Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0599766 (functional recovery)
 13,441 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of diltiazem and/or desferrioxamine to enhance the recovery of cardiac contractile function during reperfusion after prolonged hypothermic storage was assessed. Isolated rat hearts were arrested with St. Thomas' Hospital Cardioplegic Solution and stored for 10 h at 4 degrees C. Reperfusion in the Langendorff mode was initially carried out with crystalloid perfusate with or without added diltiazem (0.5 mumol/l) and/or desferrioxamine (15, 50, 100, 150 or 250 mumol/l). After 15 min the drugs were discontinued and the hearts were perfused for a further 45 min. Diltiazem reduced leakage of creatine (CK) kinase during the first 15 min of reperfusion from 102 +/- 8 IU/15 min/g dry wt to 67 +/- 9 IU/15 min/g dry wt (P less than 0.05). However, during the subsequent period of diltiazem-free perfusion, CK leakage was similar to control values (131 +/- 24 vs 142 +/- 34 IU/45 min/g dry wt, respectively). After 1 h of reperfusion there was no significant difference in total CK leakage between the diltiazem and the control groups (198 +/- 32 vs 244 +/- 39 IU/60 min/g dry wt, respectively). Desferrioxamine had no effect on CK leakage at any of the doses studied. Diltiazem significantly reduced leakage of enzyme during the initial reperfusion phase when combined with desferrioxamine; however, as with diltiazem alone, this protection was lost after the drug was withdrawn. Post-ischemic contents of adenosine triphosphate and creatine phosphate were similar in all groups as was the final recovery of function, as assessed by left ventricular developed pressure at an end-diastolic pressure of 5 mmHg. In conclusion, neither diltiazem nor desferrioxamine nor both together could be shown to confer benefit during reperfusion after long-term storage.
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PMID:Diltiazem and/or desferrioxamine administered at the time of reperfusion fail to improve post-ischemic recovery in the isolated rat heart after long-term hypothermic storage. 228 82

This study tests the hypothesis that an iron chelator, deferoxamine, can reduce oxygen-mediated myocardial injury and avoid myocardial dysfunction after cardiopulmonary bypass by its action on the iron-catalyzed Haber-Weiss pathway. Twenty-one immature 2- to 3-week-old piglets were placed on cardiopulmonary bypass for 120 minutes, and five piglets served as biochemical controls without cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (cardiopulmonary bypass control). Sixteen others became hypoxemic while undergoing cardiopulmonary bypass for 60 minutes by lowering oxygen tension to about 25 mm Hg, followed by reoxygenation at oxygen tension about 400 mm Hg for 60 minutes. Oxygen delivery was maintained during hypoxemia by increasing cardiopulmonary bypass flow and hematocrit level. In seven piglets deferoxamine (50 mg/kg total dose) was given both intravenously just before reoxygenation and by a bolus injection (5 mg/kg) into the cardiopulmonary bypass circuit; nine others were not treated (no therapy). Myocardial function after cardiopulmonary bypass was evaluated form end-systolic elastance (conductance catheter) and Starling curve analysis. Myocardial conjugated diene production and creatine kinase leakage were assessed as biochemical markers of injury, and antioxidant reserve capacity was determined by measuring malondialdehyde in postcardiopulmonary bypass myocardium incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant or functional damage. Conversely, reoxygenation (no therapy) raised myocardial conjugated diene levels and creatine kinase production (conjugated diene: 3.5 +/- 0.7 absorbance 233 nm/min/100 g, creatine kinase: 8.5 +/- 1.5 U/min/100 g; p < 0.05 versus cardiopulmonary bypass control), reduced antioxidant reserve capacity (malondialdehyde: 1115 +/- 60 nmol/g protein at 4 mmol/L t-butylhydroperoxide; p < 0.05 versus control), and produced severe post-bypass dysfunction (end-systolic elastance recovered only 39% +/- 7%, p < 0.05 versus cardiopulmonary bypass control). Deferoxamine avoided conjugated diene production and creatine kinase release and retained normal antioxidant reserve, and functional recovery was complete (95% +/- 11%, p < 0.05 versus no treatment). These findings show that iron-catalyzed oxidants may contribute to a reoxygenation injury and imply that deferoxamine may be used to surgical advantage.
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PMID:Studies of hypoxemic/reoxygenation injury: without aortic clamping. IV. Role of the iron-catalyzed pathway: deferoxamine. 747 70

Deferoxamine (DFO) was granted orphan drug status for the treatment of traumatic spinal cord injury but its neuroprotective mechanism is not well understood. We therefore investigated the mode of action of DFO in serum-starved and/or iron-stressed cultures of rat dorsal root ganglion (DRG) cells. We probed for redox signaling by determining hemeoxygenase-1 activity and by measuring expression of intracellular iron metabolism-related proteins under pro-oxidative conditions. We also employed DNA microarrays to better understand the genomic response of DRG cultures to treatment with DFO thereby enabling the generation of hypotheses. Essentially, DFO treatment resulted in outgrowth of neurofilament 200-positive neurites and induction of synapse formation as determined by immunoblotting, transmission electron microscopy and immunofluorescence confocal microscopy. Furthermore, DFO treatment of DRG cell cultures activated neuroprotective and antioxidative programs such as matrix metallopeptidase 2 and apolipoprotein D to promote neurite regeneration. Indeed, DFO reduced markedly reactive oxygen species formation, increased the expression of hemeoxygenase-1 and improved iron management through regulation of transferrin receptor and ferritin. We propose DFO treatment of DRG cell cultures to completely abolish the oxidative effect of ferrous iron (Fe(2+)). Taken collectively, DFO reduced oxidative stress and induced synthesis of neuroprotective and antioxidative molecules to foster nerve repair and functional recovery. Our findings help to better understand the therapeutic benefit of DFO in the treatment of spinal cord injury.
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PMID:Deferoxamine-induced neurite outgrowth and synapse formation in postnatal rat dorsal root ganglion (DRG) cell cultures. 1958 Oct 22

Deferoxamine (DFO) is a widely used drug for the treatment of iron-overload-related diseases in the clinic. However, its inherent shortcomings, such as a short plasma half-life and cytotoxicity, need to be addressed to widen its clinical utility. In this study, PEGylated DFO was first synthesized, and its chemical structure was characterized, and then in vitro and in vivo studies were performed. The metabolism assay showed that the stability of the PEGylated DFO was significantly improved, with a half-life 20 times greater than DFO. Furthermore, the PEGylated DFO exhibited significantly lower cytotoxicity compared with DFO. Additionally, the hemocompatibility assay showed that the PEGylated DFO had no significant effect on the coagulation system, red blood cells, complement, and platelets. In vivo studies indicated that PEGylated DFO was capable of reducing the iron accumulation, degeneration of neurons, and promotion of functional recovery. Taken together, PEGylated DFO improved stability, cytotoxicity, and iron-overload in an experimental stroke model in rats, making it a promising therapy for treating iron-overload conditions in the clinic.
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PMID:PEGylation of Deferoxamine for Improving the Stability, Cytotoxicity, and Iron-Overload in an Experimental Stroke Model in Rats. 3310 69