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Chan TS Wilson JX Selliah S Bilodeau M Zwingmann C Poon R O'Brien PJ 《Toxicology and applied pharmacology》2008,232(3):456-462
Industry-derived organochlorines are persistent environmental pollutants that are a continuing health concern. The effects of these compounds on drug metabolism are not well understood. In the current study we present evidence that the inhibition of acetaminophen (APAP) glucuronidation by minute concentrations of organochlorines correlates well with their ability to stimulate the d-glucuronate pathway leading to ascorbate synthesis. A set of 6 arylated organochlorines, including 5 PCB (polychlorinated biphenyl) congeners, were assessed for their effects on APAP glucuronidation in isolated hepatocytes from male Sprague-Dawley rats. The capacity of each organochlorine to inhibit APAP glucuronidation was found to be directly proportional to its capacity to stimulate ascorbate synthesis. PCB153, PCB28 and bis-(4-chlorophenyl sulfone) (BCPS) in increasing order were the most effective organochlorines for inhibiting APAP glucuronidation and stimulating the d-glucuronate pathway. None of the 3 inhibitors of APAP glucuronidation were able to alter the expression of UGT1A6, UGT1A7 and UGT1A8 (the major isoforms responsible for APAP glucuronidation in the rat), however, their efficacy at inhibiting APAP glucuronidation was proportional to their capacity to deplete UDP-glucuronic acid (UDPGA). BCPS-mediated inhibition of APAP glucuronidation in isolated hepatocytes had non-competitive characteristics and was insensitive to the inactivation of cytochrome P450. The effective organochlorines were also able to selectively stimulate the hydrolysis of UDPGA to UDP and glucuronate in isolated microsomes, but could not inhibit APAP glucuronidation in microsomes when UDPGA was in excess. We conclude that organochlorines are able to inhibit APAP glucuronidation in hepatocytes by depleting UDPGA via redirecting UDPGA towards the d-glucuronate pathway. Because the inhibition is non-competitive, low concentrations of these compounds could have long term inhibitory effects on the glucuronidating capacity of hepatocytes. 相似文献
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Osami Honjo Sandra L. Merklinger John B. Poe Anne-Marie Guerguerian Hargen Zhang Katherine L. Taylor Glen S. Van Arsdell 《The Journal of thoracic and cardiovascular surgery》2017,153(2):441-447
Objective
Poor survival following surgical palliation for hypoplastic left heart syndrome (HLHS) raises the question of the need for a paradigm shift. This is the first human study to investigate the possibility of primary “in-series” palliation in neonates and infants with HLHS in an acute setting with the aid of 2 types of mechanical assist: superior vena cava (SVC)–to–pulmonary artery (PA) pump assist and SVC–to–right atrium (RA) oxygenation assist.Methods
By rearranging the cannula sites and flow rates for modified ultrafiltration, 2 types of mechanically assisted bidirectional cavopulmonary shunt (BCPS) circulation were simulated for 20 minutes. Three neonates undergoing a stage I Norwood procedure were assigned to SVC-PA pump assist, and 3 infants undergoing stage II BCPS were assigned to SVC-RA oxygenation assist. Hemodynamic parameters, blood gas values, and arterial (SaO2) and regional cerebral tissue (rCTO2) saturations were analyzed.Results
All 6 patients completed the study without hemodynamic compromise. In the SVC-PA pump assist group, a mean arterial pressure >40 mm Hg was maintained. SVC pressure was lower (P = .01) and cerebral perfusion pressure (CPP) was higher (P = .03) during the last 10 minutes of assist compared with Norwood physiology. SaO2 >80%, rCTO2 >60%, and mixed venous saturation ≥59% were maintained, comparable to values with Norwood physiology. In the SVC-RA oxygenation assist group, with full or 50% support, mean blood pressure >50 mm Hg, SVC pressure <15 mm Hg, mixed venous saturation >50%, and CPP >40 mm Hg were maintained, which were comparable to BCPS physiology.Conclusions
Two types of mechanical assist to support primary in-series palliation are feasible in the acute setting. Both modes of mechanical assist maintained oxygenation, as well as systemic and cerebral perfusion. 相似文献8.
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Masamichi Ono Melchior Burri Gunter Balling Elisabeth Beran Julie Cleuziou Jelena Pabst von Ohain Martina Strbad Alfred Hager Jürgen Hörer Rüdiger Lange 《The Journal of thoracic and cardiovascular surgery》2019,157(5):2005-2013.e3
Objectives
A longer length of stay (LOS) in the intensive care unit (ICU) after the total cavopulmonary connection (TCPC) is thought to be a predictive sign of late Fontan failure. This study was performed to determine the clinical risk factors for ICU LOS.Methods
In total, 483 patients who underwent a TCPC between May 1994 and December 2016 were included the study. Patients’ main diagnosis, morphologic characteristics, palliative procedures, hemodynamic parameters, and perioperative variables, were analyzed to identify risk factors influencing ICU stay based on Cox regression. Causes of longer ICU LOS and the impact of ICU LOS on late outcomes were evaluated.Results
Age at TCPC, type of TCPC, and fenestration at TCPC did not affect the ICU LOS. With multivariable model, hypoplastic left heart syndrome (P = .001) and anomalous systemic venous drainage (P < .001) were identified as independent morphologic risk factors for prolonged ICU LOS. Of hemodynamic variables, preoperative high transpulmonary gradient (P = .037), and low aortic oxygen saturation (P = .031) were risks for longer ICU LOS. Of postoperative variables, pleural effusion (P < .001), chylothorax (P = .001), ascites (P < .001), and infection (P = .028) were risks for longer ICU LOS. The ICU LOS was found to be significantly associated with late mortality (P < .001) and late cardiac reoperation (P = .007).Conclusions
Patients with hypoplastic left heart syndrome and anomalous systemic venous drainage had longer ICU LOS. Extended cyanosis and elevated pulmonary artery pressure affect the ICU LOS. Special care should be provided during the initial postoperative phase in patients with such risk factors. 相似文献10.