known to stimulate these cells, on rat PMN functions after burn injury. In the present study the responsiveness to classical stimuli of PMN from untreated burned rats was approximately 40% lower than healthy control values. In vitro treatment with RU 41740 increased oxidative metabolism of PMNs from burned and healthy rats. The effect was dose-related but was most striking in the case of PMNs from healthy rats. Significant differences were obtained with concentrations higher than 1 micrograms/ml for healthy rats but only 10 micrograms/ml for burned rats. In vivo treatment with RU 41740 also led to an enhancement of PMN oxidative metabolism on both burned and healthy rats. The maximal effective dose was 10 mg/kg/day in both cases. In contrast, 25 and 50 mg/kg/day doses inhibited PMN oxidative metabolism.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Proteínas Bacterianas/farmacología , Quemaduras/inmunología , Neutrófilos/efectos de los fármacos , Animales , Quemaduras/metabolismo , Quemaduras/patología , Técnicas In Vitro , Inflamación/prevención & control , Mediciones Luminiscentes , Masculino , Neutrófilos/metabolismo , Ratas , Ratas Endogámicas , Superóxidos/metabolismoRESUMEN
RU 41740 is a glycoprotein extract from Klebsiella pneumoniae described as a macromolecular aggregation of a lipopolysaccharide (LPS)-associated protein (F1 fraction) and a glycoproteic complex (P1 fraction). The human polymorphonuclear (PMN) response was studied after incubation of the cells in the presence of RU 41740, F1 and P1 fractions, or F1-P1 complex. Oxidative metabolism was assessed by chemiluminescence, O2 consumption, O2- generation, and degranulation by beta-glucuronidase release. Results were compared to data obtained with a homologous LPS. RU 41740, F1 fraction, and F1-P1 complex increased the respiratory burst of PMNs stimulated by opsonized zymosan (OZ). N-formylmethionylleucylphenylalanine (fMLP), phorbol myristate acetate, or the calcium ionophore A23187. The beta-glucuronidase release was stimulated by the same compounds when OZ or fMLP were used as stimuli. These effects were dose-dependent. In contrast, P1 fraction was inactive. Addition of polymyxin B resulted in a profound inhibition of both the F1 fraction and LPS activities but only in a partial inhibition of RU 41740 effects. These results strengthen the hypothesis that different biochemical pathways are involved in the enhancement of stimulated neutrophil functions by RU 41740.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Proteínas Bacterianas/farmacología , Klebsiella pneumoniae/análisis , Neutrófilos/efectos de los fármacos , Calcimicina/farmacología , Fraccionamiento Químico , Glucuronidasa/sangre , Humanos , Mediciones Luminiscentes , N-Formilmetionina Leucil-Fenilalanina/farmacología , Consumo de Oxígeno/efectos de los fármacos , Superóxidos/sangre , Acetato de Tetradecanoilforbol/farmacología , Zimosan/farmacologíaRESUMEN
The oxidative metabolism and chemotaxis of polymorphonuclear leukocytes (PMNs) collected from patients with ankylosing spondylitis and healthy subjects were studied in parallel. The responses to opsonized zymosan were significantly lowered considering oxygen consumption and release of superoxide anions, whereas no modification of these parameters to phorbol myristate acetate and calcium ionophore (A 23187) stimulations were observed. A seric factor was not involved but the characterization of a specific intrinsic abnormality of the PMNs needs further investigations. PMN chemotaxis, assessed by two methods performed in parallel, remained unchanged.
Asunto(s)
Neutrófilos/fisiología , Espondilitis Anquilosante/sangre , Adulto , Quimiotaxis de Leucocito , Femenino , Humanos , Masculino , Persona de Mediana Edad , Consumo de Oxígeno , Superóxidos/sangreRESUMEN
The activity of RU 41740, a glycoprotein extract from Klebsiella pneumoniae has been investigated on some polymorphonuclear (PMN) functions. Chemotaxis, random migration and oxidative metabolism (assessed by chemiluminescence, O2 consumption and O2- generation) were studied in parallel. PMN were collected from adult and aged human volunteers. Experiments were performed either in vitro or in vivo in a double blind placebo assay. In both PMN populations RU 41740 enhanced oxidative metabolism either in in vivo or in vitro experiments. However, a higher and dose-related activity was observed on PMN collected from the younger subjects whereas maximal effective concentration was reached earlier with PMN collected from aged subjects. RU 41740 did not modify random migration but inhibited chemotaxis of PMN collected from the younger population in a dose-related manner. These data corroborated previous results observed on PMN collected from various animal species and suggested an interaction of RU 41740 on PMN membrane. Moreover drug-induced macrophage and lymphocyte stimulation might also explain, at least in part, the in vivo effects described in this study. Thus RU 41740 could partly account for the protective effects exerted against bacterial and fungal infections through its activity on PMN functions.
Asunto(s)
Anciano , Proteínas Bacterianas/farmacología , Neutrófilos/inmunología , Adulto , Anciano de 80 o más Años , Quimiotaxis de Leucocito/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Oxidación-ReducciónAsunto(s)
Granulocitos/fisiología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
This work demonstrates a time-dependent loss of polymorphonuclear neutrophilic leukocyte (PMN) functions during the first 48 h with only slight lysis and release of cellular LDH. It confirms that storage decreases ATP levels in PMNs and significantly increases intracellular lactate and pyruvate. These data correlated with an inhibition of PMN migratory function and a considerable decrease in chemiluminescence response.
Asunto(s)
Conservación de la Sangre , Lactatos/sangre , Neutrófilos/fisiología , Piruvatos/sangre , Adenosina Trifosfato/sangre , Movimiento Celular , Humanos , Técnicas In Vitro , L-Lactato Deshidrogenasa/metabolismo , Ácido Láctico , Ácido PirúvicoRESUMEN
The activity of RU 41740, a glycoprotein extract from Klebsiella pneumoniae, endowed with immuno-modulating properties, has been investigated on polymorphonuclear (PMN) leukocyte functions. This report deals with the effect of RU 41740 on oxidative metabolism (assessed by chemiluminescence, 02 consumption and O2- production) and on chemotaxis and random migration (using agarose and Boyden chamber techniques). PMNs were collected from the rat pleural cavity after induction of one acute inflammatory reaction (pleurisy induced by injection of a suspension of calcium pyrophosphate crystals). Experiments were performed in parallel after in vivo treatment or incubation in vitro. RU 41740 enhanced PMN oxidative metabolism and inhibited PMN chemotaxis while random migration was only affected using agarose assay at high concentration. This effect on PMN migration was observed with at least two attractants. These observations have been obtained either after incubation in vitro or administration in vivo. The minimal effective dose was 1 mg/kg in vivo and 0.1 microgram/ml in vitro. These data suggest that RU 41740 acts directly on PMN membrane receptors.