RESUMEN
Psoriasis is a chronic inflammatory skin disease accompanied by excessive keratinocyte proliferation. Corticosteroids, vitamin D3 analogs, and calcineurin inhibitors, which are used to treat psoriasis, have diverse adverse effects, whereas natural products are popular due to their high efficiency and relatively low toxicity. The roots of the Cudrania tricuspidata (C. tricuspidata) are known to have diverse pharmacological effects, among which the anti-inflammatory effect is reported as a potential therapeutic agent in skin cells. Nevertheless, its effectiveness against skin diseases, especially psoriasis, is not fully elucidated. Here, we investigated the effect of cudraxanthone D (CD), extracted from the roots the C. tricuspidata Bureau, on psoriasis using an imiquimod (IMQ)-induced mouse model and the tumor necrosis factor (TNF)-α/interferon (IFN)-γ-activated keratinocytes. IMQ was topically applied to the back skin of C57BL/6 mice for seven consecutive days, and the mice were orally administered with CD. This resulted in reduced psoriatic characteristics, such as the skin thickness and Psoriasis Area Severity Index score, and the infiltration of neutrophils in IMQ-induced skin. CD inhibited the serum levels of TNF-α, immunoglobulin G2a, and myeloperoxidase, and the expression of Th1/Th17 cells in splenocytes. In TNF-α/IFN-γ-activated keratinocytes, CD reduced the expressions of CCL17, IL-1ß, IL-6, and IL-8 by inhibiting the phosphorylation of STAT1 and the nuclear translocation of NF-kB. Taken together, these results suggest that CD could be a potential drug candidate for the treatment of psoriasis.
Asunto(s)
Antiinflamatorios/administración & dosificación , Imiquimod/efectos adversos , Queratinocitos/citología , Moraceae/química , Psoriasis/tratamiento farmacológico , Xantonas/administración & dosificación , Administración Oral , Animales , Antiinflamatorios/farmacología , Línea Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Interferón gamma/efectos adversos , Queratinocitos/efectos de los fármacos , Queratinocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , FN-kappa B/farmacología , Extractos Vegetales/química , Raíces de Plantas/química , Psoriasis/inducido químicamente , Psoriasis/inmunología , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/farmacología , Xantonas/farmacologíaRESUMEN
Pyropia yezoensis, a red alga, is popular and harvested a lot in East Asia and is famous for its medicinal properties attributable to its bioactive compounds including amino acids (porphyra-334 and shinorine, etc.), polysaccharides, phytosterols, and pigments, but its anti-inflammatory effect and mechanism of anti-atopic dermatitis (AD) have not been elucidated. In this study, we investigate the anti-AD effect of P. yezoensis extract (PYE) on mRNA and protein levels of the pro-inflammatory chemokines, thymus, and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22), in human HaCaT keratinocyte cells treated to interferon (IFN)-γ or tumor necrosis factor (TNF)-α (10 ng/mL each). The effect of the PYE on extracellular signal-regulated kinase (ERK) and other mitogen-activated protein kinases (MAPKs) was related to its suppression of TARC and MDC production by blocking NF-κB activation in HaCaT cells. Furthermore, astaxanthin and xanthophyll from P. yezoensis were identified as anti-AD candidate compounds. These results suggest that the PYE may improve AD and contained two carotenoids by regulating pro-inflammatory chemokines.
Asunto(s)
Quimiocina CCL17/metabolismo , Quimiocina CCL22/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Interferón gamma/efectos adversos , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Porphyra/química , Factor de Necrosis Tumoral alfa/efectos adversos , Antiinflamatorios , Dermatitis Atópica/tratamiento farmacológico , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células HaCaT , Humanos , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/uso terapéutico , Xantófilas/aislamiento & purificación , Xantófilas/uso terapéutico , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Interferons are polypeptides that naturally occur in the human body as a part of the innate immune response. By harnessing these immunomodulatory functions, synthetic interferons have shown efficacy in combating various diseases including cutaneous T-cell lymphoma. This article closely examines the qualities of interferon alfa and interferon gamma and the evidence behind their use in the 2 most common types of cutaneous T-cell lymphomas, namely, mycosis fungoides and Sézary syndrome.
Asunto(s)
Interferón-alfa/uso terapéutico , Interferón gamma/uso terapéutico , Micosis Fungoide/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada/métodos , Humanos , Interferón-alfa/efectos adversos , Interferón-alfa/farmacología , Interferón beta/uso terapéutico , Interferón gamma/efectos adversos , Interferón gamma/farmacología , Micosis Fungoide/terapia , Terapia PUVA/métodos , Retinoides/uso terapéutico , Neoplasias Cutáneas/terapiaRESUMEN
Geranium thunbergii Sieb. et Zucc. (GT; which belongs to the Geraniaceae family) has been used as a traditional medicine in East Asia for the treatment of inflammatory diseases, including arthritis and diarrhea. However, the underlying mechanisms of the anti-inflammatory effects of GT remain poorly understood. In the present study, we examined the mechanisms responsible for the anti-inflammatory activity of GT in macrophages. The results revealed that GT significantly inhibited the lipopolysaccharide (LPS)- and interferon-γ (IFN-γ)-induced expression of pro-inflammatory genes, such as inducible nitric oxide synthase, tumor necrosis factor-α and interleukin-1ß, as shown by RT-PCR. However, the inhibitory effects of GT on LPS- and IFN-γ-induced inflammation were associated with an enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) activity, but not with the suppression of nuclear factor (NF)-κB activity, as shown by western blot analysis. In addition, in bone marrow-derived macrophages (BMDM) isolated from Nrf2 knockout mice, GT did not exert any inhibitory effect on the LPS- and IFN-γ-induced inflammation. Taken together, our findings indicate that the anti-inflammatory effects of GT may be associated with the activation of Nrf2, an anti-inflammatory transcription factor.
Asunto(s)
Geranium/química , Inflamación/etiología , Inflamación/metabolismo , Interferón gamma/efectos adversos , Lipopolisacáridos/efectos adversos , Factor 2 Relacionado con NF-E2/metabolismo , Extractos Vegetales/farmacología , Animales , Antiinflamatorios/farmacología , Línea Celular , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , FN-kappa B/metabolismo , Extractos Vegetales/aislamiento & purificaciónRESUMEN
Awara (Astrocaryum vulgare M.) pulp oil has been shown to possess anti-inflammatory properties in vivo, and contains an unsaponifiable matter rich in bioactive compounds. This study focused on the ethanolic unsaponifiable fraction (EUF) of awara pulp oil. Its chemical composition has been characterized: carotenoid, phytosterol, and tocopherol contents represent 125.7, 152.6, and 6.8 µg/mg of EUF, respectively. We further evaluated this fraction for anti-inflammatory properties in J774 macrophages activated by lipopolysaccharide (LPS) plus interferon (IFN) γ to understand the biological effects of awara pulp oil. EUF strongly decreased nitric oxide (NO), prostaglandin E(2), tumour necrosis factor (TNF) α, and interleukin (IL) -6 and -10 production in activated J774 cells. Moreover, it inhibited expression of inducible NO synthase and cyclooxygenases-2 in vitro. The anti-inflammatory properties of EUF were also confirmed in vivo by modulation of TNFα, IL-6 and IL-10 serum concentration in an endotoxic shock model. Pre-treatment with awara oil fraction offers promise as a protective means to lower the production of excessive amounts of pro-inflammatory molecules.
Asunto(s)
Antiinflamatorios/farmacología , Arecaceae/química , Frutas/química , Aceites de Plantas/farmacología , Choque Séptico/tratamiento farmacológico , Animales , Antiinflamatorios/química , Antioxidantes/metabolismo , Carotenoides/análisis , Carotenoides/metabolismo , Línea Celular , Ciclooxigenasa 1/efectos de los fármacos , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Citocinas/sangre , Citocinas/efectos de los fármacos , Citocinas/metabolismo , Dinoprostona/sangre , Relación Dosis-Respuesta a Droga , Interferón gamma/efectos adversos , Lipopolisacáridos/efectos adversos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nitritos/metabolismo , Fitosteroles/análisis , Fitosteroles/metabolismo , Aceites de Plantas/química , Distribución Aleatoria , Choque Séptico/inducido químicamente , Choque Séptico/inmunología , Tocoferoles/análisis , Tocoferoles/metabolismoRESUMEN
BACKGROUND/AIMS: Several previous studies have suggested that interferon gamma (IFNgamma) may play a key role during hepatic progenitor cell (HPC) mediated liver regeneration. However to date, no studies have directly tested the ability of IFNgamma to mediate the HPC response in an in vivo model. METHODS/RESULTS: Administration of IFNgamma to mice receiving a choline deficient, ethionine (CDE) supplemented diet to induce chronic injury resulted in an augmented HPC response. This was accompanied by increased inflammation, altered cytokine expression and hepatic fibrosis. Serum alanine aminotransferase activity, hepatocyte apoptosis and Bak staining were significantly increased in IFNgamma-treated, CDE-fed mice, demonstrating that liver damage was exacerbated in these animals. Administration of IFNgamma to control diet fed mice did not induce liver damage, however it did stimulate hepatic inflammation. CONCLUSIONS: Our results suggest that IFNgamma increases the HPC response to injury by stimulating hepatic inflammation and aggravating liver damage. This is accompanied by an increase in hepatic fibrogenesis, supporting previous reports which suggest that the HPC response may drive fibrogenesis during chronic liver injury.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Interferón gamma/efectos adversos , Cirrosis Hepática/inducido químicamente , Células Madre/efectos de los fármacos , Animales , Enfermedad Crónica , Dieta , Modelos Animales de Enfermedad , Fibrinógeno/biosíntesis , Hepatocitos/citología , Inflamación/inducido químicamente , Interferón gamma/administración & dosificación , Ratones , Proteínas RecombinantesRESUMEN
(1) Severe malignant osteopetrosis is a very rare disease. The principal manifestations are anaemia, infections, sensory disorders and fractures, due to generalised bone condensation. The disease is generally fatal in childhood. The only treatment capable of modifying the natural outcome is bone marrow transplantation. The benefits of high-dose steroids and calcitriol are usually modest and transient. (2) Severe malignant osteopetrosis is a new licensed indication for interferon gamma-1b, a drug known to reduce the incidence of severe infections in children with chronic septic granulomatosis. (3) An unblinded trial involving 15 children with a mean age of about one year compared calcitriol plus interferon gamma-1b with calcitriol alone. The time to treatment failure was longer with the combination, based on a combined endpoint chosen to make the statistical analysis more sensitive. (4) A clinical trial involving 15 patients, who were compared with a historical series of 94 untreated patients, provided ambiguous results. (5) In these trials the main adverse effect of interferon gamma-1b was a flu-like syndrome. (6) Given the gravity of severe malignant osteopetrosis, the limited available treatment options, and the rarity of serious adverse events with interferon gamma-1b, evaluation of this therapy should continue.
Asunto(s)
Interferón gamma/uso terapéutico , Osteopetrosis/tratamiento farmacológico , Calcitriol/administración & dosificación , Calcitriol/efectos adversos , Calcitriol/uso terapéutico , Niño , Preescolar , Francia , Humanos , Lactante , Interferón gamma/administración & dosificación , Interferón gamma/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes , Resultado del TratamientoRESUMEN
Human immunodeficiency virus (HIV)-1 infection of the central nervous system occurs in the vast majority of HIV-infected patients. HIV-associated dementia (HAD) represents the most severe form of HIV-related neuropsychiatric impairment and is associated with neuropathology involving HIV proteins and activation of proinflammatory cytokine circuits. Interferon-gamma (IFN-gamma) activates the JAK/STAT1 pathway, a key regulator of inflammatory and apoptotic signaling, and is elevated in HIV-1-infected brains progressing to HAD. Recent reports suggest green tea-derived (-)-epigallocatechin-3-gallate (EGCG) can attenuate neuronal damage mediated by this pathway in conditions such as brain ischemia. In order to investigate the therapeutic potential of EGCG to mitigate the neuronal damage characteristic of HAD, IFN-gamma was evaluated for its ability to enhance well-known neurotoxic properties of HIV-1 proteins gp120 and Tat in primary neurons and mice. Indeed, IFN-gamma enhanced the neurotoxicity of gp120 and Tat via increased JAK/STAT signaling. Additionally, primary neurons pretreated with a JAK1 inhibitor, or those derived from STAT1-deficient mice, were largely resistant to the IFN-gamma-enhanced neurotoxicity of gp120 and Tat. Moreover, EGCG treatment of primary neurons from normal mice reduced IFN-gamma-enhanced neurotoxicity of gp120 and Tat by inhibiting JAK/STAT1 pathway activation. EGCG was also found to mitigate the neurotoxic properties of HIV-1 proteins in the presence of IFN-gamma in vivo. Taken together, these data suggest EGCG attenuates the neurotoxicity of IFN-gamma augmented neuronal damage from HIV-1 proteins gp120 and Tat both in vitro and in vivo. Thus EGCG may represent a novel natural copound for the prevention and treatment of HAD.
Asunto(s)
Complejo SIDA Demencia/tratamiento farmacológico , Catequina/análogos & derivados , VIH-1/inmunología , Interferón gamma/metabolismo , Quinasas Janus/metabolismo , Neuronas/enzimología , Fármacos Neuroprotectores/uso terapéutico , Factor de Transcripción STAT1/metabolismo , Complejo SIDA Demencia/enzimología , Complejo SIDA Demencia/inmunología , Complejo SIDA Demencia/patología , Análisis de Varianza , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Catequina/uso terapéutico , Células Cultivadas , Femenino , Productos del Gen tat/inmunología , Productos del Gen tat/toxicidad , Proteína gp120 de Envoltorio del VIH/inmunología , Proteína gp120 de Envoltorio del VIH/toxicidad , Interferón gamma/efectos adversos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/inmunología , Neuronas/patología , Neurotoxinas/inmunología , Neurotoxinas/toxicidad , Factor de Transcripción STAT1/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Productos del Gen tat del Virus de la Inmunodeficiencia HumanaRESUMEN
It is well known that nitric oxide (NO) plays an important role in the pathogenesis of inflammatory diseases. Eucalyptus globulus Labill. and Thymus vulgaris L. have been used in traditional medicine in the treatment of bronchitis, asthma and other respiratory diseases. The present study focuses on the effects of these two extracts on NO production induced by lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) in the murine macrophage cell line J774A.1. In addition, cell viability, scavenging activity and inducible nitric oxide synthase (iNOS) mRNA expression were evaluated. E. globulus and T. vulgaris extracts significantly inhibited the enhanced production of NO induced by LPS and IFN-gamma in a dose-dependent manner. Treatment with these two extracts did not reduce cell viability at any dose used. Both plant extracts showed significant scavenging of NO radicals released by an NO donor, PAPA-NONOate. Results also show that pre-treatment with E. globulus and T. vulgaris extracts significantly inhibits iNOS mRNA expression. This study thus suggests that the inhibition of net NO production by these two extracts may be due to their NO scavenging activity and/or their inhibitory effects on iNOS gene expression.
Asunto(s)
Antiinflamatorios/uso terapéutico , Eucalyptus/química , Macrófagos/efectos de los fármacos , Fitoterapia , Extractos Vegetales/uso terapéutico , Thymus (Planta)/química , Animales , Antiinflamatorios/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Dexametasona/farmacología , Relación Dosis-Respuesta a Droga , Eucalyptus/fisiología , Depuradores de Radicales Libres/farmacocinética , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hidrazinas/metabolismo , Hidrazinas/farmacología , Técnicas In Vitro , Interferón gamma/efectos adversos , Lipopolisacáridos/efectos adversos , Macrófagos/citología , Ratones , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Aceites Volátiles , Hojas de la Planta/química , ARN Mensajero/metabolismo , España , Thymus (Planta)/fisiologíaRESUMEN
Nitric oxide (NO) released by activated alveolar macrophages (AM) can mediate effects on target cells and can also react with superoxide anion (O2-) to form peroxynitrite (PN), a highly cytotoxic product. The role of NO and PN in AM cytotoxicity for normal lung cells was investigated using co-cultures of rat lung fibroblasts (FB) and rat AM treated with lipopolysaccharide + interferon-gamma (LI). AM and FB, alone and in co-culture, were treated with LI for 5 days and cell viability measured. The culture media was analyzed for NO, TNF-alpha, O2-, and IL-1beta. A decreased FB viability was correlated with increased NO release by LI-activated AM. Pretreatment of co-cultures with the inducible NOS inhibitor L-NAME caused dose-related decreases in NO release by AM and increases in FB viability. Although TNF-alpha release was increased in co-cultures treated with LI, the viability of FB was not affected when cultures were treated with similar concentrations of TNF-alpha in the absence of AM. O2- could not be detected in the media and addition of superoxide dismutase (SOD) did not protect FB. These data suggest that neither O2- nor PN contributed to the loss of cell viability. Activated AM may kill normal rat lung FB through a NO-mediated pathway that does not involve PN.
Asunto(s)
Fibroblastos/patología , Macrófagos Alveolares/patología , Óxido Nítrico/metabolismo , Tirosina/análogos & derivados , Animales , Técnicas de Cultivo de Célula/métodos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Técnicas de Cocultivo/métodos , Medios de Cultivo/química , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/ultraestructura , Interferón gamma/efectos adversos , Interleucina-1/biosíntesis , Interleucina-1/química , Interleucina-1/fisiología , Lipopolisacáridos/efectos adversos , Pulmón/citología , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/ultraestructura , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Ácido Peroxinitroso/efectos adversos , Ácido Peroxinitroso/biosíntesis , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/farmacología , Factor de Necrosis Tumoral alfa/química , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Tirosina/deficienciaAsunto(s)
Calcio de la Dieta/administración & dosificación , Fenómenos Fisiológicos Nutricionales Infantiles , Ingestión de Energía , Interferón gamma/uso terapéutico , Osteopetrosis/dietoterapia , Adolescente , Calcio de la Dieta/efectos adversos , Niño , Preescolar , Femenino , Fiebre/inducido químicamente , Hematócrito , Hemoglobinas/análisis , Hemoglobinas/efectos de los fármacos , Humanos , Lactante , Alimentos Infantiles/análisis , Interferón gamma/administración & dosificación , Interferón gamma/efectos adversos , Masculino , Necesidades Nutricionales , Osteopetrosis/tratamiento farmacológico , Osteopetrosis/fisiopatología , Factores de TiempoRESUMEN
OBJECTIVES: To describe the postoperative course of patients who underwent hyperthermic isolated limb perfusion with recombinant tumor necrosis factor (TNF)-alpha and melphalan after pretreatment with recombinant interferon-gamma as treatment for recurrent melanoma, primary nonresectable soft-tissue tumors, planocellular carcinoma, or metastatic carcinoma. To measure systemic TNF-alpha concentrations and relate these values with indices of disease severity. SETTING: A 12-bed surgical intensive care unit (ICU) in a university referral hospital. DESIGN: Prospective, descriptive study. PATIENTS: Consecutive patients (n=25) treated with hyperthermic isolated limb perfusion. INTERVENTIONS: Blood samples were taken at regular intervals to determine TNF-alpha concentrations during and after hyperthermic isolated limb perfusion with recombinant TNF-alpha. Hemodynamic variables were obtained with a Swan-Ganz pulmonary artery catheter. MEASUREMENTS AND MAIN RESULTS: All patients developed features of sepsis syndrome and required intensive care treatment. Most patients recovered quickly, with a median ICU stay of 2 days (range 1 to 25). Maximum systemic TNF-alpha concentrations ranged from 2284 to 83,000 ng/L (median 25,409) and returned to baseline values within 8 hrs. Despite these high concentrations of TNF-alpha, no patient died in the ICU, although the patient with the highest TNF-alpha concentration developed multiple organ failure and required continuous venovenous hemofiltration for 16 days. Linear regression analysis showed positive correlations between maximum TNF-alpha concentrations and systemic vascular resistance (p < .01), cardiac index (p < .02), Lung Injury Score (p < .02), prothrombin time (p < .02), and activated partial thromboplastin time (p < .05). CONCLUSIONS: Hyperthermic isolated limb perfusion with recombinant TNF-alpha leads to high systemic concentrations of TNF-alpha, probably due to leakage of recombinant TNF-alpha from the perfusion circuit, mainly through collateral blood flow. A sepsis-like syndrome is seen in all patients. Despite high concentrations of systemic TNF-alpha, this sepsis syndrome is short-lived and recovery is rapid and complete in most patients.
Asunto(s)
Antineoplásicos Alquilantes/efectos adversos , Quimioterapia del Cáncer por Perfusión Regional/efectos adversos , Hipertermia Inducida/efectos adversos , Interferón gamma/efectos adversos , Melfalán/efectos adversos , Neoplasias/terapia , Síndrome de Respuesta Inflamatoria Sistémica/inducido químicamente , Factor de Necrosis Tumoral alfa/efectos adversos , Factor de Necrosis Tumoral alfa/metabolismo , Adolescente , Adulto , Anciano , Terapia Combinada , Extremidades , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes , Índice de Severidad de la Enfermedad , Síndrome de Respuesta Inflamatoria Sistémica/sangreRESUMEN
In a previous paper, the synergism of gamma-interferon and tumor necrosis factor was considered with whole body hyperthermia. Because of the toxic effect of TNF due to oxygen radicals, it is suggested that vitamin C be added.
Asunto(s)
Ácido Ascórbico/uso terapéutico , Hipertermia Inducida , Interferón gamma/uso terapéutico , Factor de Necrosis Tumoral alfa/uso terapéutico , Animales , Terapia Combinada , Depuradores de Radicales Libres , Humanos , Interferón gamma/efectos adversos , Ratones , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Factor de Necrosis Tumoral alfa/efectos adversosRESUMEN
To increase the therapeutic efficacy of recombinant tumor necrosis factor alpha (rTNF alpha) and reduce the systemic side effects, a protocol was designed using isolation perfusion of the limbs with hyperthermia for in transit metastases of melanoma. A triple combination of high dose rTNF alpha + recombinant interferon-gamma (rIFN-gamma) + melphalan was chosen because of a synergistic anti-tumor effect of rTNF alpha with rIFN-gamma and of rTNF alpha with alkylating agents reported in the literature. Twenty-nine patients of mean age 60 years (range 22-82 years) entered the study after informed consent and received a total of 31 isolation perfusions with the triple combination. There were 24 women and 5 men with multiple progressive in transit melanoma metastases of the lower limb (stage IIIa or IIIab). rTNF alpha at the unique dose of 4 mg was injected as a bolus in the arterial line, under mild hyperthermic conditions (40 to 40.5 degrees C) for 90 minutes. rIFN-gamma was given subcutaneously on days -2 and -1 and in the perfusate, with rTNF alpha, at the dose of 0.2 mg. Melphalan was administered in the perfusate at dose giving a concentration of 40 micrograms/ml. In all the 31 isolation perfusions performed in the triple combination protocol, in order to prevent a septic shock-like syndrome which had been encountered in 2 patients treated outside this protocol for sarcoma and carcinoma, the patients received dopamine continuous infusion at 3 micrograms/kg/min from the start of isolation perfusion and for 48 hours, and only showed mild hypotension and very transient chills and temperature.(ABSTRACT TRUNCATED AT 250 WORDS)