Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of a potent adenosine deaminase inhibitor, deoxycoformycin, on purine and amino acid neuro-transmitter release from the ischemic rat cerebral cortex were studied with the cortical cup technique. Cerebral ischemia (20 min) was elicited by four-vessel occlusion. Purine and amino acid releases were compared from control ischemic animals and deoxycoformycin-pretreated ischemic rats. Ischemia enhanced the release of glutamate, aspartate, and gamma-aminobutyric acid into cortical perfusates. The levels of adenosine, inosine, hypoxanthine, and xanthine in the same perfusates were also elevated during and following ischemia. Deoxycoformycin (500 micrograms/kg) enhanced ischemia-evoked release of adenosine, indicating a marked rise in the adenosine content of the interstitial fluid of the cerebral cortex. Inosine, hypoxanthine, and xanthine levels were depressed by deoxycoformycin. Deoxycoformycin pretreatment failed to alter the pattern of amino acid neurotransmitter release from the cerebral cortex in comparison with that observed in control ischemic animals. The failure of deoxycoformycin to attenuate amino acid neurotransmitter release, even though it markedly enhanced adenosine levels in the extracellular space, implies that the amino acid release during ischemia occurs via an adenosine-insensitive mechanism. Inhibition of excitotoxic amino acid release is unlikely to be responsible for the cerebroprotective actions of deoxycoformycin in the ischemic brain.
 ...
PMID:Brain adenosine and transmitter amino acid release from the ischemic rat cerebral cortex: effects of the adenosine deaminase inhibitor deoxycoformycin. 167 Oct 90

Deoxycoformycin, a potent and specific adenosine deaminase antagonist, reduced ischemic hippocampal damage and the associated hypermotility in Mongolian gerbils. Cerebral ischemia was induced by a bilateral 5 min occlusion of the carotid arteries. Deoxycoformycin (500 micrograms/kg IP), administered 15 min prior to ischemia, prevented the increase in locomotor activity normally observed with this model and significantly reduced the ischemia-induced damage to CA1 hippocampal neurons. The results suggest that deoxycoformycin may be useful in the prevention of brain damage due to cerebral ischemia.
 ...
PMID:Deoxycoformycin antagonizes ischemia-induced neuronal degeneration. 278 31

The effects of the adenosine deaminase inhibitor, deoxycoformycin, on purine release from the rat cerebral cortex were studied with the cortical cup technique. Deoxycoformycin (5 and 500 micrograms/kg i.v.) enhanced the hypoxia/ischemia-evoked release of adenosine from the cerebral cortex, indicating a marked rise in the adenosine content of interstitial fluid in the cerebral cortex. Inosine and hypoxanthine release were attenuated at the higher dose of deoxycoformycin. Uric acid release into the cortical perfusates was enhanced at the higher dose level. These results demonstrate that low doses of deoxycoformycin can be used to elevate interstitial levels of adenosine in the brain during hypoxia, and to depress the formation of some of its metabolites. The elevation of hypoxia/ischemia-evoked adenosine levels can account for the previously reported potentiation of hypoxia-evoked increases in rat cerebral blood flow after deoxycoformycin administration. The potential therapeutic utility of these findings is discussed.
 ...
PMID:Effects of deoxycoformycin on adenosine, inosine, hypoxanthine, xanthine, and uric acid release from the hypoxemic rat cerebral cortex. 326 16

Pentostatin (2-deoxycoformycin) is a potent inhibitor of adenosine deaminase and has been demonstrated to augment endogenous adenosine levels during regional and global myocardial ischemia. Based on the rationale that increasing endogenous adenosine during ischemia may be cardioprotective, the objective of this study was to determine if adenosine deaminase inhibition with pentostatin could improve postischemic contractile dysfunction (stunning) in open-chest anesthetized dogs. All animals underwent 15 min of coronary occlusion followed by 3 h of reperfusion preceded by an intravenous bolus of either 0.2 mg/kg of pentostatin (n = 8) or saline (n = 7). Sonomicrometers were placed in the ischemic area and were used to measure systolic wall thickening before, during, and after occlusion of the left anterior descending artery. Myocardial blood flow was measured with tracer labeled microspheres at baseline, 10 min of occlusion and at 1 h of reperfusion. Both groups were equally dyskinetic during occlusion (-21 +/- 5% of baseline thickening in the controls and -28 +/- 8% in the pentostatin group). The pentostatin group, however, demonstrated better contractile function at all time points during reperfusion, which was significantly different from the control group at 3 h of reperfusion. The improvement in regional function in the pentostatin group was not due to significant disparities in hemodynamic variables, size of the region at risk, or in collateral blood flow. These results indicate that pentostatin can ameliorate the severity of myocardial stunning, an effect we propose is due to increasing endogenous levels of adenosine during the ischemic interval. Although significant improvement was detected with pentostatin, the improvement was modest compared to controls, suggesting that the utility of inhibiting adenosine deaminase to modify regional mechanical stunning is limited.
 ...
PMID:Effect of adenosine deaminase inhibition with pentostatin on myocardial stunning in dogs. 764 20

The effect of 2-chloroadenosine, stable adenosine analog, and deoxycoformycin, adenosine deaminase inhibitor on brain ATP level and Na-K ATPase activity in ischemia were studied. The brain ATP level was increased after we administered both 2-chloroadenosine and deoxycoformycin, but Na-K ATPase activity did not change after deoxycoformycin. The results suggest that 2-chloroadenosine treatment influenced both the ATP production and membrane permeability due to cerebral ischemia. Deoxycoformycin did not protect the membrane permeability, although it increased the ATP production.
 ...
PMID:The effects of 2-chloroadenosine and deoxycoformycin on the ATP level, Na-K ATPase activity in experimental brain ischemia of gerbil. 887 54

The effects of an adenosine deaminase inhibitor (deoxycoformycin, 500 mu g/kg) and of an inhibitor of nucleoside transport (propentofylline, 10 mg/kg) on adenosine and adenine nucleotide levels in the ischemic rat brain were investigated. The brains of the rats were microwaved before, at the end of a 20 min period of cerebral ischemia (4 vessel occlusion + hypotension), or after 5, 10, 45, and 90 min of reperfusion. Deoxycoformycin increased brain adenosine levels during both ischemia and the initial phases of reperfusion. AMP levels were elevated during ischemia and after 5 min of reperfusion. ATP levels were elevated above those in the non-treated animals after 10 and 45 min of reperfusion. ADP levels were elevated above the non-drug controls at 90 min. These increases in ATP, ADP and AMP resulted in significant increases in total adenylates during ischemia, and after 10 min and 90 min of reperfusion. Propentofylline administration resulted in enhanced AMP levels during ischemia but did not alter adenosine or adenine nucleotide levels during reperfusion in comparison with non-treated controls.
 ...
PMID:Effects of an inhibitor of adenosine deaminase, deoxycoformycin, and of nucleoside transport, propentofylline, on post-ischemic recovery of adenine nucleotides in rat brain. 913 41

In order to examine the relationship between local adenosine concentrations before, during, and after ischemia and the extent of ischemic myocardial damage, measurements of interstitial fluid (ISF) nucleosides were made using microdialysis probes implanted in the ischemic region of isoflurane anesthetized Micropigs undergoing 60' coronary artery occlusion (CAO) and 3 h of reperfusion (REP). Nucleoside concentrations in the dialysate collected from the microdialysis probes were used as an index of ISF levels. Dialysate nucleoside concentrations (ADO, inosine and hypoxanthine), myocardial infarct size, and myocardial blood flow (MBF) were determined in control animals (n = 6), animals preconditioned with a single 10' cycle of CAO and REP (PC, n = 6), and those treated with the adenosine deaminase inhibitor pentostatin (n = 6, 0.2 mg/Kg i.v. 30' prior to CAO). The brief PC occlusion resulted in a transient but significant increase in dialysate ADO (6.7 +/- 1.8 microM vs. 0.67 +/- 0.1 microM at baseline). Pentostatin administration had no significant effect on either dialysate nucleosides or MBF at baseline. During the 60' CAO, dialysate ADO increased in control animals. In PC animals, however, dialysate ADO during CAO was lower than control. Pretreatment with pentostatin resulted in a six-fold augmentation in dialysate ADO during the 60 min CAO when compared to the control values (110.62 +/- 30.2 microM vs. 16.31 +/- 2.1 microM at 60 min of ischemia). Pentostatin also resulted in a significant reduction in the accumulation of inosine and hypoxanthine, indicating inhibition of adenosine deaminase activity. There were no significant differences in MBF between groups at any time point. Following 3 h REP, infarct size was 35.4 +/- 5.5%, 8.1 +/- 1.5% and 8.3 +/- 1.8% of the region at risk in control, PC, and pentostatin groups, respectively. These data suggest that marked increase in ISF ADO during CAO, may be as effective in reducing INF as a modest increase in ISF ADO prior to prolonged CAO.
 ...
PMID:Effects of ischemia, preconditioning, and adenosine deaminase inhibition on interstitial adenosine levels and infarct size. 934 31

Pentostatin (2prime prime or minute-deoxycoformycin, dCF) is a product of the fermentation of Streptomyces antibioticus. It is a tight-binding inhibitor of adenosine deaminase (ADA), an enzyme essential in cellular metabolism of purines. Children with congenital absence of ADA suffer from atrophy of lymphoid tissues and severe combined immune deficiency (SCID) syndrome. It was speculated that pentostatin would be lymphocytotoxic, and this proved to be the case, promoting its investigation in lymphoid neoplasms. It was anticipated that pentostatin would be most active in neoplasms with high intracellular concentrations of ADA---e.g., acute lymphocytic leukemia (ALL), particularly its T cell variety. Although pentostatin proved to be active in ALL, large doses were required and toxic effects outweighted therapeutic benefits. By contrast, pentostatin proved to be exceptionally active in hairy cell leukemia (HCL), a B cell neoplasm with low intracellular concentrations of ADA. Pentostatin has since been shown to possess activity in chronic lymphocytic leukemia, prolymphocytic leukemia, cutaneous T cell lymphomas, adult T cell lymphoma-leukemia, and low-grade non-Hodgkin's lymphomas. It potentiates the activity of vidarabine against viruses and against the cells of acute myeloid leukemia. Pentostatin is inactive in melanoma and renal carcinoma, but has not been adequately evaluated in other solid tumors. The toxic effects of pentostatin include renal failure, central nervous system (CNS) depression, immunosuppression, keratoconjunctivitis, and opportunistic infections. In the absence of pre-existing bone marrow compromise, pentostatin produces only mild myelosuppression. Aside from its use as an antineoplastic agent, pentostatin has potential applications as an immunosuppresive drug, as an antiviral agent, as an antimalarial compound, and in the protection of cells of the CNS from damage induced by ischemia and anoxia.
 ...
PMID:Pentostatin (2prime prime or minute-Deoxycoformycin): Clinical Pharmacology, Role In Cancer Chemotherapy, and Future Prospects. 1184 52

Pentostatin (2'-deoxycoformycin, dCF) is a purine nucleoside analog and a product of the fermentation of Streptomyces antibioticus. It is a tight-binding inhibitor of adenosine deaminase (ADA), an enzyme essential in the cellular metabolism of purines. Children with congenital absence of ADA suffer from atrophy of lymphoid tissues and severe combined immune deficiency (SCID) syndrome. It was hypothesized that pentostatin would be lymphocytotoxic and this proved to be true; this finding prompted its investigation in lymphoid neoplasms. It was anticipated that pentostatin would be most active in neoplasms with high intracellular concentrations of ADA, e.g. acute lymphocytic leukemia (ALL), particularly of the T-cell variety. Although pentostatin proved to be active in ALL, large doses were required and major toxic effects outweighed therapeutic benefits. By contrast, pentostatin proved to be exceptionally active in hairy cell leukemia (HCL), a B-cell neoplasm with low intracellular concentrations of ADA. Pentostatin has since been shown to possess activity in chronic lymphocytic leukemia, prolymphocytic leukemia, cutaneous T-cell lymphomas, adult T-cell lymphoma-leukemia, and low grade non-Hodgkin's lymphomas. It potentiates the activity of vidarabine against viruses and against the cells of acute myeloid leukemia. Pentostatin is inactive in melanoma and renal carcinoma, but has not been adequately evaluated in other solid tumors. The toxic effects of pentostatin include renal failure, central nervous system (CNS) depression, immunosuppresion, keratoconjunctivitis, and opportunistic infections. In the absence of pre-existing bone marrow compromise, pentostatin produces only mild myelosuppression. Aside from its use as an antineoplastic agent, pentostatin has potential applications as an immunosuppressive drug, as an antiviral agent, as an antimalarial compound, and in the protection of cells of the CNS from damage induced by ischemia and anoxia. Clinical studies with pentostatin are ongoing, and its roles in the management of neoplastic and non-neoplastic diseases have yet to be fully defined.
 ...
PMID:Deoxycoformycin (pentostatin): clinical pharmacology, role in the chemotherapy of cancer, and use in other diseases. 1465 Dec 24