A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.uk original articleT h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med

A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.ukT h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med

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Background: The treatment of ischaemic stroke with neuroprotective drugs has been unsuccessful, and whether these compounds can be used to reduce disability after recurrent stroke is unknown. The putative neuroprotective effects of antiplatelet compounds and the angiotensin II receptor antagonist telmisartan were investigated in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial. Methods: Patients who had had an ischaemic stroke were randomly assigned in a two by two factorial design to receive either 25 mg aspirin (ASA) and 200 mg extended-release dipyridamole (ER-DP) twice a day or 75 mg clopidogrel once a day, and either 80 mg telmisartan or placebo once per day. The predefined endpoints for this substudy were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and Barthel index at 3 months, and cognitive function, assessed with the mini-mental state examination (MMSE) score at 4 weeks after randomisation and at the penultimate visit. Analysis was by intention to treat. The study was registered with ClinicalTrials.gov, number NTC00153062. Findings: 20 332 patients (mean age 66 years) were randomised and followed-up for a median of 2·4 years. Recurrent strokes occurred in 916 (9%) patients randomly assigned to ASA with ER-DP and 898 (9%) patients randomly assigned to clopidogrel; 880 (9%) patients randomly assigned to telmisartan and 934 (9%) patients given placebo had recurrent strokes. mRS scores were not statistically different in patients with recurrent stroke who were treated with ASA and ER-DP versus clopidogrel (p=0·38), or with telmisartan versus placebo (p=0·61). There was no significant difference in the proportion of patients with recurrent stroke with a good outcome, as measured with the Barthel index, across all treatment groups. Additionally, there was no significant difference in the median MMSE scores, the percentage of patients with an MMSE score of 24 points or less, the percentage of patients with a drop in MMSE score of 3 points or more between 1 month and the penultimate visit, and the number of patients with dementia among the treatment groups. There were no significant differences in the proportion of patients with cognitive impairment or dementia among the treatment groups. Interpretation: Disability due to recurrent stroke and cognitive decline in patients with ischaemic stroke were not different between the two antiplatelet regimens and were not affected by the preventive use of telmisartan. Funding: Boehringer Ingelheim; Bayer-Schering Pharma (in selected countries); GlaxoSmithKline (in selected countries). © 2008 Elsevier Ltd. All rights reserved

Intracellular recordings in vivo from noradrenergic neurons in the rat locus coeruleus showed that membrane potential was hyperpolarized by the administration of clonidine (an alpha 2-adrenoceptor agonist) or after a burst of spikes evoked by intracellular pulses; both types of hyperpolarization were associated with a decrease in membrane input resistance, and both could be blocked by the alpha 2-adrenoceptor antagonist piperoxane. These results suggest that a hyperpolarization of membrane potential mediated by an alpha 2-adrenoceptor underlies both clonidine- and activation-induced inhibition of locus coeruleus cell firing.