Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00530 (Portal)
 4,208 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytoprotective effect of prostaglandin E(1) (PGE(1)) has been demonstrated experimentally and clinically against hepatic ischemia and reperfusion injury and against the effects of partial hepatectomy in both individual and combined models of noncirrhotic livers. Cirrhotic livers are more vulnerable to ischemia/reperfusion injury during hepatectomy than are noncirrhotic livers, and postoperative malfunctioning complicates life with multiple organ failure. Cirrhotic livers with tumors have mostly been treated conservatively because extended hepatectomy with induced ischemia during surgery is impossible. The purpose of our study was to document postoperative surgical adaptation in inoperable cases with improved survival after extended hepatectomy in a rat model of cirrhosis treated by PGE(1). Cirrhosis was induced by intraperitoneal injections of 1% dimethylnitrosamine. The liver was subjected to 15 minutes of total ischemia by occluding the hepatoduodenal ligament. Hepatectomy was performed during ischemia. Pretreatment with PGE(1) (0.4 microg/kg/min) (or without it in the controls) was given for 15 minutes by intravenous infusion prior to inducing ischemia and during reperfusion. Portal venous flow (PVF) and liver tissue blood flow (LTBF) were measured during reperfusion. At the end of 60 minutes of reperfusion, venous blood was collected for liver function tests. The animals were followed up regarding survival for 48 hours. The PVF and LTBF were significantly improved in the PGE(1) group. The blood chemical analysis indicated that PGE(1) significantly suppressed posthepatectomy liver dysfunction. Most importantly, PGE(1) treatment markedly improved the survival rate, from 42% in the controls to 75% in the test animals at 24 hours after hepatectomy and from 17% in the controls to 58% in the test animals at 48 hours. We concluded that short-term administration of PGE(1) makes extensive hepatectomy possible under ischemic conditions in cirrhotic livers.
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PMID:Effect of short-term administration of prostaglandin E1 on viability after ischemia/reperfusion injury with extended hepatectomy in cirrhotic rat liver. 1292 1

Haemorrhage during resection of the liver remains a significant threat to clinical outcome. Portal triad occlusion, with complete clamping of the hepatic inflow at the hepatoduodenal ligament, is a well-documented, safe, and useful means of alleviating this problem. Although this technique is effective in limiting blood loss, there is still controversy concerning the potential drawbacks of ischemia and subsequent reperfusion injury of the liver. This article highlights recent advances in our understanding of the clinical factors influencing ischemia-reperfusion injury of the liver, particularly in human patients. These factors include the cell components involved, the mechanisms that enable the human liver to tolerate long-term inflow occlusion, factors affecting clinical outcomes, and surgical and pharmacological techniques used to alleviate ischemia-reperfusion injury, including hypothermic hepatectomy.
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PMID:Ischemia-reperfusion injury of the human liver during hepatic resection. 1460 75

A growing body of evidence indicates that heme degradation products may counteract the deleterious consequences of hypoxia and/or ischemia-reperfusion injury. Because heme oxygenase (HO)-1 induction after adverse circulatory conditions is known to be protective, and because females in the proestrus cycle (with high estrogen) have better hepatic function and less hepatic damage than males after trauma-hemorrhage, we hypothesized that estrogen administration in males after trauma-hemorrhage will upregulate HO activity and protect the organs against dysfunction and injury. To test this hypothesis, male Sprague-Dawley rats underwent 5-cm laparotomy and hemorrhagic shock (35-40 mmHg for 93 +/- 2 min), followed by resuscitation with four times the shed blood volume in the form of Ringer lactate. 17beta-Estradiol and/or the specific HO enzyme inhibitor chromium mesoporphyrin (CrMP) were administered at the end of resuscitation, and the animals were killed 24 h thereafter. Trauma-hemorrhage reduced cardiac output, myocardial contractility, and serum albumin levels. Portal pressure and serum alanine aminotransferase levels were markedly increased under those conditions. These parameters were significantly improved in the 17beta-estradiol-treated rats. Estradiol treatment also induced increased HO-1 mRNA expression, HO-1 protein levels, and HO enzymatic activity in cardiac and hepatic tissue compared with vehicle-treated trauma-hemorrhage rats. Administration of the HO inhibitor CrMP prevented the estradiol-induced attenuation of shock-induced organ dysfunction and damage. Thus the salutary effects of estradiol administration on organ function after trauma-hemorrhage are mediated in part via upregulation of HO-1 expression and activity.
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PMID:Mechanism of salutary effects of estradiol on organ function after trauma-hemorrhage: upregulation of heme oxygenase. 1573 76

Neuroprotective therapies and tissue plasminogen activator (t-PA) have limited application for most stroke patients and thus rehabilitation is the primary treatment option for improving recovery of function. Following brain injury, environmental enrichment, pharmacological and rehabilitative treatments can markedly alter neuronal plasticity and behavioral recovery even when delayed by several weeks after the insult. Fluoxetine has been given to stroke patients to combat depression but its effects on recovery of function are not known. Functional magnetic resonance imaging reveals that fluoxetine alters brain activity and modulates motor performance in stroke patients in a use-dependent fashion. Several antidepressants, including fluoxetine, increase growth factors and other proteins associated with plasticity, such as brain-derived neurotrophic factor (BDNF). In this study, we examined whether chronic administration of fluoxetine combined with rehabilitation affected recovery of function on 3 separate tests of forelimb reaching, preference and limb coordination after focal ischemia in rats. Ischemia was induced in male Long-Evans rats by intracortical and striatal injections of endothelin-1. Fluoxetine (10 mg/kg/day) combined with rehabilitation therapy (6 h/day) for 4 weeks did not alter the degree or rate of recovery of function compared to non-treated animals. Despite the ability of fluoxetine to alter brain activity and increase growth factors, it does not appear to be an effective pharmacological adjunct to functional recovery after ischemia in rats.
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PMID:Fluoxetine and recovery of motor function after focal ischemia in rats. 1586 86

Portal and mesenteric venous thrombosis is an uncommon disease, but clinically important, because it accounts for 5% to 15% of acute mesenteric ischemia. The diagnosis is often delayed because the conditions are nonspecific abdominal symptoms. In addition, when this occurs in young individual without any known predisposing factor, the diagnosis may become even more difficult. The treatment of mesenteric venous thrombosis involves anticoagulation therapy alone or in combination with surgery. The addition of thrombolytic therapy to the treatment of portal and mesenteric venous thrombosis may enhance the clearance of thrombus and hasten the clinical improvements. We present a case of mesenteric venous thrombosis treated with catheter-directed infusion of urokinase via the superior mesenteric artery and systemic anticoagulation.
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PMID:[Portal and superior mesenteric venous thrombosis treated with urokinase infusion via superior mesenteric artery]. 1686 82

This study examined the efficacy of the caspase inhibitor, IDN-6556, in a rat model of liver ischemia-reperfusion injury. Livers from male Sprague-Dawley rats were reperfused for 120 minutes after 24 hours of 4 degrees C cold storage in University of Wisconsin solution. Portal blood flow measurements estimated sinusoidal resistance, and bile production, alanine aminotransferase activities, and Suzuki scores were evaluated as parameters of hepatocyte/liver injury. Treated livers were exposed to 25 or 50 microM of IDN-6556 in University of Wisconsin storage solution and/or the perfusate. All treatment regimens with IDN-6556 significantly improved portal blood flow measured at 120 minutes, and significant improvements were seen as early as 30 minutes when inhibitor was also present in the perfusate (P < 0.01). All treatment groups with IDN-6556 significantly increased bile production by 3-4-fold compared with controls (P < 0.01), and reductions in alanine aminotransferase activities were seen within 90 minutes of reperfusion (P < 0.05). These data were confirmed by improved Suzuki scores (less sinusoidal congestion, necrosis, and vacuolization) in all treated groups. Livers from the IDN-6556-treated groups had markedly reduced caspase activities and TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-positive cells, suggesting reductions in apoptosis. IDN-6556 present in cold storage media ameliorated liver injury due to cold ischemia and reperfusion injury and may be a rational therapeutic approach to reduce the risk of liver ischemia in the clinical setting.
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PMID:A caspase inhibitor, IDN-6556, ameliorates early hepatic injury in an ex vivo rat model of warm and cold ischemia. 1731 74

Fluoxetine, a selective serotonin reuptake inhibitor, alters several physiological processes, for example, elevating intracellular cAMP level, in the hippocampus. We examined the effect of fluoxetine on ischemia-induced neuronal death, the expression of brain-derived neurotrophic factor (BDNF) and changes in some antioxidative enzymes in the hippocampal CA1 region induced by transient ischemia. In addition, we also studied the effect of fluoxetine on locomotor activity in gerbils after ischemia/reperfusion. Animals were administered with various doses of fluoxetine (10, 20, and 40 mg/kg, i.p.) once daily for 3 days before the ischemic surgery. The treatment of 10 mg/kg and 20 mg/kg fluoxetine did not show significant neuroprotective effects on CA1 pyramidal cells 4 days after ischemia/reperfusion, while the treatment with 40 mg/kg fluoxetine in ischemic animals showed about 77% neuronal survival rate compared to the control group. The treatment of 40 mg/kg fluoxetine in ischemic animals enhanced significantly BDNF, catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase-1 (SOD1) immunoreactivity in the CA1 region compared to those in the saline-treated group 4 days after ischemia/reperfusion. In addition, the treatment of fluoxetine (10, 20, 40 mg/kg) significantly inhibited post-ischemic hyperactivity. In brief, treatment with fluoxetine protects neuronal damage after transient ischemia, and the neuroprotective effect of fluoxetine in an ischemic animal model may be related with the up-regulation of BDNF, CAT, GPX, and SOD1 expression.
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PMID:Effects of fluoxetine on ischemic cells and expressions in BDNF and some antioxidants in the gerbil hippocampal CA1 region induced by transient ischemia. 1732 94

The liver function and perfusion following brain death is mainly influenced by the sympathetic nerves and hormones. We examined the specific influence of surgical liver denervation on systemic and hepatic perfusion parameters, bowel ischemia and oxidative stress in hemodynamically stable BD and control (living donor [LD]) pigs. Brain death was induced in 8 pigs via saline infusion into the balloon of an epidural Tieman-catheter (1 mL/15 minutes) and compared to the control group (n = 6) over 4 hours. At 2 hours postoperatively, complete liver denervation was initiated. We analyzed systemic cardiocirculatory parameters (mean arterial pressure, aortic flow, bowel ischemia (endotoxin, and endotoxin-neutralizing capacity) and oxidative stress (total glutathione in erythrocytes [tGSH(E)]) and compared them to local/hepatic perfusion parameters (hepatic artery and portal venous flow, liver blood flow index, and microperfusion), local bowel ischemia (intramucosal pH [pHi] of stomach [pHi(S)]/colon[pHi(C)]), and liver oxidative stress (glutathione [rGSH(L), GSSG(L)]). Following brain death, the parameters including mean arterial pressure, aortic flow, pHi, endotoxin, and tGSH(E) showed no significant changes at 2 hours. Portal venous flow and microperfusion were decreased significantly and hepatic arterial buffer response was ineffective. Hepatic oxidative stress was increased in BD animals (decrease rGSH(L), increase GSSG(L)). Surgical denervation/manipulation increased portal venous flow significantly, hepatic arterial buffer response became effective, and stomach pHi decreased (BD and LD groups). Hepatic oxidative stress was reduced in the BD group (increase rGSH(L)/GSSG(L); P < 0.001) while it was increased in the LD group (decrease rGSH(L)/GSSG(L); P < 0.001). In conclusion, denervation reduces hepatic oxidative stress in BD only in contrast to the LD. The reciprocal effect of denervation depends on the state of neural activation and postulates a potential benefit of surgical denervation before organ harvesting in brain death.
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PMID:Distinct effects of surgical denervation on hepatic perfusion, bowel ischemia, and oxidative stress in brain dead and living donor porcine models. 1739 67

Cognitive deficits, including spatial memory impairment, are very common after ischemic stroke. Neurogenesis in the dentate gyrus (DG) contributes to forming spatial memory in the ischemic brain. Fluoxetine, a selective serotonin reuptake inhibitor, can enhance neurogenesis in the hippocampus in physiological situations and some neurological diseases. However, whether it has effects on ischemia-induced spatial cognitive impairment and hippocampal neurogenesis has not been determined. Here we report that fluoxetine treatment (10 mg kg(-1), i.p.) for 4 weeks promoted the survival of newborn cells in the ischemic hippocampus and, consequently, attenuated spatial memory impairment of mice after focal cerebral ischemia. Disrupting hippocampal neurogenesis blocked the beneficial effect of fluoxetine on ischemia-induced spatial cognitive impairment. These results suggest that chronic fluoxetine treatment benefits spatial cognitive function recovery following ischemic insult, and the improved cognitive function is associated with enhanced newborn cell survival in the hippocampus. Our results raise the possibility that fluoxetine can be used as a drug to treat poststroke spatial cognitive deficits.
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PMID:Chronic fluoxetine treatment improves ischemia-induced spatial cognitive deficits through increasing hippocampal neurogenesis after stroke. 1871 44

Changes in liver microcirculation are considered essential in assessing ischemia-reperfusion injury, which in turn has an impact on liver graft function and outcome following liver transplantation (LTx). The aim of this study was to introduce dynamic magnetic resonance imaging (dMRI) as a new technique for overall quantification of hepatic microcirculation and compare it to perfusion measured by laser Doppler flowmetry (LDF; hepatic artery/portal vein) and thermal diffusion (TD). The study included 3 groups, measuring hepatic blood flow and microcirculation with the help of TD, LDF, and dMRI. In group I (9 landrace pigs; 26 +/- 5 kg), the native liver before and after partial portal occlusion was studied; in group II (6 landrace pigs; 25.5 +/- 4.4 kg), the liver 24 hours after LTx was studied; and in group III (14 patients), the liver on days 4 to 7 following LTx was studied. A close correlation was found between dMRI measurements and TD (r = 0.7-0.9, P < 0.01) in 4 defined regions of interest. Portal blood flow and partial occlusion of the portal vein were accurately detected by LDF flowmetry and correlated well with dMRI (r = 0.95, P < 0.01). In the clinical setting, representative TD measurements in segment 4b of the transplanted liver correlated well with dMRI analysis in other segments. Quantification of the portal blood flow and imaging of the whole liver could be performed simultaneously by dMRI. In conclusion, dMRI has been proved to be a sensitive modality for the quantification of liver microcirculation and hepatic blood flow in experimental and clinical LTx. It allows for a synchronous, noninvasive assessment of macrocirculation and microcirculation of the liver and could become a valuable diagnostic tool in advanced liver surgery and transplantation.
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PMID:Quantification of liver perfusion by dynamic magnetic resonance imaging: experimental evaluation and clinical pilot study. 1956 2


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