RESUMO
Glutamine may be a precursor for NO synthesis, which may play a crucial role in bacterial translocation (BT). The goal of the present study was to investigate the potential effects of glutamine on BT and the immunological response in an experimental model of NO synthase inhibition by NG-nitro-L-arginine methyl ester (l-NAME). Mice were randomly assigned to four groups: sham; intestinal obstruction (IO); IO+500 mg/kg per d glutamine (GLN); IO+GLN plus 10 mg/kg per d l-NAME (GLN/LN). The groups were pretreated for 7 d. BT was induced by ileal ligation and was assessed 18 h later by measuring the radioactivity of 99mTc-Escherichia coli in the blood and organs. Mucosal damage was determined using a histological analysis. Intestinal permeability (IP) was assessed by measuring the levels of 99mTc-diethylenetriaminepentaacetic acid in the blood at 4, 8 and 18 h after surgery. IgA and cytokine concentrations were determined by ELISA in the intestinal fluid and plasma, respectively. BT was increased in the GLN/LN and IO groups than in the GLN and sham groups. IP and intestinal mucosa structure of the sham, GLN and GLN/LN groups were similar. The GLN group had the highest levels of interferon-γ, while IL-10 and secretory IgA levels were higher than those of the IO group but similar to those of the GLN/LN group. The present results suggest that effects of the glutamine pathway on BT were mediated by NO. The latter also interferes with the pro-inflammatory systemic immunological response. On the other hand, IP integrity preserved by the use of glutamine is independent of NO.
Assuntos
Translocação Bacteriana , Glutamina/metabolismo , Íleo/metabolismo , Mucosa Intestinal/metabolismo , Obstrução Intestinal , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico/metabolismo , Animais , Translocação Bacteriana/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Escherichia coli , Glutamina/farmacologia , Íleo/efeitos dos fármacos , Íleo/microbiologia , Íleo/patologia , Imunoglobulina A/metabolismo , Imunoglobulina A Secretora/metabolismo , Interferon gama/metabolismo , Interleucina-10/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Obstrução Intestinal/microbiologia , Obstrução Intestinal/patologia , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/imunologia , Ácido Pentético/sangue , Permeabilidade , Transdução de SinaisRESUMO
OBJECTIVES: To examine the feasibility and accuracy of glomerular filtration rate (GFR) measurements in infants with sickle cell anemia (SCA). STUDY DESIGN: The NHLBI/NICHD-sponsored Phase III randomized double-blinded placebo-controlled trial (BABY HUG) tests the hypothesis that hydroxyurea can prevent chronic organ damage in SCA. GFR elevation is a coprimary endpoint, measured quantitatively by technetium 99m-labeled diethylenetriaminepentaacetic acid (DTPA) plasma clearance and estimated by the Schwartz equation with height and creatinine. RESULTS: Baseline DTPA GFR measurement was attempted in 191 infants; 176 of 184 completed studies (96%) were interpretable. Average age (mean +/- 1SD) was 13.7 +/- 2.6 months. Average DTPA GFR was 125.2 +/- 34.4 (range 40.2-300.9, normal 91.5 +/- 17.8 mL/min/1.73m(2)), while Schwartz estimates were higher at 184.4 +/- 55.5 mL/min/1.73m(2). DTPA GFR was correlated with Schwartz GFR (r(2) = 0.0658, P = .0012); also with age, weight, height, and kidney volume (all P < .002); but not with hemoglobin, HbF, white blood cell count, reticulocytes, medical events, or splenic function. CONCLUSIONS: Quantitative GFR measurement is feasible but variable among infants with SCA. Schwartz GFR estimates are not highly correlated with quantitative DTPA GFR values. Baseline GFR measurements suggest that renal dysfunction in SCA, evidenced by glomerular hyperfiltration, begins during infancy.
Assuntos
Anemia Falciforme/fisiopatologia , Rim/fisiopatologia , Baço/fisiopatologia , Creatinina/sangue , Taxa de Filtração Glomerular , Humanos , Lactente , Ácido Pentético/sangueRESUMO
The aim of this work was to synthesize [166Dy]Dy/166Ho-DTPA-Biotin to evaluate its potential as a new radiopharmaceutical for targeted radiotherapy. Dysprosium-166 (166Dy) was obtained by neutron irradiation of enriched 164Dy(2)O(3) in a Triga Mark III reactor. The labeling was carried out in aqueous media at pH 8.0 by addition of [166Dy]DyCl(3) to diethylenetriaminepentaacetic-alpha,omega-bis(biocytinamide) (DTPA-Biotin). Radiochemical purity was determined by high-performance liquid chromatography (HPLC) and TLC. The biological integrity of labeled biotin was studied evaluating its avidity for avidin in an agarose column and by size-exclusion HPLC analysis of the radiolabeled DTPA-Biotin with and without the addition of avidin. Stability studies against dilution were carried out by diluting the radiocomplex solution with saline solution and with human serum at 37 degrees C for 24 h. The [166Dy]Dy/166Ho-labeled biotin was obtained with a 99.1+/-0.6% radiochemical purity. In vitro studies demonstrated that [166Dy]Dy/166Ho-DTPA-Biotin is stable after dilution in saline and in human serum and no translocation of the daughter nucleus occurs subsequent to beta(-) decay of 166Dy that could produce release of 166Ho(3+). Avidity of labeled biotin for avidin was not affected by the labeling procedure. Biodistribution studies in normal mice showed that the [166Dy]Dy/166Ho-DTPA-Biotin has a high renal clearance. In conclusion, the radiolabeled biotin prepared in this investigation has adequate properties to work as a stable in vivo generator system for targeted radiotherapy.
Assuntos
Biotina/análogos & derivados , Biotina/química , Disprósio/química , Hólmio/química , Ácido Pentético/análogos & derivados , Ácido Pentético/química , Compostos Radiofarmacêuticos/química , Animais , Biotina/sangue , Biotina/farmacocinética , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Estabilidade de Medicamentos , Feminino , Injeções Intravenosas , Marcação por Isótopo , Camundongos , Camundongos Endogâmicos BALB C , Ácido Pentético/sangue , Ácido Pentético/farmacocinética , Radioisótopos/química , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
A study was conducted to examine renal function in 10 healthy control subjects and eight patients with cystic fibrosis in stable condition. Sequential bolus injections of 99mTc-DTPA and 125I-OIH were administered to assess glomerular filtration rate and effective renal plasma flow, respectively. Blood was subsequently collected for 3 hours, and urine for 24 hours. Renal clearances of both radioisotope markers were virtually identical in patients and controls. Inasmuch as neither glomerular filtration rate nor effective renal plasma flow was enhanced in patients with cystic fibrosis, increased clearance of drugs in these patients is unlikely to be the result of enhanced glomerular filtration or tubular secretion.