Ischaemia stroke

PI (adenosine) receptors were explored as therapeutic targets before P2 receptors. Adenosine was identified early and is in current use to treat supraventricular tachycardia. A2a receptor antagonists are being investigated for the treatment of Parkinson s disease and patents have been lodged for the application of PI receptor subtype agonists and antagonists for myocardial ischaemia and reperfusion injury, cerebral ischaemia, stroke, intermittent claudication and renal insufficiency. 

Harris RJ, Branston NM, Symon L, Bayhan M, Watson A The effects of a calcium antagonist, nimodipine, upon physiological responses of the cerebral vasculature and its possible influence upon focal cerebral ischaemia. Stroke 13 759-766,1982... 

Furlow, T. W., Flallenbeck, J. M., 1978 Indomethacin prevents impaired perfusion of the dog s brain after global ischaemia. Stroke 9, 591-594. 

Kerckhoff, W., Hossmann, K. A., Hossmann, V., 1983 No effect of prostacyclin on blood flow, regulation of blood flow and blood coagulation following global cerebral ischaemia. Stroke 14, 724-730. 

The European/Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) confirmed the finding of ESPS 2, showing that the combination of aspirin and dipyridamole is more effective than aspirin alone in the prevention of new vascular events in patients with nondisabling cerebral ischaemia of presumed arterial origin. Adding the ESPRIT data to the meta-analysis of previous trials resulted in an overall risk ratio for the composite of vascular death, stroke, or MI of 0.82 (95% Cl 0.74-0.91). 

A series of dihydrodibenzoxepines, represented by AJ3941, was tested in animal models of global ischaemia and hypoxia, and found to be protective. AJ3941 is an inhibitor of lipid peroxidation (Kurakawa etal., 1991). A novel quinazoline fumarate (KB56666, was found to inhibit lipid peroxidation in rat brain homogenates and isolated mitochondria. In a rat focal stroke model, KE56666 prevented brain oedema and neuronal damage in the ischaemic zone (Hara etal., 1991). 

The potential therapeutic benefit of brain-derived neurotrophic factor BDNF for rescuing neurons after stroke was demonstrated in a forebrain ischaemia model [93]. In that study,... 

There are a number of microdialysis studies in animals indicating that there is a consistent increase in extracellular glutamate concentration during experimental ischaemia (Benveniste et al. 1984 Globus et al. 1988). In man, there is also an increase in CSF and plasma content of glutamate and glycine in patients with progressive, but not with stable stroke (Castillo et al. 1997). 

The most prominent effect of halothane on the circulation is a dose-related decrease in arterial blood pressure. This is due mainly to reduced myocardial contractility and ventricular slowing. Cardiac output falls due to a decrease in stroke volume and bradycardia. Systemic vascular resistance also falls but this is less pronounced than with some other agents. Although halothane reduces myocardial oxygen consumption it also reduces oxygen demand and it is suitable for patients with myocardial ischaemia. 

Plasma malondialdehyde-like material, an indicator of lipid peroxidation, is increased in conditions of ischaemia, such as stroke [83, 84] and myocardial infarction [85]. Mitochondria extracted from hearts of vitamin-E-deficient rabbits showed a decreased mitochondrial function and an increased formation of oxygen radicals associated with a reduced superoxide dismutase activity. This was partially reversed by addition of vitamin E in vitro [86]. Measurement of in vitro susceptibility to lipid peroxidation in cardiac muscle from vitamin-E-deficient mice showed a highly significant negative correlation between the concentration of vitamin E and in vitro lipid peroxidation. The results indicate that short-term vitamin E deficiency may expose cardiac muscle to peroxidation injuries [ 87 ]. In rats, treatment for 2 days with isoprenaline increased lipid peroxide activity, as measured by malondialdehyde levels, in the myocardium. Vitamin-E-deficient animals were even more sensitive to this effect, and pretreatment with a-tocopheryl acetate for 2 weeks prevented the effect induced by isoprenaline. The authors [88] propose that free-radical-mediated increases in lipid peroxide activity may have a role in catecholamine-induced heart disease. 

Because it is necessary for the stroke patient to receive prompt treatment before brain cell death occurs, any useful drug must be effective even when there is considerable time lapse (often several hours) between the occurrence of the stroke and the onset of treatment. The term "therapeutic window" refers to the critical time of intervention between the onset of the ischaemia and occurrence of brain infarction. Some of the drugs that have been developed and shown to be effective in the treatment of various animal models of stroke are listed in Table 14.5. It should be emphasized that none of these drugs is currently marketed for the treatment of stroke. All have been developed on animal models and recent positron emission tomography and magnetic resonance imaging studies have shown that the therapeutic window may be much more variable and prolonged in man than in such models. Only extensive double-blind clinical trials (estimated... 

Wise RJ S, Bernardi S, Frackowiak RS J et al. (1983). Serial observations on the pathophysiology of acute stroke. The transition from ischaemia to infarction as reflected in regional oxygen extraction. Brain 106 197-222... 

Sylaja PN, Coutts SB, Subramaniam S et al (2007). Acute ischemic lesions of varying ages predict risk of ischemic events in stroke/TIA patients. Neurology 68 415-419 UK TIA Study Group (1993). Intracranial tumours that mimic transient cerebral ischaemia lessons from a large multicentre trial. Journal of Neurology, Neurosurgery and Psychiatry 56 563-566... 

Kernan WN, Viscoli CM, Brass LM et al. (2000). The Stroke Prognosis Instrument II (SPIII) a clinical prediction instrument for patients with transient ischaemia and non-disabling ischaemic stroke. Stroke 31 456-462 Mathur KS, Kashyap SK, Kumar V (1963). Correlation of the extent and severity of atherosclerosis in the coronary and cerebral arteries. Circulation 27 929-934 Petty GW, Brown RD Jr., Whisnant JP et al. (2000). Ischemic stroke subtypes. 

Fine PEM (1995). Variation in protection by BCG implications of and for heterologous immunity. Lancet 346 1339-1345 Gorter JW for the Stroke Prevention in Reversible Ischaemia Trial (SPIRIT) and European Atrial Fibrillation Trial (EAFT) Groups (1999). Major bleeding during anticoagulation after cerebral ischaemia patterns and risk factors. Neurology 53 1319-1327... 

Lai BK. (2007). Cognitive function after carotid artery revascularization. Vascular and Endovascular Surgery 41 5-13 Levi CR, O Malley HM, Fell G et al. (1997). Transcranial Doppler detected cerebral microembolism following carotid endarterectomy. High microembolic signal loads predict postoperative cerebral ischaemia. Brain 120 621-629 Lindblad B, Persson NH, Takolander R et al. (1993). Does low-dose acetylsalicylic acid prevent stroke after carotid surgery ... 

Schroeder T (1988). Hemodynamic significance of internal carotid artery disease. Acta Neurologica Scandinavica 77 353-372 Schroeder T, Sillesen H, Sorensen O et al. (1987). Cerebral hyperfusion following carotid endarterectomy. Journal of Neurosurgery 66 824-829 Shaw DA, Venables GS, Cartlidge NEF et al. (1984). Carotid endarterectomy in patients with transient cerebral ischaemia. Journal of Neurological Sciences 64 45-53 Silvestrini M, Vernieri F, Pasqualetti P et al. (2000). Impaired cerebral vasoreactivity and risk of stroke in patients with asymptomatic carotid artery stenosis. 

Malek AM, Higashida RT, Phatouros CC et al. (1999). Treatment of posterior circulation ischaemia with extracranial percutaneous balloon angioplasty and stent placement. Stroke 30 2073-2085... 

Endothelin may also have a role in ischaemic stroke. Endothelin, released after ischaemia caused by thrombo-embolic occlusion of a cerebral vessel, could propagate further infarction by constricting the collateral circulation. Much less information is available on endothelin in ischaemic stroke but endothelin levels are raised in animal models of focal ischaemia [183] and in ischaemic stroke patients [184]. 

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