Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ticlopidine is a new prototype antiplatelet drug chemically unrelated to currently available agents. It causes an alteration in platelet membrane reactivity to a variety of aggregating stimuli and a marked prolongation of bleeding time, the mechanism of which remains unclear. Two major phase III multicenter trials, the ticlopidine-aspirin stroke study (TASS) and the Canadian-American ticlopidine study (CATS) reported that the agent may reduce the occurrence of stroke, myocardial infarction, or vascular death in patients of both sexes who have had recent cerebral ischemia. Ticlopidine has been well tolerated in preliminary studies, with the most commonly described adverse effects being rash and gastrointestinal complaints. The most important adverse effect is neutropenia, which was reported in both TASS and CATS, approximating a frequency of 0.9% and 0.8%, respectively. Ticlopidine holds considerable promise as adjunctive therapy in selected patients.
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PMID:Ticlopidine: a new antiplatelet agent for cerebrovascular disease. 192 14

The most significant impact on cerebral infarction comes from the primary prevention of the processes that lead to stroke in at-risk individuals prior to the development of symptoms. Antithrombotic therapy with warfarin or aspirin significantly reduces thromboembolic risk in non-valvular atrial fibrillation. The failure of primary preventive measures and the progression of disease is heralded by the development of cerebral or retinal ischaemic events; the majority of clinical trials investigating stroke prevention have targeted the secondary prevention of stroke in patients with ischaemic symptoms. A 25% risk reduction has been demonstrated with antiplatelet therapy. This was typically aspirin 1000 to 1300 mg/day, but more recently even lower doses have been beneficial, with lower rates of minor and major bleeding. Ticlopidine has demonstrated efficacy in the secondary prevention of stroke after transient ischaemic attacks and completed stroke, with a 2% risk of significant neutropenia. The benefits of carotid endarterectomy have been demonstrated in patients with symptomatic internal carotid artery stenosis involving 70 to 99% of the arterial diameter. Surgery is not indicated in patients with less than 30% internal carotid artery stenosis; 30 to 69% continues to be studied. When primary and secondary preventive measures have failed, strategies directed at managing acute focal cerebral ischaemia include re-establishing cerebral blood flow and limiting ischaemic neuronal injury. Advances in basic research that have identified components of the ischaemic cascade have been translated clinically into numerous clinical trials, each targeted to one or sometimes two steps in the hope of improving neuronal salvage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prophylaxis and treatment of stroke. The state of the art in 1993. 768 4

The involvement of neutrophils in the pathogenesis of cerebral ischemic injury in two rat models of focal ischemia was investigated. In Experiment I, a model of focal ischemia with partial reperfusion was used. Although significant and discrete ischemic damage within the neocortex was nearly maximal at 12 h postocclusion, no elevation in neutrophils was seen at this time point. Even after 21 h postocclusion, only a subtle increase in neutrophils within the ischemic tissue was observed. To further investigate the possible role of neutrophils in cerebral ischemia, the effect of cyclophosphamide-induced neutropenia was investigated (Experiment II). While a marked reduction (>98%) in systemic neutrophils was achieved in advance of and during the ischemic challenge, no reduction in the volume of ischemic damage was observed. In Experiment III, variations in the rat model of focal ischemia were made to produce a larger area of ischemic damage, as well as to permit complete reperfusion of blood to the affected cortex. While more neutrophils were seen in this variation of the model, very few were observed (< 1 per field) prior to the time that maximal ischemic damage had already occurred. Together, these experiments revealed that substantial brain necrosis occurred prior to the appearance of neutrophils, under conditions of partial, as well as complete, reperfusion. Moreover, at the time points when elevations in neutrophils were observed, no further increase in volume of ischemic damage was noted. Finally, pharmacologic removal of neutrophils prior to ischemia did not alter the size of the ischemic region. These data therefore fail to support the hypothesis that neutrophils play a general and essential role in infarct formation following focal brain ischemia and argue that further studies are required to more clearly elucidate the conditions under which neutrophils might participate in ischemic pathogenesis.
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PMID:Lack of evidence for neutrophil participation during infarct formation following focal cerebral ischemia in the rat. 865 22

Ticlopidine is a thienopyridine derivative which reduces the risk of reversible ischaemia and stroke in patients who have previously experienced a cerebral ischaemic episode. In comparison with aspirin, ticlopidine produced a significant reduction in the risk of stroke in a multicentre clinical trial involving more than 3000 patients with previous transient or persistent minor ischaemia, and was superior to placebo for the prevention of stroke recurrence in more than 1000 patients who had experienced a major thrombotic stroke. The cost-utility ratio for ticlopidine in comparison with aspirin was estimated to be $US31 200 to 55,000 per quality-adjusted life-year gained. Diarrhoea is the most common adverse event in ticlopidine recipients (20 to 22% incidence versus about 10% with placebo), although skin rash, nausea, dyspepsia, bleeding events, abnormal liver function and haematological disturbances were also observed in clinical trials. Severe neutropenia is the most serious event: this developed in 0.85% of patients receiving ticlopidine in 2 large clinical studies (n = 4098) but resolved after treatment withdrawal. Fatal neutropenia, although rare, has been reported in some patients receiving ticlopidine. Thus, ticlopidine is effective in reducing the risk of recurrent cerebral ischaemia and stroke. It appears to provide a gain over aspirin for the prevention of stroke after reversible ischaemia, particularly during the first year of treatment (when the risk of stroke is greatest), although further data on its absolute relative benefit would be useful. The extent to which ticlopidine is prescribed will probably depend on individual clinicians' perception of its risk/benefit and cost-effectiveness profiles. Ticlopidine is likely to be particularly useful for stroke prophylaxis in patients who do not tolerate aspirin or who have an ischaemic episode during aspirin treatment, and for the prevention of stroke recurrence in patients who have previously experienced a major stroke.
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PMID:Ticlopidine. A review of its pharmacology, clinical efficacy and tolerability in the prevention of cerebral ischaemia and stroke. 872 Jul 46

Neutrophils (PMN) accumulate and are associated with cerebrovascular disturbances after experimental traumatic or ischemic brain injury, and meningitis. We hypothesized that posttraumatic PMN accumulation in brain is mediated by the PMN adhesion receptor Mac-1 (CD11b/CD18). Anesthetized rats were randomized to receive 2 mg/kg intravenously of murine monoclonal antibody to rat Mac-1 (1-B6) or anti-Mac-1 F(ab)2' [1-B6F(ab)2'] fragment (Repligen Corp., Cambridge, MA). Control rats were treated with isotype matched control antibody. Rats were subjected to percussive trauma to the right parietal cortex 30 min after treatment. Rats were killed 24 h posttrauma, and PMN accumulation was assessed by myeloperoxidase (MPO) activity. The presence of 1-B6F(ab)2' bound to PMN in brain after trauma was assessed by immunohistochemistry. Complete blood cell counts were obtained before treatment and 24 h after trauma. Brain MPO activity was reduced by 43% in the 1-B6-treated rats vs. controls (0.31 +/- 0.09 vs 0.55 +/- 0.10 U/g, n = 6/group, p = 0.013) and by 34% in the 1-B6F(ab)2'-treated rats vs. controls (0.43 +/- 0.10 vs. 0.65 +/- 0.09 U/g, n = 6/group, p = 0.006). Systemic neutropenia developed in the 1-B6-treated rats (absolute PMN count decreased by 73% vs. baseline) but not in rats treated with 1-B6F(ab)2' (absolute PMN count increased by 26 and 25% vs. baseline in treated and controls, respectively). Immunohistochemical staining showed 1-B6F(ab)2' on the surface of infiltrated PMN 24 h after trauma. Mac-1 mediates posttraumatic PMN accumulation in brain. This accumulation can be attenuated by 34%, without reducing circulating PMN, using an anti-Mac-1 F(ab)2' fragment; however, some PMN coated with 1-B6F(ab)2' still infiltrate into traumatized tissue. These results are similar to those reported in models of cerebral ischemia, and suggest the participation of multiple PMN adhesion pathways after ischemic and traumatic brain injury.
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PMID:Antibodies against Mac-1 attenuate neutrophil accumulation after traumatic brain injury in rats. 883 1

Using a gerbil model of severe, temporary focal ischemia (3 h unilateral carotid occlusion), preliminary experiments identified an involvement of neutrophils in the reperfusion injury to the ischemic hemisphere. The present experiments were designed to (1) quantitate the temporal accumulation of neutrophils in the gerbil model, (2) determine if cyclophosphamide-induced neutropenia provided cytoprotection to the ischemic hemisphere, and (3) attempt to correlate the cytoprotective efficacy of tirilazad mesylate with possible effects on postischemic neutrophil accumulation. Following 3 h of unilateral carotid occlusion, animals were collected at increasing times of reperfusion and the CA1 region of the hippocampus and the lateral cortex were assessed for postischemic neuronal damage using a semiquantitative index (N.D.I.) of 0 (no damage) to 4 (>75% neuronal loss). The extent of neutrophil accumulation was determined by counting intensely cytochrome oxidase-positive cells. Minimal neuronal death was evident after 2 h of reperfusion, mean N.D.I. = 0.36. However, between 2 and 4 h of reperfusion, neuronal death did not increase. By 6 h of reperfusion, the neuronal death began to proceed at an accelerated rate, N.D.I. = 0.78. By 12 h, the N.D.I. reached 3.20. The accelerated neuronal death coincided with parenchymal invasion of neutrophils. Cyclophosphamide administration delayed neuronal death in the hippocampus, but exhibited a more sustained protective effect in the lateral cortex. Administration of tirilazad mesylate also resulted in a significant reduction in neutrophil accumulation and significant neuronal protection in both brain areas. Thus, in this gerbil model of transient, but prolonged focal cerebral ischemia, neutrophils appear to play an active role in the reperfusion injury to brain tissue. Our experiments confirm the previously demonstrated neuroprotective efficacy of tirilazad mesylate in this model and provide evidence for a similar protective effect of cyclophosphamide. Although other effects of this antioxidant are also thought to contribute to the overall efficacy, the data are consistent with the hypothesis that one mechanism by which tirilazad acts involves limiting the ability of neutrophils to participate in the reperfusion phase of ischemic cerebral injury.
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PMID:Cyclophosphamide is neuroprotective in a gerbil model of transient severe focal cerebral ischemia: correlation with effects of tirilazad mesylate (U-74006F). 909 81

Data accumulated over the last 10 years have led to the popular hypothesis that neutrophils and other inflammatory cells play a prominent role in the neuropathology of cerebral ischemia. This hypothesis was derived from a large number of studies involving three general observations: (1) leukocytes, particularly neutrophils, are present in ischemic tissue at the approximate time that substantial neuronal death occurs; (2) neutropenia is sometimes associated with reduced ischemic damage; and (3) treatments that prevent leukocyte vascular adhesion and extravasation into the brain parenchyma can be neuroprotective. This review reexamines the literature to ascertain its support for a pathogenic role for neutrophils in ischemia-induced neuronal loss. To accomplish this goal, we employed several logical theorems of "cause-effect" relationships, as they pertain to leukocytes and ischemic brain damage. Since the majority of studies focused on neutrophils as the most likely pathogenic inflammatory cell, this review necessarily does so here. We reasoned that if neutrophils play an important pathogenic (i.e., cause-effect) role in the neuronal damage that follows a stroke, then one should expect to find clear evidence that: (1) neutrophils invade the ischemic area prior to terminal stage infarction, (2) greater numbers of early appearing neutrophils are accompanied by evidence of greater neuronal loss, and (3) dose-related inhibition of neutrophil trafficking or activity produces a corresponding decrease in the degree of brain damage following ischemia. This review of the literature reveals that the existing evidence does not readily support any of these predictions and that, therefore, it consistently falls short of establishing a clear cause-effect relationship between leukocyte recruitment and the pathogenesis of ischemia. While the available evidence does not necessarily rule out a potential pathogenic role of neutrophils and other leukocytes, it nevertheless does expose serious weaknesses in the existing studies intended to support that hypothesis. For this reason we also offer suggestions for additional experiments and the inclusion of control groups that, in the future, might provide more effective or conclusive tests of the hypothesis.
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PMID:The role of leukocytes following cerebral ischemia: pathogenic variable or bystander reaction to emerging infarct? 1177 49

Polymorphonuclear leukocytes (PMNs) were reported to contribute to ischemia-reperfusion-induced brain damage. The present work examined whether PMN infiltration is deleterious in a severe model of transient focal cerebral ischemia and in which part PMNs contribute to oxidative stress and nitric oxide (NO) production. A 20-min occlusion of the left middle cerebral artery and both common carotid arteries was performed in rats. Infarction was maximal 24 h after reperfusion, while accumulation of PMNs in infarcted tissue was not significant before 48 h. Moreover, neutropenia induced by vinblastine (0.5 mg/kg iv) significantly decreased by 60-80% PMN infiltration 48 h after reperfusion but did not reduce the infarct volume. Thus PMNs do not contribute to cerebral injury in our model. Furthermore, decreased PMN infiltration modified neither oxidative stress evaluated by glutathione concentrations nor NO synthase activities 48 h after reperfusion. In conclusion, our results suggest that PMNs are not involved in severe cerebral ischemia and that anti-PMN strategies may be inefficient in some pathological conditions.
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PMID:Neutrophils do not contribute to infarction, oxidative stress, and NO synthase activity in severe brain ischemia. 1289 55

The present work examined whether polymorphonuclear neutrophil (PMN) infiltration contributes to cortical and striatal brain damage and oxidative stress in a model of transient focal cerebral ischemia. A 2-h occlusion of the left middle cerebral artery and ipsilateral common carotid artery was performed in rats. Administration of the neutropenic agent vinblastine (0.5 mg/kg, i.v.) resulted in a profound decrease in circulating PMNs which was associated with a 80% decrease in myeloperoxidase activity, a marker of PMN infiltration, in both the cortex and the striatum. In the cortex, vinblastine-treated animals exhibited a 44% decrease in the infarct volume and also reduced the oxidative stress (evaluated by the decrease in glutathione concentrations). By contrast, in the striatum, neutropenia modified neither the lesion size nor the oxidative stress. These results indicate that PMN contribution to postischemic injury and oxidative stress is dependent on the brain structure.
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PMID:Polymorphonuclear neutrophils contribute to infarction and oxidative stress in the cortex but not in the striatum after ischemia-reperfusion in rats. 1449 43

1. The polymorphonuclear neutrophils (PMN) activation and mobilization observed in acute cerebral infarction contribute to the brain tissue damage, but PMN could also be involved in postischemic functional injury of ischemied blood vessel. 2. This study was undertaken to investigate whether pharmacological neutropenia could modify the postischemic endothelial dysfunction in comparison to smooth muscle whose impairment is likely more related to reperfusion and oxidative stress. 3. A cerebral ischemia-reperfusion by endoluminal occlusion of right middle cerebral artery (MCA) was performed 4 days after intravenous administration of vinblastine or 12 h after RP-3 anti-rat neutrophils monoclonal antibody (mAb RP-3) injection into the peritoneal cavity, on male Wistar rats with 1-h ischemia then followed by 24-h reperfusion period. Brain infarct volume was measured by histomorphometric analysis and vascular endothelial and smooth muscle reactivity of MCA was analysed using Halpern myograph. 4. Neutropenia induced a neuroprotective effect as demonstrated by a significant decrease of brain infarct size. In parallel to neuroprotection, neutropenia prevented postischemic impairment of endothelium-dependent relaxing response to acetylcholine. In contrast, smooth muscle functional alterations were not prevented by neutropenia. Ischemia-reperfusion-induced myogenic tone impairment remained unchanged in vinblastine and mAb RP-3-treated rats. Postischemic Kir2.x-dependent relaxation impairment was not prevented in neutropenic conditions. The fully relaxation of smooth muscle response to sodium nitroprusside was similar in all groups. 5. Our results evidenced the dissociate prevention of pharmacologically induced neutropenia on postischemic vascular endothelial and smooth muscle impairment. The selective endothelial protection by neutropenia is parallel to a neuroprotective effect suggesting a possible relationship between the two phenomena.
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PMID:Pharmacological neutropenia prevents endothelial dysfunction but not smooth muscle functions impairment induced by middle cerebral artery occlusion. 1570 30


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