Background and Purpose-There is growing evidence that pharmacologic interference with the renin-angiotensin system may reduce risk of stroke, although the mechanism is unclear. Impaired reactivity of cerebral vessels has recently been recognized as a risk factor for stroke. We examined the effect of the angiotensin-converting enzyme (ACE) inhibitor perindopril on cerebral vasomotor reactivity to acetazolamide in patients with lacunar cerebral infarction. Methods-We studied a cohort of male patients between 3 and 12 months after lacunar infarction confirmed on computed tomography. Each patient received perindopril 4 mg daily or matching placebo for 2 weeks in a randomized, double-blind, placebo-controlled crossover fashion. A 1-week washout period was observed between dosing periods. Cerebral vasomotor reactivity (increase in middle cerebral artery mean flow velocity in response to intravenous injection of 15 mg/kg acetazolamide) was measured before and after each dosing period using standard Doppler ultrasound techniques. Results-Twelve patients (mean age 63.2Ϯ2.3 years) completed the protocol. There was no treatment order effect.Cerebral vasomotor reactivity was significantly greater after perindopril treatment (percent change from baseline ϩ18.8Ϯ10.1% after perindopril, Ϫ4.6Ϯ4.1% after placebo; Pϭ0.032). Dosing with perindopril did not affect resting cerebral blood flow velocity (percent change from baseline ϩ3.1Ϯ9.5% after perindopril, Ϫ0.6Ϯ5.4% after placebo), nor was there a change in resting blood pressure (ϩ1.8 mm HgϮ3.1 after perindopril, ϩ1.4 mm HgϮ2.5 after placebo). Conclusions-This study provides evidence of a significant improvement in cerebral vasomotor reactivity induced by perindopril, beyond any effect on blood pressure. The results suggest a possible mechanism for the beneficial effect of ACE inhibition on stroke risk observed in recent clinical trials, and suggest a role for the renin-angiotensin axis in the pathophysiology of subcortical small vessel disease.

AimsThe main objective of this study was to investigate the safety, tolerability and pharmacodynamics of the novel proteasome inhibitor PS − 519 in young male volunteers. Many pro-inflammatory mediators such as cytokines and cell adhesion molecules that are responsible for the development of the cerebral infarct are under the control of the transcription factor Nuclear Factor kappa-B (NF-κ B). The activity of NF-κ B is itself tightly regulated through the multicatalytic enzyme known as the proteasome. PS-519 is a novel and highly selective small molecule that inhibits the proteasome. An ex vivo assay of 20S proteasome activity allows monitoring of the drug effect in blood. PS-519 is protective in multiple animal models of cerebral ischaemia over a range of doses that achieve 20S inhibition of 40% − 80%. Methods PS-519 has been administered to healthy male volunteers as single and repeated doses up to 1.6 mg m − 2 . It was given as an intravenous bolus over 20-30 s in a double blind, randomized, placebo-controlled phase I study, examining vital signs, safety, tolerability and blood 20S proteasome inhibition. Results Thirty-nine subjects received single doses of 0.012 mg m − 2 − 1.6 mg m − 2 and 28 subjects received doses of 0.5 mg m − 2 − 1.6 mg m − 2 on three consecutive days. The drug was well tolerated. There was no clear treatment-emergent symptom or abnormality of laboratory tests. Proteasome inhibition in blood samples as measured by 20S assay achieved the intended maximum target level of 70-80% with 1.6 mg m − 2 , and was reproducible with repeated dosing. Conclusions This study has demonstrated that proteasome inhibition is well tolerated by healthy subjects at levels that are maximally neuroprotective in experimental conditions. Further clinical evaluation appears justified.

Cerebrovascular disease is one of the commonest causes of disability and mortality worldwide. Over the past two decades, a tremendous amount of research has been undertaken into developing effective therapeutic strategies for the treatment of acute stroke. Unfortunately, many neuroprotective agents that have shown successful results in treating animal models of acute stroke have failed to translate into clinical treatments. Only tissue-plasminogen activator (t-PA) is currently licensed for use in the treatment of acute ischaemic stroke. One of the important pathophysiological mechanisms involved during the acute phase of stroke is neuroinflammation. This review article will discuss the molecular aspects of neuroinflammation in acute ischaemic stroke and potential therapeutic strategies as part of translational medicine research.

This approach to blended learning is popular with our medical students. Online evaluation has helped with curriculum development and, by identifying important areas of acute medicine teaching that can be improved, is feeding into our curriculum revision.