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J Toxicol Environ Health A ; 70(3-4): 284-94, 2007 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-17365591


Little is known about antioxidant status, selenium status in particular, and lung response to NO2, which acts as a proinflammatory air pollutant. The effects of a low selenium diet (1.3 microg Se/d) with or without selenium supplementation were therefore studied in 128 Wistar rats, 2 mo old, male exposed to either acute (50 ppm, 30 min), intermittent subacute (5 ppm, 6 h/d, 5 d), intermittent long-term NO2 (1 ppm, 10 ppm, 6 h/d, 5 d/wk, 28 d), or normal atmospheric air (controls). Following sacrifice, measurements of lipid peroxidation (thiobarbituric acid-reactive substances, chemiluminescence), antioxidative protective enzymes (glutathione peroxidase [GPx], superoxide dismutase [SOD], glutathione S-transferase [GST], ceruloplasmin), lung damage (lactate dehydrogenase, alkaline and acid phosphatases), lung permeability (total protein, albumin), and inflammation (cell populations), along with the determination of new biomarkers such as CC16 (Clara-cell protein), were performed in serum and bronchoalveolar lavage fluid (BALF). While selenium-supplemented animals had increased GPx activity in serum prior to inhalation experiments, they also had decreased BALF CC16, blood SOD, and GST levels. Nevertheless, the protective role of normal selenium status with respect to NO2 lung toxicity was evident both for long-term and acute exposures, as the increase in BALF total proteins and corresponding decrease in serum (indicating increased lung permeability) was significantly more pronounced in selenium-deficient animals. During the various inhalation experiments, serum CC16 demonstrated its key role as an early marker of increased lung permeability. These findings corroborate the important role of selenium status in NO2 oxidative damage modulation, but also indicate, in view of its negative impact on CC16, a natural anti-inflammatory and immunosuppressor, that caution should be used prior to advocating selenium supplementation.

Antioxidantes/metabolismo , Pulmón/efectos de los fármacos , Dióxido de Nitrógeno/efectos adversos , Permeabilidad/efectos de los fármacos , Selenio/farmacología , Fosfatasa Ácida/metabolismo , Contaminantes Atmosféricos/efectos adversos , Fosfatasa Alcalina/metabolismo , Animales , Biomarcadores/análisis , Biomarcadores/sangre , Líquido del Lavado Bronquioalveolar/química , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Exposición por Inhalación , L-Lactato Deshidrogenasa/metabolismo , Masculino , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Uteroglobina/metabolismo
Kidney Int ; 59(6): 2164-73, 2001 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-11380818


BACKGROUND: Chinese herbs nephropathy (CHN) is a new type of subacute interstitial nephritis that is attributed to aristolochic acid (AA), which inadvertently has been included in slimming pills. The contribution of other simultaneously prescribed drugs remains disputed. In the present study, the effects of a chronic intake of AA given as a single drug was evaluated through renal histology and function in rabbits. METHODS: Female New Zealand White rabbits were injected intraperitoneally with either 0.1 mg AA/kg or with saline 5 days a week for 17 to 21 months. Body weight, renal function, and urinary excretion of glucose and low molecular weight proteins were monitored prior to sacrifice at the end of the study period. RESULTS: All animals given AA developed renal hypocellular interstitial fibrosis, which was classified into three patterns. Fibrosis was confined to medullary rays (MRs) in pattern I (N = 3), extended to the outer cortical labyrinth (OCL) in pattern II (N = 2), and eventually to the inner cortical labyrinth (ICL) in pattern III (N = 6). Fibrosis in MR and OCL was associated with mainly proximal tubular epithelial cell flattening. All treated animals displayed urothelial atypia. Three of them also developed tumors of the urinary tract. No significant pathologic changes were found in control rabbits. AA-treated animals differed from controls by an impaired growth, increased serum creatinine, glucosuria, tubular proteinuria, and anemia. CONCLUSION: The observed pattern of renal histopathological lesions and disorders of the renal function, as well as urothelial atypia and malignancy, are very reminiscent of CHN. Our observations therefore support a causal role of AA alone in the genesis of this new nephropathy.

Ácidos Aristolóquicos , Medicamentos Herbarios Chinos/toxicidad , Inhibidores Enzimáticos/toxicidad , Nefritis Intersticial/inducido químicamente , Fenantrenos/toxicidad , Animales , Modelos Animales de Enfermedad , Femenino , Fibrosis , Riñón/patología , Nefritis Intersticial/patología , Tamaño de los Órganos , Conejos , Estómago/patología
Arch Toxicol ; 72(11): 738-43, 1998 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-9879812


Chinese herbs nephropathy (CHN), a rapidly progressive interstitial fibrosis of the kidney, has been described in approximately 100 young Belgian women who had followed a slimming regimen containing some Chinese herbs. In 4 patients multifocal transitional cell carcinomas (TCC) were observed. Aristolochic acid (AA), suspected as the causal factor of CHN, is a well known carcinogen but its ability to induce fibrosis has never been demonstrated. The objective of this study was to evaluate the latter using doses of AA, durations of intoxication and delays of sacrifice known to yield tumours in rats. We also tested the hypothesis that a possible fibrogenic role of AA was enhanced by the other components of the slimming regimen. Male and female rats were treated orally with 10 mg isolated AA/kg per day for 5 days/week, or with approximately 0.15 mg AA/ kg per day 5 days/week contained in the herbal powder together with the other components prescribed in the slimming pills for 3 months. The animals were killed respectively 3 and 11 months later. At sacrifice, animals in both groups had developed the expected tumours but not fibrosis of the renal interstitium. Whether the fibrotic response observed in man is due to species and/or strain related differences in the response to AA or to other factors, remains to be determined. Interestingly, despite the addition of fenfluramine and diethylpropion, two drugs incriminated in the development of valvular heart disease, no cardiac abnormalities were observed.

Fármacos Antiobesidad/toxicidad , Ácidos Aristolóquicos , Fibrina/efectos de los fármacos , Nefritis Intersticial/inducido químicamente , Fenantrenos/toxicidad , Neoplasias Gástricas/inducido químicamente , Animales , Carcinógenos/toxicidad , Medicamentos Herbarios Chinos/química , Femenino , Fibrina/metabolismo , Masculino , Ratas , Ratas Wistar
Kidney Int ; 51(1): 288-93, 1997 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8995745


Neutral endopeptidase (NEP) is a 94 kDa ectoenzyme of the proximal tubule brush border, physiologically released into the urine with apical membrane fragments. As proximal tubular atrophy was a histological hallmark of Chinese herbs nephropathy (CHN), this study firstly determined renal excretion of NEP in healthy control subjects (N = 31), in patients with CHN (N = 26) and in women having consumed Chinese herbs and whose renal function was normal but running the risk of developing CHN (N = 27). Another patient group consisted of female patients with glomerular diseases (N = 12). At the same time, measurements of urinary microproteins (Clara cell protein, retinol binding protein, beta 2-microglobulin and alpha 1-microglobulin) were performed, as indicators of tubular dysfunction. Cell damage was estimated by the excretion of N-acetyl-beta-D-glucosaminidase (NAG). In the control group, the physiological NEP enzymuria was 43.1 micrograms/24 hr (geometric mean). In CHN patients, levels of urinary NEP were significantly decreased in those with moderate renal failure (26.7 micrograms/24 hr; N = 21; P < 0.05) and almost abolished in end-stage renal failure patients (4.35 micrograms/24 hr; N = 5; P < 0.05). In patients at risk as well as in patients with glomerular diseases, urinary NEP levels were not statistically different from those observed in control subjects (40.68 micrograms/24 hr and 48.5 micrograms/24 hr, respectively). Several degrees of tubular dysfunction and injury were noted in patients groups, as attested by increased urinary microproteins and NAG excretions. Considering the data from control and CHN patients, NEP enzymuria positively correlated with individual creatinine clearance values (r = 0.76; P = 0.0001) and negatively correlated with urinary microproteins levels (r = -0.55; P = 0.00001). Finally, NEP was regularly quantitated in the urine of 6 CHN patients for a period ranging from six months to two years and in 19 patients at risk during two years, respectively. In the first group, renal function progressively deteriorated in 3 patients, leading them to renal replacement therapy after 38 to 115 weeks. Stable parameters were observed in the remaining 3 patients. A direct correlation between creatinine clearance and NEP excretion was found longitudinally in each case. In the second group, no significant change of urinary NEP levels was observed (45.9 micrograms/24 hr), in parallel with stable renal function. Taken together, these results indicate that, in CHN patients, NEP enzymuria provides a rapid and noninvasive determination of the degree of structural impairment affecting the proximal tubular population and further reflecting the severity of the renal disease. The interest of this urinary marker in monitoring the progression of other tubulointerstitial diseases remains to be assessed.

Medicamentos Herbarios Chinos/efectos adversos , Túbulos Renales Proximales/enzimología , Túbulos Renales Proximales/patología , Nefritis Intersticial/inducido químicamente , Neprilisina/orina , Adulto , Biomarcadores , Femenino , Glomerulonefritis/inducido químicamente , Glomerulonefritis/enzimología , Glomerulonefritis/patología , Humanos , Glomérulos Renales/patología , Túbulos Renales Proximales/efectos de los fármacos , Persona de Mediana Edad , Nefritis Intersticial/enzimología , Nefritis Intersticial/patología , Estudios Prospectivos