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1.
Am J Perinatol ; 33(2): 180-7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26344007

RESUMO

OBJECTIVE: We evaluated whether urinary excretion of tubular injury markers could be useful for early detection of gentamicin (GM)-induced renal damage in neonates. STUDY DESIGN: We conducted a prospective, observational trial in neonates admitted to the neonatal intensive care unit (26 GM treated, 20 control). Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-ß-D-glucosaminidase (NAG), and π- and α-glutathione-S-transferase (GSTP1-1 and GSTA1-1) were measured every 2 hours during admission and compared with serum creatinine (sCr) and urine output. RESULTS: Nine neonates developed AKI during the course of the study. The peak in excretion of urinary biomarkers preceded the peak in sCr (p < 0.0001). GM administration resulted in a more pronounced increase of sCr compared with control (13 [12-28] vs. 10 µmol/L [8.5-17]; p < 0.05). The urinary excretion of NAG (178 [104-698] vs. 32 ng/mol Cr [9-82]; p < 0.001) and NGAL (569 [168-1,681] vs. 222 ng/mol Cr [90-497]; p < 0.05) was higher in the GM group compared with control and preceded the peak of sCr and urine output decrease. CONCLUSION: GM administration to neonates is associated with renal damage reflected by a more pronounced increase in sCr preceded by urinary excretion of biomarkers. Urinary biomarkers may be useful for earlier identification of renal injury in neonates.


Assuntos
Injúria Renal Aguda/metabolismo , Antibacterianos/efeitos adversos , Gentamicinas/efeitos adversos , Idade Gestacional , Acetilglucosaminidase/urina , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Proteínas de Fase Aguda/urina , Asfixia Neonatal , Biomarcadores/sangue , Biomarcadores/urina , Estudos de Coortes , Anormalidades Congênitas , Creatinina/sangue , Feminino , Glutationa S-Transferase pi/urina , Glutationa Transferase/urina , Receptor Celular 1 do Vírus da Hepatite A , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Unidades de Terapia Intensiva Neonatal , Lipocalina-2 , Lipocalinas/urina , Masculino , Glicoproteínas de Membrana/urina , Estudos Prospectivos , Proteínas Proto-Oncogênicas/urina , Receptores Virais
2.
Am J Kidney Dis ; 63(6): 1038-48, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24462020

RESUMO

Acute kidney injury (AKI) is a common disease in the intensive care unit and accounts for high morbidity and mortality. Sepsis, the predominant cause of AKI in this setting, involves a complex pathogenesis in which renal inflammation and hypoxia are believed to play an important role. A new therapy should be aimed at targeting both these processes, and the enzyme alkaline phosphatase, with its dual mode of action, might be a promising candidate. First, alkaline phosphatase is able to reduce inflammation through dephosphorylation and thereby detoxification of endotoxin (lipopolysaccharide), which is an important mediator of sepsis. Second, adenosine triphosphate, released during cellular stress caused by inflammation and hypoxia, has detrimental effects but can be converted by alkaline phosphatase into adenosine with anti-inflammatory and tissue-protective effects. These postulated beneficial effects of alkaline phosphatase have been confirmed in animal experiments and two phase 2a clinical trials showing that kidney function improved in critically ill patients with sepsis-associated AKI. Because renal inflammation and hypoxia also are observed commonly in AKI induced by other causes, it would be of interest to investigate the therapeutic effect of alkaline phosphatase in these nephropathies as well.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Fosfatase Alcalina/uso terapêutico , Sepse/complicações , Injúria Renal Aguda/etiologia , Idoso , Fosfatase Alcalina/farmacologia , Estado Terminal , Humanos , Hipóxia/fisiopatologia , Rim/irrigação sanguínea , Rim/fisiopatologia , Masculino , Microcirculação/fisiologia , Fosforilação/efeitos dos fármacos , Sepse/fisiopatologia
3.
Haematologica ; 99(3): 579-87, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24241495

RESUMO

In this double-blind randomized placebo-controlled trial involving 30 healthy male volunteers we investigated the acute effects of iron loading (single dose of 1.25 mg/kg iron sucrose) and iron chelation therapy (single dose of 30 mg/kg deferasirox) on iron parameters, oxidative stress, the innate immune response, and subclinical organ injury during experimental human endotoxemia. The administration of iron sucrose induced a profound increase in plasma malondialdehyde 1 h after administration (433±37% of baseline; P<0.0001), but did not potentiate the endotoxemia-induced increase in malondialdehyde, as was seen 3 h after endotoxin administration in the placebo group (P=0.34) and the iron chelation group (P=0.008). Endotoxemia resulted in an initial increase in serum iron levels and transferrin saturation that was accompanied by an increase in labile plasma iron, especially when transferrin saturation reached levels above 90%. Thereafter, serum iron decreased to 51.6±9.7% of baseline at T=8 h in the placebo group versus 84±15% and 60.4±8.9% of baseline at 24 h in the groups treated with iron sucrose and deferasirox, respectively. No significant differences in the endotoxemia-induced cytokine response (TNF-α, IL-6, IL-10 and IL-1RA), subclinical vascular injury and kidney injury were observed between groups. However, vascular reactivity to noradrenalin was impaired in the 6 subjects in whom labile plasma iron was elevated during endotoxemia as opposed to those in whom no labile plasma iron was detected (P=0.029). In conclusion, a single dose of iron sucrose does not affect the innate immune response in a model of experimental human endotoxemia, but may impair vascular reactivity when labile plasma iron is formed. (Clinicaltrials.gov identifier:01349699).


Assuntos
Endotoxemia/imunologia , Endotoxemia/patologia , Imunidade Inata/efeitos dos fármacos , Quelantes de Ferro/administração & dosagem , Ferro/administração & dosagem , Injúria Renal Aguda/etiologia , Adulto , Citocinas/sangue , Endotoxemia/complicações , Endotoxemia/metabolismo , Hemodinâmica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/sangue , Ferro/farmacocinética , Masculino , Estresse Oxidativo/efeitos dos fármacos , Adulto Jovem
4.
J Pharmacol Exp Ther ; 344(1): 2-7, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23131595

RESUMO

Currently there are no pharmacological therapies licensed to treat sepsis-associated acute kidney injury (AKI). Considering the high incidence and mortality of sepsis-associated AKI, there is an urgent medical need to develop effective pharmacological interventions. Two phase II clinical trials recently demonstrated beneficial effects of the enzyme alkaline phosphatase (AP). In critically ill patients with sepsis-associated AKI, treatment with AP reduced the urinary excretion of tubular injury biomarkers and plasma markers of inflammation, which was associated with improvement of renal function. The dephosphorylating enzyme, AP, is endogenously present in the renal proximal tubule apical membrane but becomes depleted during ischemia-induced AKI, thereby possibly contributing to further renal damage. The exact mechanism of action of AP in AKI is unknown, but might be related to detoxification of circulating lipopolysaccharide and other proinflammatory mediators that lose their proinflammatory effects after dephosphorylation. Alternatively, tissue damage associated with systemic inflammation might be attenuated by an AP-mediated effect on adenosine metabolism. Adenosine is a signaling molecule that has been shown to protect the body from inflammation-induced tissue injury, which is derived through dephosphorylation of ATP. In this Perspectives article, we discuss the clinical activity of AP and its putative molecular modes of action, and we speculate on its use to treat and possibly prevent sepsis-associated AKI.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Fosfatase Alcalina/uso terapêutico , Sepse/complicações , Trifosfato de Adenosina/metabolismo , Fosfatase Alcalina/farmacologia , Animais , Ensaios Clínicos como Assunto , Ensaios Clínicos Fase II como Assunto , Humanos , Lipopolissacarídeos/metabolismo
5.
Nephrol Dial Transplant ; 28(2): 345-51, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23222415

RESUMO

BACKGROUND: Cardiac surgery-related acute kidney injury (CS-AKI) results in increased morbidity and mortality. Different models have been developed to identify patients at risk of CS-AKI. While models that predict dialysis and CS-AKI defined by the RIFLE criteria are available, their predictive power and clinical applicability have not been compared head to head. METHODS: Of 1388 consecutive adult cardiac surgery patients operated with cardiopulmonary bypass, risk scores of eight prediction models were calculated. Four models were only applicable to a subgroup of patients. The area under the receiver operating curve (AUROC) was calculated for all levels of CS-AKI and for need for dialysis (AKI-D) for each risk model and compared for the models applicable to the largest subgroup (n = 1243). RESULTS: The incidence of AKI-D was 1.9% and for CS-AKI 9.3%. The models of Rahmanian, Palomba and Aronson could not be used for preoperative risk assessment as postoperative data are necessary. The three best AUROCs for AKI-D were of the model of Thakar: 0.93 [95% confidence interval (CI) 0.91-0.94], Fortescue: 0.88 (95% CI 0.87-0.90) and Wijeysundera: 0.87 (95% CI 0.85-0.89). The three best AUROCs for CS-AKI-risk were 0.75 (95% CI 0.73-0.78), 0.74 (95% CI 0.71-0.76) and 0.70 (95% CI 0.73-0.78), for Thakar, Mehta and both Fortescue and Wijeysundera, respectively. The model of Thakar performed significantly better compared with the models of Mehta, Rahmanian, Fortescue and Wijeysundera (all P-values <0.01) at different levels of severity of CS-AKI. CONCLUSIONS: The Thakar model offers the best discriminative value to predict CS-AKI and is applicable in a preoperative setting and for all patients undergoing cardiac surgery.


Assuntos
Injúria Renal Aguda/epidemiologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Técnicas de Apoio para a Decisão , Modelos Estatísticos , Idoso , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Curva ROC , Medição de Risco/métodos , Sensibilidade e Especificidade
6.
Front Immunol ; 14: 1176775, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37261364

RESUMO

Objective: Inflammation-induced free radical release is important in the pathogenesis of several diseases, including atherosclerosis and sepsis. Heme oxygenase (HO) breaks down heme into carbon monoxide, iron, and biliverdin. Biliverdin IXα is directly converted to bilirubin by biliverdin reductase. Unconjugated bilirubin is a powerful antioxidant, and elevated levels have beneficial effects in preclinical models and human cardiovascular disease. However, its impact during acute inflammation in humans is unknown. In the present study, we investigated the impact of atazanavir-induced (unconjugated) hyperbilirubinemia on antioxidant capacity, inflammation, and vascular dysfunction in human experimental endotoxemia. Approach and results: Following double-blinded four-day treatment with atazanavir 2dd300 mg (or placebo), twenty healthy male volunteers received 2 ng/kg Escherichia coli lipopolysaccharide intravenously. Blood was drawn to determine the bilirubin levels, antioxidant capacity, and cytokine response. It was demonstrated that following atazanavir treatment, total bilirubin concentrations increased to maximum values of 4.67 (95%CI 3.91-5.59) compared to 0.82 (95%CI 0.64-1.07) mg/dL in the control group (p<0.01). Furthermore, the anti-oxidant capacity, as measured by the ferric-reducing ability of plasma (FRAP), was significantly increased with 36% in hyperbilirubinemia subjects (p<0.0001), and FRAP concentrations correlated strongly to bilirubin concentrations (R2 = 0.77, p<0.001). Hyperbilirubinemia attenuated the release of interleukin-10 from 377 (95%CI 233-609) to 219 (95%CI 152-318) pg/mL (p=0.01), whereas the release of pro-inflammatory cytokines remained unaltered. In vitro, in the absence of hyperbilirubinemia, atazanavir did not influence lipopolysaccharide-induced cytokine release in a whole blood assay. Vascular function was assessed using forearm venous occlusion plethysmography after intra-arterial infusion of acetylcholine and nitroglycerin. Hyperbilirubinemia completely prevented the LPS-associated blunted vascular response to acetylcholine and nitroglycerin. Conclusions: Atazanavir-induced hyperbilirubinemia increases antioxidant capacity, attenuates interleukin-10 release, and prevents vascular hyporesponsiveness during human systemic inflammation elicited by experimental endotoxemia. Clinical trial registration: http://clinicaltrials.gov, identifier NCT00916448.


Assuntos
Endotoxemia , Interleucina-10 , Humanos , Masculino , Sulfato de Atazanavir/efeitos adversos , Nitroglicerina/efeitos adversos , Endotoxemia/tratamento farmacológico , Lipopolissacarídeos/efeitos adversos , Acetilcolina/farmacologia , Antioxidantes/uso terapêutico , Biliverdina , Hiperbilirrubinemia/induzido quimicamente , Hiperbilirrubinemia/tratamento farmacológico , Bilirrubina
7.
Arterioscler Thromb Vasc Biol ; 31(2): 458-63, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21088253

RESUMO

OBJECTIVE: In type 2 diabetes mellitus (T2DM), oxidative stress gives rise to endothelial dysfunction. Bilirubin, a powerful endogenous antioxidant, significantly attenuates endothelial dysfunction in preclinical experiments. The Gilbert syndrome is accompanied by a mild and lifelong hyperbilirubinemia and associated with only one third of the usual cardiovascular mortality risk. The hyperbilirubinemia caused by atazanavir treatment closely resembles the Gilbert syndrome. We thus hypothesized that treatment with atazanavir would ameliorate oxidative stress and vascular inflammation and improve endothelial function in T2DM. METHODS AND RESULTS: In a double-blind, placebo-controlled crossover design, we induced a moderate hyperbilirubinemia by a 3-day atazanavir treatment in 16 subjects experiencing T2DM. On the fourth day, endothelial function was assessed by venous occlusion plethysmography. Endothelium-dependent and endothelium-independent vasodilation were assessed by intraarterial infusion of acetylcholine and nitroglycerin, respectively. Atazanavir treatment induced an increase in average bilirubin levels from 7 µmol/L (0.4 mg/dL) to 64 µmol/L (3.8 mg/dL). A significant improvement in plasma antioxidant capacity (P<0.001) and endothelium-dependent vasodilation (P=0.036) and a decrease in plasma von Willebrand factor (P=0.052) were observed. CONCLUSIONS: Experimental hyperbilirubinemia is associated with a significant improvement of endothelial function in T2DM.


Assuntos
Bilirrubina/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Oligopeptídeos/farmacologia , Piridinas/farmacologia , Acetilcolina/farmacologia , Idoso , Sulfato de Atazanavir , Estudos Cross-Over , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitroglicerina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/farmacologia , Fator de von Willebrand/metabolismo
8.
Crit Care ; 16(1): R14, 2012 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-22269279

RESUMO

INTRODUCTION: To evaluate whether alkaline phosphatase (AP) treatment improves renal function in sepsis-induced acute kidney injury (AKI), a prospective, double-blind, randomized, placebo-controlled study in critically ill patients with severe sepsis or septic shock with evidence of AKI was performed. METHODS: Thirty-six adult patients with severe sepsis or septic shock according to Systemic Inflammatory Response Syndrome criteria and renal injury defined according to the AKI Network criteria were included. Dialysis intervention was standardized according to Acute Dialysis Quality Initiative consensus. Intravenous infusion of alkaline phosphatase (bolus injection of 67.5 U/kg body weight followed by continuous infusion of 132.5 U/kg/24 h for 48 hours, or placebo) starting within 48 hours of AKI onset and followed up to 28 days post-treatment. The primary outcome variable was progress in renal function variables (endogenous creatinine clearance, requirement and duration of renal replacement therapy, RRT) after 28 days. The secondary outcome variables included changes in circulating inflammatory mediators, urinary excretion of biomarkers of tubular injury, and safety. RESULTS: There was a significant (P=0.02) difference in favor of AP treatment relative to controls for the primary outcome variable. Individual renal parameters showed that endogenous creatinine clearance (baseline to Day 28) was significantly higher in the treated group relative to placebo (from 50±27 to 108±73 mL/minute (mean±SEM) for the AP group; and from 40±37 to 65±30 mL/minute for placebo; P=0.01). Reductions in RRT requirement and duration did not reach significance. The results in renal parameters were supported by significantly more pronounced reductions in the systemic markers C-reactive protein, Interleukin-6, LPS-binding protein and in the urinary excretion of Kidney Injury Molecule-1 and Interleukin-18 in AP-treated patients relative to placebo. The Drug Safety Monitoring Board did not raise any issues throughout the trial. CONCLUSIONS: The improvements in renal function suggest alkaline phosphatase is a promising new treatment for patients with severe sepsis or septic shock with AKI. TRIAL REGISTRATION: www.clinicaltrials.gov: NCT00511186.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Fosfatase Alcalina/administração & dosagem , Sepse/complicações , Sepse/tratamento farmacológico , Injúria Renal Aguda/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/fisiopatologia , Resultado do Tratamento
9.
Proteome Sci ; 9: 13, 2011 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-21426560

RESUMO

BACKGROUND: Suitable biomarkers associated with the development of delirium are still not known. Urinary proteomics has successfully been applied to identify novel biomarkers associated with various disease states, but its value has not been investigated in delirium patients. RESULTS: In a prospective explorative study hyperactive delirium patients after cardiac surgery were included for urinary proteomic analyses. Delirium patients were matched with non-delirium patients after cardiac surgery on age, gender, severity of illness score, LOS-ICU, Euro-score, C-reactive protein, renal function and aorta clamping time. Urine was collected within 24 hours after the onset of delirium. Matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI-TOF MS) was applied to detect differences in the urinary proteome associated with delirium in these ICU patients. We included 10 hyperactive delirium and 10 meticulously matched non-delirium post-cardiac surgery patients. No relevant differences in the urinary excretion of proteins could be observed. CONCLUSIONS: We conclude that MALDI-TOF MS of urine does not reveal a clear hyperactive delirium proteome fingerprint in ICU patients. TRIAL REGISTRATION: Clinical Trial Register number: NCT00604773.

10.
Crit Care ; 15(6): R289, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22129171

RESUMO

INTRODUCTION: In animal models of systemic inflammation, the endogenous nucleoside adenosine controls inflammation and prevents organ injury. Dipyridamole blocks the cellular uptake of endogenous adenosine and increases the extracellular adenosine concentration. We studied the effects of oral dipyridamole treatment on innate immunity and organ injury during human experimental endotoxemia. METHODS: In a randomized double-blind placebo-controlled study, 20 healthy male subjects received 2 ng/kg Escherichia coli endotoxin (lipopolysaccharide; LPS) intravenously after 7-day pretreatment with dipyridamole, 200 mg slow release twice daily, or placebo. RESULTS: Nucleoside transporter activity on circulating erythrocytes was reduced by dipyridamole with 89% ± 2% (P < 0.0001), and the circulating endogenous adenosine concentration was increased. Treatment with dipyridamole augmented the LPS-induced increase in the antiinflammatory cytokine interleukin (IL)-10 with 274%, and resulted in a more rapid decrease in proinflammatory cytokines tumor necrosis factor-α (TNF-α) and IL-6 levels directly after their peak level (P < 0.05 and < 0.01, respectively). A strong correlation was found between the plasma dipyridamole concentration and the adenosine concentration (r = 0.82; P < 0.01), and between the adenosine concentration and the IL-10 concentration (r = 0.88; P < 0.0001), and the subsequent decrease in TNF-α (r = -0.54; P = 0.02). Dipyridamole treatment did not affect the LPS-induced endothelial dysfunction or renal injury during experimental endotoxemia. CONCLUSIONS: Seven-day oral treatment with dipyridamole increases the circulating adenosine concentration and augments the antiinflammatory response during experimental human endotoxemia, which is associated with a faster decline in proinflammatory cytokines. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT01091571.


Assuntos
Dipiridamol/uso terapêutico , Endotoxemia/tratamento farmacológico , Proteínas de Transporte de Nucleosídeo Equilibrativas/antagonistas & inibidores , Acetilcolina/farmacologia , Creatinina/urina , Método Duplo-Cego , Endotoxemia/imunologia , Endotoxinas/farmacologia , Antebraço/irrigação sanguínea , Glutationa Transferase/urina , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação/microbiologia , Masculino , Nitroprussiato/farmacologia , Norepinefrina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Adulto Jovem
11.
J Biomed Biotechnol ; 2010: 525180, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20300455

RESUMO

During endotoxemia, the ATP-dependent drug efflux pump P-glycoprotein (Abcb1/P-gp) is upregulated in kidney proximal tubule epithelial cells. The signaling pathway through which lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha) regulates P-gp expression and activity was investigated further in the present study. Exposure of rat kidney proximal tubule cells to TNF-alpha alone or TNF-alpha and LPS increased P-gp gene and protein expression levels and efflux activity, suggesting de novo P-gp synthesis. Upon exposure to TNF-alpha in combination with LPS, P-gp activity in renal proximal tubule cells is increased under influence of nitric oxide (NO) produced by inducible NO synthase. Upon exposure to TNF-alpha alone, P-gp upregulation seems to involve TLR4 activation and nuclear factor kappaB (NF-kappaB) translocation, a pathway that is likely independent of NO. These findings indicate that at least two pathways regulate P-gp expression in the kidney during endotoxemia.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Células Epiteliais/metabolismo , Túbulos Renais Proximais/metabolismo , Lipopolissacarídeos/administração & dosagem , Fator de Necrose Tumoral alfa/administração & dosagem , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Células Epiteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Ratos
12.
Regul Toxicol Pharmacol ; 57(1): 31-42, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20026148

RESUMO

Pectin-derived acidic oligosaccharides (pAOS) are non-digestible carbohydrates to be used in infant formulae and medical nutrition. To support its safety, the genotoxic potential of pAOS was evaluated. pAOS was not mutagenic in the Ames test. Positive results were obtained in the chromosome aberration test only at highly cytotoxic concentrations. The effects obtained in the mouse lymphoma test were equivocal; pAOS was not mutagenic in vivo. A sub-chronic dietary study, preceded by 4-week parental and in utero exposure phase, investigated general safety. Administration of pAOS did not affect parental health nor pup characteristics. No effects specific for acidic oligosaccharides were observed in the subsequent sub-chronic study. Slight diffuse hyperplasia of epithelial layer of the urinary bladder was noted to result from concurrently elevated urinary sodium, due to high sodium in pAOS, and elevated urinary pH. This phenomenon was confirmed in a mechanistic (sub-chronic) study. In contrast, in rats fed pAOS in combination with NH(4)Cl, an acidifying agent, the induced low urinary pH completely prevented the development of urothelial hyperplasia. Hyperplasia induced by this mechanism in rats is considered not relevant to man. Based on the current knowledge we consider pAOS safe for human consumption under its intended use.


Assuntos
Aberrações Cromossômicas , Qualidade de Produtos para o Consumidor , Fórmulas Infantis/normas , Oligossacarídeos/toxicidade , Pectinas/química , Administração Oral , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Células CHO , Linhagem Celular Tumoral , Aberrações Cromossômicas/induzido quimicamente , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Feminino , Fórmulas Infantis/química , Lactação , Masculino , Exposição Materna/efeitos adversos , Camundongos , Índice Mitótico , Testes de Mutagenicidade , Oligossacarídeos/química , Oligossacarídeos/isolamento & purificação , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Ratos , Ratos Wistar , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Testes de Toxicidade Crônica , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia
13.
Ned Tijdschr Geneeskd ; 1642020 10 08.
Artigo em Holandês | MEDLINE | ID: mdl-33331720

RESUMO

Recently in a national newspaper presumed large hazards in care were described. Visible black particles were seen in blood plasma and a cancerogenic substance was found in paracetamol. Every year 300.000 bags of plasma are produced. The black particles were found in 11 bags of plasma. Possibly one of these was administered. During administration 175 micron filters are used. Presumably remaining particles will be degraded by the mononuclear-phagocytic system. In paracetamol 6 ppm of para-chloroaniline was found. Depending of the limit used by either the ICH or the EFSA this means for patients using lifelong 6 grams of paracetamol a risk off respectively 1: 200.000 or 1:20.000. This risk is neglectable compared of the life time risks of cancer in the population (1:3). Journalists should realize that this exaggerated commentary can lead to real serious risks (taking NSAID's instead of paracetamol) and mistrust in regular care.


Assuntos
Acetaminofen/análise , Analgésicos não Narcóticos/análise , Carcinógenos/análise , Preparações Farmacêuticas/análise , Plasma/química , Fraude , Humanos , Meios de Comunicação de Massa
14.
Crit Care Med ; 37(2): 417-23, e1, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19114895

RESUMO

OBJECTIVE: Alkaline phosphatase (AP) attenuates inflammatory responses by lipopolysaccharide detoxification and may prevent organ damage during sepsis. To investigate the effect of AP in patients with severe sepsis or septic shock on acute kidney injury. DESIGN AND SETTING: A multicenter double-blind, randomized, placebo-controlled phase IIa study (2:1 ratio). PATIENTS: Thirty-six intensive care unit patients (20 men/16 women, mean age 58 +/- 3 years) with a proven or suspected Gram-negative bacterial infection, >or=2 systemic inflammatory response syndrome criteria (<24 hours), and <12 hours end-organ dysfunction onset were included. INTERVENTION: An initial bolus intravenous injection (67.5 U/kg body weight) over 10 minutes of AP or placebo, followed by continuous infusion (132.5 U/kg) over the following 23 hours and 50 minutes. MEASUREMENTS AND MAIN RESULTS: Median plasma creatinine levels declined significantly from 91 (73-138) to 70 (60-92) micromol/L only after AP treatment. Pathophysiology of nitric oxide (NO) production and subsequent renal damage were assessed in a subgroup of 15 patients. A 42-fold induction (vs. healthy subjects) in renal inducible NO synthase expression was reduced by 80% +/- 5% after AP treatment. In AP-treated patients, the increase in cumulative urinary NO metabolite excretion was attenuated, whereas the opposite occurred after placebo. Reduced excretion of NO metabolites correlated with the proximal tubule injury marker glutathione S-transferase A1-1 in urine, which decreased by 70 (50-80)% in AP-treated patients compared with an increase by 200 (45-525)% in placebo-treated patients. CONCLUSIONS: In severe sepsis and septic shock, infusion of AP inhibits the upregulation of renal inducible NO synthase, leading to subsequent reduced NO metabolite production, and attenuated tubular enzymuria. This mechanism may account for the observed improvement in renal function.


Assuntos
Fosfatase Alcalina/uso terapêutico , Rim/efeitos dos fármacos , Sepse/fisiopatologia , Choque Séptico/fisiopatologia , Doença Aguda , Fosfatase Alcalina/administração & dosagem , Creatinina/sangue , Método Duplo-Cego , Indução Enzimática , Feminino , Glutationa Transferase/urina , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/biossíntese , Placebos , Índice de Gravidade de Doença
15.
Intensive Care Med ; 34(2): 350-4, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17926021

RESUMO

OBJECTIVE: We previously demonstrated that upregulation of renal inducible nitric oxide synthase (iNOS) is associated with proximal tubule injury during systemic inflammation in humans. In this study we investigated the short-term effect of methylene blue (MB), an inhibitor of the NO pathway, on kidney damage and function in septic shock patients. DESIGN AND SETTING: A prospective clinical study conducted in an intensive care unit. PATIENTS: Nine patients (four men, five women, mean age 71 +/- 3 years) with confirmed or suspected bacterial infection and with refractory septic shock defined as a mean arterial pressure < or = 70 mmHg despite norepinephrine infusion > or = 0.2 microg/kg per minute. INTERVENTIONS: A 4 h continuous intravenous infusion of 1 mg/kg MB per hour. MEASUREMENTS AND RESULTS: The urinary excretion of NO metabolites decreased with median 90% (range 75-95%) from baseline to 6 h after MB administration. The first 24 h creatinine clearance improved by 51% (18-173%) after MB treatment but was still strongly impaired. During the first 6 h after the start of MB treatment both the urinary excretion of cytosolic glutathione S-transferase A1-1 and P1-1, markers for proximal and distal tubule damage, respectively, decreased by 45% (10-70%) and 70% (40-85) vs. baseline. After termination of the MB infusion the NO metabolites and markers of tubular injury returned to pretreatment levels. CONCLUSIONS: In septic patients with refractory shock short-term infusion of MB is associated with a decrease in NO production and an attenuation of the urinary excretion of renal tubular injury markers.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Inibidores Enzimáticos/uso terapêutico , Azul de Metileno/uso terapêutico , Choque Séptico/complicações , Injúria Renal Aguda/enzimologia , Idoso , Análise de Variância , Feminino , Glutationa Transferase/metabolismo , Humanos , Masculino , Óxido Nítrico Sintase/metabolismo , Estudos Prospectivos , Choque Séptico/enzimologia , Resultado do Tratamento
16.
Eur J Pharmacol ; 584(2-3): 390-7, 2008 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-18313662

RESUMO

In the kidney, P-glycoprotein (Abcb1), an ATP-driven drug efflux pump, plays an important role in the detoxification of proximal tubule cells through the excretion of cationic and amphipathic organic compounds. We recently found that NO, produced by renal inducible NO synthase (iNOS), is involved in an up-regulation of P-glycoprotein during endotoxemia in rats. In the present study, we investigated the functional consequences of endotoxemia on the renal handling of rhodamine 123 by using isolated perfused rat kidneys. Wistar Hannover rats were injected intraperitoneally with 5 mg/kg body weight lipopolysaccharide (LPS) or with both LPS and the iNOS inhibitor, aminoguanidine. Despite an increased P-glycoprotein expression, we found a diminished urinary rhodamine 123 clearance 12 h after LPS (P<0.001). In addition, we found a diminished perfusate clearance (P<0.05) for rhodamine 123 after LPS treatment, suggesting a predominant role of influx carriers in urinary rhodamine 123 excretion. We examined the expression levels of organic cation transporter 1 (Slc22a1/Oct1) and Slc22a2/Oct2. Both appeared to be down-regulated at the mRNA and protein level, 12 h after LPS. Co-administration of aminoguanidine attenuated the down-regulation of both Oct1 and Oct2 protein expression and reversed the decrease in rhodamine 123 clearance (P<0.001). These findings indicate that NO, produced by iNOS, is responsible for a down-regulation of the influx carriers, Oct1 and Oct2.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/metabolismo , Endotoxemia/metabolismo , Rim/metabolismo , Óxido Nítrico/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Proteínas da Membrana Plasmática de Transporte de Catecolaminas/genética , Modelos Animais de Doenças , Regulação para Baixo , Endotoxemia/induzido quimicamente , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Rim/efeitos dos fármacos , Rim/enzimologia , Masculino , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Transportador 2 de Cátion Orgânico , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Rodamina 123/urina , Fatores de Tempo , Regulação para Cima
17.
Food Chem Toxicol ; 41(12): 1739-47, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14563399

RESUMO

Modulating effects of high fat fish oil (HFFO) and high fat corn oil (HFCO) diets on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were studied in male F344 rats following 8 weeks of dietary treatment. The incidence of AOM-induced ACF was significantly lower in the proximal colon of rats fed the HFFO diets compared with rats fed the HFCO diets. No differential effects were found on enzyme activities that are involved in metabolic activation and detoxification of AOM. Activities of hepatic P450 IAI and P450 IIBI and hepatic and feacal levels of lipid peroxidation were increased by feeding the HFFO diet. Hepatic GST activity and plasma levels of PGE(2) were significantly lower in rats fed the HFFO diets compared with those fed the HFCO diets. These observations demonstrate that HFFO diets with high levels of n-3 PUFAs are also protective against preneoplastic lesions in the early stages of chemically induced colon carcinogenesis. It seems unlikely from our results that the inhibitory effect of a HFFO diet can be attributed to an altered metabolic activation and detoxification of AOM. Other mechanisms such as oxidative stress or reduction of PGE(2) levels may play an important role in the anticarcinogenic effects of n-3 PUFAs.


Assuntos
Azoximetano/antagonistas & inibidores , Azoximetano/toxicidade , Carcinógenos/antagonistas & inibidores , Carcinógenos/toxicidade , Coristoma/induzido quimicamente , Doenças do Colo/induzido quimicamente , Óleo de Milho/farmacologia , Dieta/efeitos adversos , Óleos de Peixe/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Ceco/efeitos dos fármacos , Ceco/enzimologia , Coristoma/patologia , Doenças do Colo/patologia , Dinoprostona/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Células Epiteliais/patologia , Fezes/química , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344
18.
J Crit Care ; 25(2): 358.e1-7, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20381302

RESUMO

OBJECTIVE: We prospectively studied the effect of methylene blue (MB) infusion on gastric mucosal metabolism perfusion ratio, assessed by gastric tonometry, and on mucosal cell damage, assessed by urinary levels of intestinal fatty acid binding protein, in septic shock patients. METHODS: Methylene blue (MB) infusion (1 mg/kg per hour) during 4 hours in 10 consecutive patients with a proven or suspected bacterial infection and with severe vasodilatory shock, defined as a mean arterial pressure 70 mm Hg or lower for at least 1 hour despite adequate volume resuscitation and norepinephrine infusion at a rate >or=0.2 microg/kg per minute. RESULTS: Methylene blue infusion did not significantly change the P(g-a)CO(2) gradient (P = .16). Post hoc analysis of the subgroup of patients with an elevated baseline P(g-a)CO(2) gradient, defined as >or=20 mm Hg, showed that the median P(g-a)CO(2) gradient (interquartile range [IQR]) decreased from 45 (41-56) mm Hg before infusion to 41 (28-52) at the end of the 4-hour infusion and decreased further to 32 (26-36) mm Hg 2 hours after cessation of MB infusion (P = .012). The median urinary intestinal fatty acid binding protein concentration at baseline was elevated (210 [79-437] pg/mumol creatinine) and did not change significantly after 24 hours (116 [53-601] pg/mumol creatinine, P = .15). The median mean arterial blood pressure (IQR) increased from 70 (69-71) mm Hg at baseline to 77 (67-83) mm Hg after 1 hour (P = .04), the norepinephrine dose did not change significantly. The median (IQR) cardiac index decreased from 4.4 (3.2-5.5) L min(-1) m(-2) at baseline to 3.6 (3.3-4.7) L min(-1) m(-2) after 2 h, returning back to baseline values after cessation of MB infusion P = .02). CONCLUSION: Although MB infusion in patients with septic shock and advanced multi-organ failure increases mean arterial blood pressure and decreases cardiac index, it does not compromise the gastric mucosal perfusion metabolism ratio as indicated by tonometry, and by the release of a mucosal cellular injury marker.


Assuntos
Inibidores Enzimáticos/farmacologia , Proteínas de Ligação a Ácido Graxo/efeitos dos fármacos , Mucosa Gástrica/efeitos dos fármacos , Azul de Metileno/farmacologia , Choque Séptico/metabolismo , Idoso , Idoso de 80 Anos ou mais , Inibidores Enzimáticos/administração & dosagem , Proteínas de Ligação a Ácido Graxo/urina , Feminino , Mucosa Gástrica/irrigação sanguínea , Mucosa Gástrica/metabolismo , Humanos , Masculino , Manometria , Azul de Metileno/administração & dosagem , Pessoa de Meia-Idade , Estudos Prospectivos , Choque Séptico/tratamento farmacológico , Choque Séptico/urina , Resultado do Tratamento
19.
Nat Rev Nephrol ; 5(11): 629-40, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19786992

RESUMO

The incidence and mortality of sepsis and the associated development of acute kidney injury (AKI) remain high, despite intense research into potential treatments. Targeting the inflammatory response and/or sepsis-induced alterations in the (micro)circulation are two therapeutic strategies. Another approach could involve modulating the downstream mechanisms that are responsible for organ system dysfunction. Activation of inducible nitric oxide (NO) synthase (iNOS) during sepsis leads to elevated NO levels that influence renal hemodynamics and cause peroxynitrite-related tubular injury through the local generation of reactive nitrogen species. In many organs iNOS is not constitutively expressed; however, it is constitutively expressed in the kidney and, in humans, a relationship between the upregulation of renal iNOS and proximal tubular injury during systemic inflammation has been demonstrated. For these reasons, the selective inhibition of renal iNOS might have important implications for the treatment of sepsis-induced AKI. Various animal studies have demonstrated that selective iNOS inhibition-in contrast to nonselective NOS inhibition-attenuates sepsis-induced renal dysfunction and improves survival, a finding that warrants investigation in clinical trials. In this Review, the selective inhibition of iNOS as a potential novel treatment for sepsis-induced AKI is discussed.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Inibidores Enzimáticos/uso terapêutico , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Sepse/complicações , Animais , Humanos , Óxido Nítrico Sintase Tipo II/metabolismo
20.
Pflugers Arch ; 454(2): 321-34, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17285300

RESUMO

Nitric oxide (NO) is an important regulator of renal transport processes. In the present study, we investigated the role of NO, produced by inducible NO synthase (iNOS), in the regulation of renal ATP-binding cassette (ABC) transporters in vivo during endotoxemia. Wistar-Hannover rats were injected with lipopolysaccharide (LPS(+)) alone or in combination with the iNOS inhibitor, aminoguanidine. Controls received detoxified LPS (LPS(-)). After LPS(+), proximal tubular damage and a reduction in renal function were observed. Furthermore, iNOS mRNA and protein, and the amount of NO metabolites in plasma and urine, increased compared to the LPS(-) group. Coadministration with aminoguanidine resulted in an attenuation of iNOS induction and reduction of renal damage. Gene expression of 20 ABC transporters was determined. After LPS(+), a clear up-regulation in Abca1, Abcb1/P-glycoprotein (P-gp), Abcb11/bile salt export pump (Bsep), and Abcc2/multidrug resistance protein (Mrp2) was found, whereas Abcc8 was down-regulated. Up-regulation of Abcc2/Mrp2 was accompanied by enhanced calcein excretion. Aminoguanidine attenuated the effects on transporter expression. Our data indicate that NO, produced locally by renal iNOS, regulates the expression of ABC transporters in vivo. Furthermore, we showed, for the first time, expression and subcellular localization of Abcb11/Bsep in rat kidney.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Endotoxemia/metabolismo , Rim/metabolismo , Óxido Nítrico/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Nitrogênio da Ureia Sanguínea , Regulação para Baixo/efeitos dos fármacos , Endotoxemia/induzido quimicamente , Endotoxemia/patologia , Inibidores Enzimáticos/farmacologia , Fluoresceínas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Guanidinas/farmacologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Rim/efeitos dos fármacos , Rim/patologia , Córtex Renal/efeitos dos fármacos , Córtex Renal/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Óxidos de Nitrogênio/sangue , Óxidos de Nitrogênio/urina , Ácido Peroxinitroso/análise , Ratos , Ratos Wistar , Regulação para Cima/efeitos dos fármacos
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