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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pharmacogenomics is defined to identify the genes which are involved in determining the responsiveness and to distinguish responders and non-responders to a given drug. Genome sequencing, transcriptome and proteome analysis are of particular significance in pharmacogenomics. Sequencing is used to locate polymorphisms, and monitoring of gene expression can provide clue about the genomic response to disease and treatment. The transcriptome analysis can be done by methods of random cDNA sequencing (expressed sequence tag project, body map project, serial analysis of gene expression, et al), mRNA display (differential display, fluorescent differential display, RNA arbitraly primed PCR, molecular indexing, gene expression fingerprinting, et al) and differential hybridization(cDNA high density filter, cDNA microarray, oligomicrochip, et al). We used transcriptome analysis to identify therapeutic target genes by studying change of gene expression in animal models of cerebral vasospasm (1) and of hypoxia/ischemia and found novel drug target candidates through this pharmacogenomic strategy (2). We found remarkable up-regulation of heme oxygenase-1(HO-1) mRNA in the basilar artery and it might be closely related to the occurrence of delayed vasospasm after subarachnoid hemorrhage. In this report, we clearly demonstrate that intrathecal administration of antisense HO-1 oligodeoxynucleotide aggravates vasospasm, suggesting HO-1 gene induction has spasmolytic effects. Furthermore, we found the protective effects of HO-1 gene induction by endogenous or clinical compounds in cerebral vasospasm. Therapeutic gene induction of HO-1 could be a novel strategy for the prevention and treatment of Hb-induced pathologic conditions including delayed cerebral vasospasm. Our results suggest that the pharmacogenomic transcriptome analysis and pharmainformatics has the potential for strategy to define novel drug targets in various diseases (3). (1) J Clin Invest 104: 59-66, 1999. (2) J Biol Chem 276: 19921-19928, 2001. (3) J Cardiovasc Pharm 36: S1-S4, 2000.
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PMID:[Pharmacogenomics and pharmainformatics]. 1180 38

The purpose of this study was to critically analyze the effectiveness of two tools used by nurses to assess neurological status of individuals at risk of developing cerebral vasospasm following aneurysmal subarachnoid hemorrhage due to aneurysm rupture. Early detection of vasospasm provides an opportunity for prompt treatment so that further ischemia or infarction can be prevented. We hypothesized that the National Institutes of Health Stroke Scale would detect symptomatic vasospasm earlier than the standard neurological record currently used in the practice setting of a tertiary care teaching hospital. Thirty participants were entered into the study, and a differential diagnostic process identified 15 with symptomatic vasospasm. Quantitative prospective and retrospective analysis showed that there was no statistical difference between the two scales in early detection of vasospasm. This finding may partially be explained by the clinical similarities between the vasospasm and nonvasospasm groups and by the challenges experienced by nurses in administering the stroke scale. Clinically relevant observations suggested the stroke scale was more effective in the assessment of focal symptoms. Qualitative content analysis of nursing notes also provided insight into clinical findings not captured on either scale regarding generalized changes such as restlessness, impulsiveness, and unusual behavior. This study demonstrates the need to develop a more appropriate tool for early detection of vasospasm.
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PMID:Comparison of a standard neurological tool with a stroke scale for detecting symptomatic cerebral vasospasm. 1250 15

Delayed cerebral vasospasm has a major impact on the outcome of subarachnoid hemorrhage. Two important candidates to cause the arterial spasm are the red blood cell product oxyhemoglobin and the vasoconstrictor endothelin-1, although oxyhemoglobin alone is not sufficient to induce cerebral ischemia and endothelin-1 leads to ischemia only at relatively high concentrations. In this study, we demonstrated that the combination of oxyhemoglobin and endothelin-1 triggered spreading neuronal activation in rat cortex in vivo. In contrast with the expected transient increase of regional cerebral blood flow during spreading depression, however, cerebral blood flow decreased profoundly and was long-lasting, paralleled by delayed repolarization of the steady (direct current) potential. These changes are characteristic of cortical spreading ischemia. Replacing oxyhemoglobin for the nitric oxide synthase inhibitor Nomega-nitro-L-arginine mimicked these effects, implicating nitric oxide scavenging functions of oxyhemoglobin. Furthermore, the effect of endothelin-1 was related to a reduction of Na(+)-/K(+)-ATPase activity rather than solely to its vasoconstrictive properties. In conclusion, the threshold concentration of endothelin-1 that induces cerebral ischemia is profoundly reduced via a complex interaction between the neuronal/astroglial network and the cortical microcirculation if nitric oxide availability declines. The results may have implications for the understanding of subarachnoid hemorrhage-related cortical lesions.
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PMID:Ischemia triggered by spreading neuronal activation is induced by endothelin-1 and hemoglobin in the subarachnoid space. 1459 48

To date, the pharmacologic approach to cerebral vasospasm and ischemia has been hampered in part by an inability to attain sufficiently high concentrations of drugs in the cerebrospinal fluid (CSF). To overcome this limitation of current drug therapy, we have developed a sustained-release preparation of the protein kinase inhibitor fasudil. Experimental cerebral vasospasm in rats and dogs was induced by double injection of autologous arterial blood into the cisterna magna. Focal cerebral ischemia in rats was induced by middle cerebral artery occlusion using an intraluminal suture technique. A single intrathecal injection of liposomal fasudil can maintain a therapeutic the drug concentration in the CSF due to the sustained-release property of liposomes, significantly decreasing intact size of acute ischemia and decreasing vasoconstriction of the basilar artery in cerebral vasospasm. This novel approach for the treatment of cerebral vasospasm and ischemia may have significant potential for use in the clinical setting.
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PMID:[Development of drug delivery system for intrathecal administration and its therapeutic effect on cerebral vasospasm and ischemia]. 1529 23

Delayed cerebral ischemia as a result of cerebral vasospasm is the most common cause of death and disability after aneurysmal subarachnoid hemorrhage (SAH). It leads to death or permanent neurologic deficits in over 17-40% of SAH patients. The initial and main symptom of cerebral vasospasm is diffuse headache and may be accompanied with a slight increase in discomfort from neck stiffness and fever. The clinical diagnosis of cerebral vasospasm is made when the patient experiences an altered level of consciousness or a new focal neurologic deficit. There has been a great progress in identifying the patients at risk, putative mechanisms, and possible treatment options for cerebral vasospasm. However, the problem is by no means solved, mainly due to a limited understanding of the pathologic mechanisms of this complex disease. The iatrogenic factors that can increase the risk of cerebral vasospasm include prolongation of the subarachnoid clot by antifibrinolytic drugs, hypotension, inappropriate treatment of hyponatremia, hypovolemia, hyperthermia and increased intracranial pressure. Nimodipine has been shown to improve neurologic outcome and decrease the incidence of cerebral vasospasm. Triple H therapy is a treatment designed to augment cerebral blood flow for patient with cerebral vasospasm. Hypervolemic hypertension is induced with intravenous volume expansion with crystalloid or colloid to increase cardiac output and raise blood pressure. However, small randomized trials showed no clear benefit. Recently, balloon and chemical angioplasty with superselective intra-arterial injection of vasodilators has emerged as the primary intervention for treating medically refractory ischemia from cerebral vasospasm and in many centers is being used as a first-line treatment or even prophylactically. In addition, promising new treatments for cerebral vasospasm or its ischemic complications include magnesium sulfate, fasudil hydrochloride, tirilazad mesylate, erythropoietin, and induced hypothermia; however, all still need further clinical trials. Newly recognized mediators of cerebral vasospasm after SAH include endothelium-derived mediators, vascular smooth-muscle-derived mediators, proinflammatory mediators involved in blood-brain barrier disruption, cytokines and adhesion molecules, stress-induced gene activation, and platelet-derived growth factors. Moreover, observations in the laboratory have, in many circumstances, matched those of reported small series. Larger, prospective, randomized trials are needed to verify several hypotheses of molecular pathophysiology and clinical treatment regimens.
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PMID:Treatment of cerebral vasospasm after subarachnoid hemorrhage--a review. 1567 31

Subarachnoid hemorrhage from a ruptured aneurysm is a subset of stroke. The young age (median 55 years) and poor outcome (50% of patients die; 30% of survivors remain dependent) explain why in the population the loss of productive life years from aneurysmal subarachnoid hemorrhage (SAH) is as large as that from brain infarcts, the most common type of stroke. Ischemia plays an important role in the pathophysiological process after SAH. A period of global cerebral ischemia firstly occurs in the acute phase, immediately after rupture of the aneurysm, due to acute vasoconstriction and elevated intracranial pressure, which leads to a drop in perfusion pressure. This is quite distinct from the secondly, delayed cerebral ischemia (DCI), which is focal or multi-focal. DCI usually occurs between 4 and 10 days after the initial bleeding, has a gradual onset and is multi-focal, and is an important cause of death and dependency after SAH. The interval between the bleeding and the onset of ischemia provides an opportunity for preventive treatment. Magnesium is readily available, inexpensive and has a well-established clinical profile in obstetrical and cardiovascular practice. It is beneficial in the treatment of eclampsia, a disease with a pathophysiology comparable to DCI after subarachnoid hemorrhage. Neuroprotective mechanisms of magnesium include inhibition of the release of excitatory amino-acids and blockade of the NMDA-glutamate receptor. Magnesium is also a non-competitive antagonist of voltage dependent calcium channels, has cerebrovascular dilatory activity and is an important co-factor of cellular ATPases, including the Na/K-ATPase. Magnesium can reverse delayed cerebral vasospasm and reduces the extent of acute ischemic cerebral lesions after experimental subarachnoid hemorrhage in rats. In this article we discuss the neuroprotective potency of magnesium in SAH by describing the pathophysiology of ischaemia after SAH and the many ways magnesium may interfere with this.
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PMID:Potentials of magnesium treatment in subarachnoid haemorrhage. 1572 6

Aneurysmal subarachnoid hemorrhage (SAH) remains a very prevalent challenge in neurosurgery associated with a high morbidity and mortality due to the lack of specific treatment modalities. The prognosis of SAH patients depends primarily on three factors: (i) the severity of the initial bleed, (ii) the endovascular or neurosurgical procedure to occlude the aneurysm and (iii) the occurrence of late sequelae, namely delayed ischemic neurological deficits due to cerebral vasospasm. While neurosurgeons and interventionalists have put significant efforts in minimizing periprocedural complications and a multitude of investigators have been devoted to the research on chronic vasospasm, the acute phase of SAH has not been studied in comparable detail. In various experimental studies during the past decade, hypothermia has been shown to reduce neuronal damage after ischemia, traumatic brain injury and other cerebrovascular diseases. Clinically, only some of these encouraging results could be reproduced. This review analyses results of studies on the effects of hypothermia on SAH with special respect to the acute phase in an experimental setting. Based on the available data, some considerations for the application of mild to moderate hypothermia in patients with subarachnoid hemorrhage are given.
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PMID:Hypothermia as a neuroprotective strategy in subarachnoid hemorrhage: a pathophysiological review focusing on the acute phase. 1584 6

Vascular smooth muscle is the contractile component of arteries and veins. The control of contraction and relaxation is dependent upon intracellular and extracellular signals. Abnormal contractions can cause and or contribute to pathology such as hypertension, ischemia and infarction. In this review, we address the vascular pathogenesis associated with hypertension and subarachnoid hemorrhage induced cerebral vasospasm. Hypertension is a multifactorial disease with many causes and a profound impact on the cardiovascular system, whereas subarachnoid hemorrhage induced cerebral vasospasm is a pathological vasoconstriction often causing infarction that is thought to be 'caused' by a factor or factors in the CSF following the hemorrhage. However, the mechanism by which the vessels are constricted is unknown. Although the causes for these two pathological vasoconstrictions remain to be determined, we conclude that the common denominator is that these contractile changes result in pathology with devastating consequences to human health.
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PMID:Vascular smooth muscle function: The physiology and pathology of vasoconstriction. 1592 23

Rovelizumab is a humanized monoclonal leukointegrin antibody under development by ICOS as a potential treatment for multiple sclerosis (MS), hemorrhagic shock, myocardial infarction (MI) and stroke. ICOS announced the commencement of phase II studies in MS patients experiencing acute exacerbations in January 1997; a randomized, double-blind, placebo-controlled phase III trial for acute ischemic stroke, to involve 800 patients, was initiated in January 1999 [312467,313014]. The compound is also undergoing preclinical investigation for cerebral vasospasm, head trauma, kidney transplantation and restenosis [346437]. In September 1999, results from a phase II clinical trial in 45 patients suffering from acute exacerbations of MS were presented at the Warburg Dillion Read Global Life Sciences Conference (New York). The study was designed to evaluate the safety and efficacy of four weekly doses of rovelizumab, as compared to placebo. Rovelizumab was shown to be safe, but demonstrated no clinical benefit for the recovery of neurological functioning [341638]. In February 1997, ICOS announced the initiation of a phase II trial in MI. The placebo-controlled trial is being coordinated by the Mayo Physician Alliance for Cardiovascular Trials and will evaluate safety, pharmacokinetics and infarct size in 60 patients [234046,264363]. Patient enrollment for this, and an open label phase II trial in trauma-induced hemorrhagic shock, was completed in September 1997 [264363]. An expanded shock trial in 150 trauma patients, is expected to complete enrollment by the end of 1998 [296831]. An expanded trial for MI was also planned [264363]. The company is to evaluate rovelizumab in patients with ischemic stroke, and a double-blind, dose-escalating, placebo-controlled phase II trial has been initiated at several centers in the US [264363]. A patient population of 48 was tested, with patient dosing occurring within 12 h of stroke onset symptoms. There was no significant difference in SAEs between rovelizumab and placebo treatment, and no immunogenicity was observed [315799]. Neuroprotection was observed in a rabbit model of focal ischemia, with greatest reduction in infarct noted in the cortical areas of the brain. Neutrophil infiltration to ischemic brain parenchyma was reduced by 90% [315799]. Rovelizumab is a monoclonal antibody directed against the CD11/CD18 cell adhesion proteins. By binding to these receptors, rovelizumab prevents the migration and adhesion of neutrophils in the central nervous system, which may cause brain inflammation and neuronal loss [167725]. Rovelizumab binds to all four known leukointegrin receptors, blocking neutrophil adhesion and binding to ICAMs [307344]. ICOS collaborated with the University of Washington on the preclinical development of this compound [175193].
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PMID:Rovelizumab (ICOS Corp). 1610 Jul

Upregulation of endothelin B (ET(B)) and 5-hydroxytryptamine 1B (5-HT(1B)) receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ET(B) and 5-HT(1B) receptor upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ET(A) and ET(B) receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1 receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ET(B) and 5-HT(1B) receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH.
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PMID:ERK1/2 inhibition attenuates cerebral blood flow reduction and abolishes ET(B) and 5-HT(1B) receptor upregulation after subarachnoid hemorrhage in rat. 1625 86


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