Model infarcted

In rodent stroke models, statin pretreatment has been shown to reduce infarct volumes and improve outcomes. Similarly, several clinical studies have shown that prior statin use reduced the severity of acute ischemic stroke and myocardial infarction. Recent studies indicate that beneftt can be achieved even when treatment is initiated after the onset of symptoms. In rodents, atorvastatin and simvastatin have been shown to reduce the growth of ischemic lesions, enhance functional outcome, and induce brain plasticity when administered after stroke onset. A retrospective analysis of the population-based Northern Manhattan Stroke Study (NOMASS) showed that patients using lipid-lowering agents at the time of ischemic stroke have a lower incidence of in-hospital stroke progression and reduced 90-day mortality rates. Retrospective analysis of data of the phase III citicoline trial showed... 

Tris-hydroxymethyl-aminomethane (THAM) has been evaluated in ischemic stroke to reduce mass effect and ICP. It acts as a bulfer, neutralizing acidosis on a local level, including in the brain parenchyma. It has been studied in animal models of stroke, showing an effect in reducing the size of and swelling from cerebral infarction. To date, however, THAM has not been studied in a controlled fashion in humans with ischemic stroke. 

Table 5.1 Effects of compound 231617 on infarct volume in the middle cerebral occlusion model of focal stroke...

Synaptic stimulation, ischemia or seizure activates phospholipase A2 and releases arachidonic and docosahexaenoic acids. Ischemia or seizure triggers accumulation of free AA, DHA and other FFA in the brain( see also Chs 32, 37). This reflects PLA2 activation in excitable membranes [24]. While little is known about the mechanisms that control its activity, the importance of cPLA2 in ischemic brain injury is strongly supported by the recent finding that cPLA2-knockout mice have substantially reduced infarcts and neurologic deficits in a model of stroke [25],... 

The lack of tolerance has been explained by the fact that the N O-release from these compounds is spontaneous and independent of the presence of thiols [124], that, by contrast, may be an essential cofactor in the action of the nitrate. Martorana et al. [125] showed a marked antiischemic effect of Pirsidomine in a dog model of myocardial infarction. 

No information on potentially susceptible populations was located for HCFC-141b. A structurally related chemical, 1,1,1,2-tetrafluoroethane, has been tested in metered-dose inhalers for the treatment of asthma. Test subjects included adult and pediatric asthma patients as well as individuals with severe COPD. No adverse effects were reported (Smith et al. 1994 Taggart et al. 1994 Ventresca 1995 Woodcock 1995). The structurally related chemicals trichlorofluoromethane (CFC-11) and dichlorodifluoromethane (CFC-12) are presently used in metered-dose inhalers for the treatment of asthma but are phased out under the Montreal Protocol of 1987 (Alexander 1995). Structurally related compounds including 1,1,1-trichloroethane and trichlorofluoromethane were also tested for cardiac sensitization in a dog model with experimentally induced myocardial infarction. In these experiments cardiac sensitization occurred under the same conditions as in healthy dogs (Trochimowicz et al. 1976). 

Since the early 1980s, much effort has focused on animal models of acute and chronic neurodegeneration in search of therapeutics for stroke. Neuronal cell death follows strokes, acute ischemic insults, and chronic neurodegeneration, such as Parkinson s disease, Alzheimer s disease (AD), epilepsy, and Huntington s disease. Up to 80% of all strokes result from focal infarcts and ischemia in the middle cerebral artery (MCA), so the commonly used animal models for neuroprotection are produced by temporary or permanent occlusion of the MCA.5 Lesions of the MCA include occlusion by electrocoagulation, intraluminal monofilaments, photochemical effects, thrombosis, and endothelin-1, but all of these models necessitate studying reperfusion events and validating MCA occlusion by behavioral assessments. 

Docebenone has shown anti-inflammatory effects in several animal models following local dosing phorbol ester-induced oedema and neutrophil influx in mouse skin [208,209], arachidonate-induced plasma extravasation in rabbit skin [210], the pleural reversed passive Arthus reaction in rats [211], and GPB [212], An oral dose of 80 mg/kg reduced infarct size, LTB4 levels and neutrophil infiltration in a rat myocardial infarction model [213,214], and in a rat brain ischaemia-reperfusion model oedema and LTC4 levels were reduced at 200 mg/kg [107]. Significant, but not dramatic, improvement in nasal symptoms was seen in humans following 150 mg of docebenone twice daily for 8 weeks [215], but there was no effect on bronchial hyperresponsiveness to acetylcholine in asthmatics [216]. 

More recent studies continue to support the unique antifibrillatory activity of bretylium. Kowey et al. [38] have shown that bretylium prevented spontaneous VF and decreased the effects on VF threshold in a feline myocardial infarction model. They attributed this beneficial effect to a decrease in the dispersion of refractoriness between normal and ischaemic regions of the heart. In contrast, clofilium (14, see below), which had little effect on dispersion of refractoriness after coronary occlusion, was unable to prevent spontaneous VF. Similar results were seen in isolated tissue studies with canine subendocardial Purkinje fibres and ventricular muscle which contained both normal and ischaemic regions [39]. In these studies bretylium caused a smaller increase in dispersion of refractoriness in subendocardial Purkinje fibres than either sotalol or clofilium. In ventricular muscle tissue, bretylium decreased dispersion while sotalol and clofilium increased dispersion of refractoriness. 

Katzov, H., Bennet, A.M., Kehoe, P., et al. (2004) A cladistic model of ACE sequence variation with implications for myocardial infarction, Alzheimer disease and obesity. Hutu, Mol Genet., 13, 2647-2657. 

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