Asunto(s)
Pancreatoyeyunostomía/métodos , Anestesia General , Animales , Cianoacrilatos/administración & dosificación , Estudios de Seguimiento , Humanos , Intubación , Modelos Animales , Conductos Pancreáticos , Fístula Pancreática/etiología , Fístula Pancreática/prevención & control , Proteínas/administración & dosificación , Porcinos , Factores de Tiempo , Adhesivos Tisulares/administración & dosificación , Resultado del TratamientoRESUMEN
The hapten-induced irritant and contact hypersensitivity reactions are experimental models of cutaneous inflammation in which tumor necrosis factor-alpha is an important mediator. N-acetylcysteine is an anti-oxidant that inhibits the action of the nuclear factor-kB, which promotes the transcription of many genes, including the gene for tumor necrosis factor-alpha. We tested the ability of N-acetylcysteine to antagonize the development of the irritant and contact hypersensitivity reactions induced by the epicutaneous application of trinitrochlorobenzene in mice. Systemic and topical treatment with N-acetylcysteine reduced skin swelling in both the irritant and contact hypersensitivity reactions; in the latter it also reduced the dermal leukocyte infiltrate. It also reduced the cutaneous expression of the mRNA for tumor necrosis factor-alpha in both conditions. These results show that N-acetylcysteine antagonizes the development of irritant and contact hypersensitivity reactions and that its action includes a reduction in the expression of tumor necrosis factor-alpha mRNA. N-acetylcysteine may be useful in the treatment of cutaneous inflammation mediated by tumor necrosis factor-alpha.
Asunto(s)
Acetilcisteína/farmacología , Dermatitis por Contacto/etiología , Dermatitis por Contacto/prevención & control , Haptenos/efectos adversos , Acetilcisteína/uso terapéutico , Animales , Dermatitis por Contacto/patología , Femenino , Interleucina-1/análisis , Interleucina-1/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos CBA , Cloruro de Picrilo/efectos adversos , ARN Mensajero/análisis , ARN Mensajero/genética , Piel/química , Piel/efectos de los fármacos , Piel/patología , Transcripción Genética , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
The role of neutrophils (PMNs) and leukocyte integrins was investigated in two models of lipopolysaccharide (LPS)-induced toxicity: the systemic lethality assay in D-galactosamine-sensitized mice and the local reaction elicited by intradermal injection of LPS and tumor necrosis factor (TNF) at 24-h intervals. In the local reaction, depletion of PMNs with an anti-PMN monoclonal antibody (mAb) and mAbs against CD-11a (or LFA1) and CD-11b (or CR3) completely prevented the hemorrhagic necrosis. Evaluation of histological sections and myeloperoxidase levels suggested different mechanism of protection because PMNs were abundant in anti-CD-11- and absent in anti-PMN-treated mice. In the systemic assay, depletion of PMNs ensured 100% survival, whereas after administration of anti-CD-11a or b mAb, the percentages of survivors were 6 and 59%, respectively. One hour after LPS injection, the serum TNF-alpha level was higher in PMN-depleted mice than in controls. These studies provide evidence that neutrophils are essential for the expression of local or systemic LPS-induced injury, whereas the requirement for their leukocytic integrins is obvious only in the local reaction.
Asunto(s)
Lipopolisacáridos/toxicidad , Antígeno-1 Asociado a Función de Linfocito/fisiología , Antígeno de Macrófago-1/fisiología , Neutrófilos/fisiología , Animales , Anticuerpos Monoclonales/inmunología , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos CBA , Proteínas Recombinantes/farmacología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
The clinical effects of a murine monoclonal antibody (CB0006) directed against tumour necrosis factor were investigated in an open study of 41 Gambian children receiving otherwise conventional therapy for cerebral malaria. Ten children received a single i.v. dose of CB0006 at 0.1 mg/kg, 10 received 1 mg/kg, 10 received 5 mg/kg, and 11 were randomly selected as controls. CB0006 rapidly formed complexes with tumour necrosis factor, which were cleared from the circulation over several days. This was associated with a dose-dependent increase in total plasma tumour necrosis factor levels and a dose-dependent reduction of fever, implying that CB0006 inhibits tumour necrosis factor by retaining it in the circulation and reducing its availability to tissue receptors. Parasite clearance rates were not impaired. The fatality rate (29% overall) was similar in CB0006-treated patients and controls, but evaluation of possible effects on mortality requires a much larger blinded study. These data show that tumour necrosis factor is involved in the pathogenesis of malaria fever, and are the first direct evidence that inhibition of a specific endogenous pyrogen can attenuate fever in man.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Fiebre/terapia , Inmunoglobulina G/uso terapéutico , Malaria Cerebral/complicaciones , Factor de Necrosis Tumoral alfa/inmunología , Animales , Anticuerpos Monoclonales/sangre , Niño , Preescolar , Femenino , Fiebre/parasitología , Humanos , Inmunoglobulina G/sangre , Lactante , Interleucina-6/sangre , Malaria Cerebral/parasitología , Masculino , Plasmodium falciparum/aislamiento & purificación , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Tumor necrosis factor alpha (TNF-alpha), a major mediator of inflammation, also possesses a wide pleiotropism of actions, suggesting its involvement in physiological conditions. TNF-alpha mRNA is present in mouse embryonic tissues and also in fetal thymus and spleen. Repeated injections of a monospecific polyclonal rabbit anti-mouse TNF-alpha antibody in mice, starting either during pregnancy or at birth, led to a severe but transient growth retardation, already present at birth, reaching a 35% decrease in body weight at 3 wk, with complete recovery at 8 wk. The insulin growth factor I (IGF-I) blood levels were decreased to about 50%; growth hormone release and other endocrine functions were unaltered. A marked atrophy of the thymus, spleen, and lymph nodes was also observed, with lymphopenia and impaired development of T and B cell peripheral lymphoid structures. The pathways involving TNF-alpha in IGF-I release and early body growth are probably distinct from those by which TNF-alpha participates in early development of lymphoid tissues, where its low physiological release may contribute to enhance lymphoid cell expansion.
Asunto(s)
Crecimiento , Tejido Linfoide/fisiología , Factor de Necrosis Tumoral alfa/fisiología , Animales , Anticuerpos/inmunología , Femenino , Hormona del Crecimiento/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Linfocitos/fisiología , Ratones , Embarazo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
The in vivo efficacy of human recombinant soluble tumor necrosis factor (TNF) receptor protein to prevent and to treat lipopolysaccharide (LPS)-induced lethal toxicity in D-galactosamine-treated mice was investigated. Chimeric proteins of the receptor extracellular domains fused to the hinge region of human IgG3 were expressed in myeloma cells (rsTNFR-h gamma 3). The fusion proteins had a disulfide-bonded dimeric structure. Upon intravenous injection, their serum concentration decreased relatively slowly after an initial phase of rapid elimination. D-galactosamine-sensitized mice were fully protected from the toxic effects of LPS, if the animal were pretreated with rsTNFR-h gamma 3 at 20 micrograms/animal. Partial protection was seen at significantly lower doses and when rsTNFR-h gamma 3 was given up to 3 h after LPS.
Asunto(s)
Endotoxinas/antagonistas & inhibidores , Lipopolisacáridos/toxicidad , Receptores de Superficie Celular , Choque Séptico/prevención & control , Animales , Inmunoglobulina G/genética , Ratones , Receptores de Superficie Celular/química , Receptores de Superficie Celular/genética , Receptores del Factor de Necrosis Tumoral , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes de Fusión/farmacología , Solubilidad , Factor de Necrosis Tumoral alfaRESUMEN
We analyzed the role of adhesion molecules in the pathogenesis of experimental cerebral malaria (ECM), since tumor necrosis factor (TNF) plays a major role in this condition and has been shown to up-regulate in vitro expression of cell adhesion molecules (CAM), particularly intercellular CAM-1 (ICAM-1). We found increased expression of ICAM-1 on brain endothelial cells from mice with ECM. Treatment with monoclonal antibodies (mAb) directed against leukocyte function-antigen 1 (LFA-1, the ligand of ICAM-1) on days 6, 8 and 10 almost totally prevented ECM, while decreasing blood TNF levels. To exclude the possibility that the effects of anti-LFA-1 mAb resulted from an even partial inhibition of TNF overproduction, mice with signs of imminent death (hypothermia and neurologic defects) were treated with the anti-LFA-1 mAb, with dramatically protective effect. In contrast, injection of anti-ICAM-1 mAb on day 6 caused rapid death, while it was innocuous in normal mice. An mAb directed against complement receptor type 3 (CR3) was ineffective, as were injections of soluble human ICAM-1. These results suggest that adhesion of LFA-1+ cells to endothelial cells, stimulated by TNF to express high levels of ICAM-1, is critical in the pathogenesis of ECM. Emergency therapy at interfering with cytoadherence could be considered in the treatment of cerebral malaria in man, in which high blood TNF levels are also observed.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Encéfalo/patología , Antígeno-1 Asociado a Función de Linfocito/inmunología , Malaria/prevención & control , Animales , Encéfalo/metabolismo , Encéfalo/microbiología , Moléculas de Adhesión Celular/fisiología , Modelos Animales de Enfermedad , Hipotermia/prevención & control , Molécula 1 de Adhesión Intercelular , Malaria/inmunología , Masculino , Ratones , Ratones Endogámicos CBA , Plasmodium berghei , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
The pathological expression in malaria infection depends largely on immunopathologic responses induced by the parasite. In the past few years, we have attempted to analyze mechanisms by which inappropriate immune response to some malarial antigens can generate major complications of malaria and particularly neurovascular lesions. To this end, we have undertaken a study aimed at a more precise definition of immunopathological parameters of malaria infection, and more particularly those involved in cerebral malaria (CM). CM, the most severe complication of falciparum infection in man, represents a major problem of public health at the world level.
Asunto(s)
Moléculas de Adhesión Celular/fisiología , Citocinas/fisiología , Malaria/inmunología , Enfermedades del Sistema Nervioso/parasitología , Plasmodium berghei/inmunología , Animales , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/inmunología , Humanos , Malaria/complicaciones , Ratones , Ratones Endogámicos , Enfermedades del Sistema Nervioso/inmunología , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Experimental cerebral malaria (ECM), a lethal hyperacute neurological syndrome associated with high blood levels of tumor necrosis factor, develops in genetically susceptible (CBA/Ca) mice 7 days after infection with Plasmodium berghei ANKA strain. Injections of neutralizing monoclonal antibody against recombinant murine interferon gamma, not later than 4 days after infection, markedly reduced the incidence of ECM and the elevation in serum levels of tumor necrosis factor. This treatment prevented the cerebral lesions (plugging of brain vessels by monocytes, lymphocytes, and parasitized erythrocytes). In contrast, the extent of macrophage infiltration in lymphoid organs (which is a characteristic feature of mice developing ECM), as well as the course of infection, remained unaffected by the antibody treatment. Protected mice died at a later time of severe anemia and overwhelming parasitemia, the usual outcome of P. berghei infection in mice that are not susceptible to ECM. The present data indicate that interferon gamma constitutes an important link in the cytokine network that leads to brain vessel inflammation in experimental malaria. It is proposed that interferon gamma released by activated CD4+ T cells acts by augmenting both production and action of tumor necrosis factor.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Encefalopatías/prevención & control , Interferón gamma/inmunología , Malaria/prevención & control , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Susceptibilidad a Enfermedades , Femenino , Macrófagos/fisiología , Ratones , Ratones Endogámicos CBA , Plasmodium berghei , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
The pharmacokinetics of dextromoramide were studied in nine patients undergoing peripheral vascular surgery. All the patients were anaesthetised with thiopentone and vecuronium. After tracheal intubation, anaesthesia was maintained with 0.5 to 1.5 vol % halothane and a 60%-40% vol nitrous oxide-oxygen mixture. Once the patient's status was stable, a 0.8 mg.kg-1 bolus of dextromoramide was given intravenously. Blood samples were obtained 2, 5, 10, 30, 60, 90, 120, 180, 240, 300, 360, and 420 min afterwards by an arterial catheter. Dextromoramide serum concentrations were measured with high performance liquid chromatography after extraction with an original technique. The pharmacokinetic parameters were calculated by computer using TRIOMPHE. In five patients, a bi-exponential equation best fitted the results, whereas a tri-exponential equation was necessary for the other four. Mean elimination half-life was 215.3 +/- 78.4 min, and the apparent final volume of distribution was 0.58 +/- 0.20 l.kg-1. Hepatic extraction was low, as shown by a mean systemic clearance of 2.0 +/- 0.9 ml.kg-1.min-1. Liposolubility of this drug is the highest of all opiates, with a heptane/water partition coefficient of 12.3. These parameters demonstrate that, in the opiate drug group, dextromoramide has a place apart from the others.
Asunto(s)
Dextromoramida/farmacocinética , Anciano , Analgésicos Opioides/farmacocinética , Anestesia General , Dextromoramida/sangre , Humanos , Persona de Mediana Edad , Procedimientos Quirúrgicos VascularesRESUMEN
Any state of stress originates a reduction of gastric pH contributing to the development of digestive lesions. The objective of this prospective work was to evaluate in subjects having undergone a heart surgical procedure, the effect of an anti-H2 agent, ranitidine, on the changes with time of gastric pH during the first 24 hours following induced anaesthesia. Administered discontinuously intravenously, ranitidine was shown to have a clearcut effect on gastric pH, shifting the pH profiles towards higher values. This phenomenon proves to be statistically significant from the 12th hour following the beginning of anesthesia.