Therapeutic Approaches to Stroke: Prevention and Acute Treatment

The work submitted for examination concerns several aspects of stroke patient management. Chapter one is a general overview of the relevant literature concerning prevention of stroke both primary and secondary. The rationale for acute therapy, pathophysiology and specific treatments such as thrombolysis, anti-platelet agents, anticoagulation and novel neuroprotective agents are discussed within the introduction. In Chapter two I examined the effects of the ACE inhibitor perindopril on blood pressure and total cerebral blood flow in hypertensive patients with recent ischaemic stroke. At present it is unclear at what stage it is safe to initiate anti-hypertensive therapy but in most cases this is delayed at least 72 hours. Patients admitted to the Acute Stroke Unit of the Western Infirmary are generally discharged either to the care of their general practitioners or to a further in-patient facility within 5 to 7 days of admission. It is therefore important to devise a risk factor intervention plan prior to discharge. Deferring decisions can result in unacceptable delays or even failure in the initiation of antihypertensive treatment. A total of 28 patients were recruited to the study with 24 completing the protocol. With a sample size of 24 patients we would expect to detect a difference in cerebral blood flow of 16% with 80% power. I hypothesised that the ACE inhibitor perindopril could be instituted within 3-7 days of ischaemic stroke onset, and this treatment would be effective and safe. 1 used transcranial and carotid duplex Doppler ultrasound to assess any effect on cerebral blood flow. Blood pressure was effectively reduced, but there was no drug associated neurological deterioration and cerebral blood flow was unaltered. Patients were screened for underlying hypertension and following informed written consent allocated either perindopril 4 mg or placebo for a period of 2 weeks within a double-blind, randomised, placebo-controlled study. Blood flow was calculated from bilateral internal carotid artery Doppler ultrasound coupled to a wall tracker device. Arterial flow was calculated equal to pi x diameter2. Doppler recordings were undertaken pre-treatment and at 2, 4, 8 and 24 hours and again at 2 weeks. In chapter three I examined the relationship between cholesterol and outcome following stroke with surprising results. All patients admitted through the Acute Stroke Unit of the Western Infirmary had total serum cholesterol measured routinely. 1,165 patients were included in the analysis. The results of the study suggested a clear dose dependent effect of elevated cholesterol on survival following stroke. The results were, however, counterintuitive with those patients with a significantly higher cholesterol having a better chance of survival. As the data linking cerebrovascular disease and elevated cholesterol is not wholly convincing appropriate placebo controlled intervention studies in patients with cerebrovascular disease are indicated before elderly patients should be routinely prescribed lipid lowering agents. I am currently involved in setting up such a placebo controlled study. In chapter four I assessed the relationship between poor stroke outcome and hyperglycaemia. A number of studies have suggested a relationship between poor functional outcome and hyperglycaemia. 811 patients with computed tomography confirmed acute stroke and plasma glucose data were included in the study. The analysis was carried out retrospectively and represent consecutive admissions for which CT and immediate blood glucose data were available. Our results were consistent with the hypothesis that hyperglycaemia exerts a direct and independent effect predisposing to poor stroke outcome. These results have been confirmed by other investigators and there are a number of postulated mechanisms which have been put forward to explain this trial of insulin therapy to correct hyperglycaemia versus standard observation in patients with acute stroke. Chapters five, six and seven were phase II placebo controlled trials of novel neuroprotective compounds currently being evaluated as treatment for acute stroke. The studies were not powered to demonstrate efficacy but rather to evaluate tolerability, safety and clinical pharmacology prior to phase III studies. In chapter five we evaluated the safety and tolerability of GV150526 (a glycine receptor antagonist) in patients with acute stroke. This drug was found to be extremely well tolerated when compared with other neuroprotective agents and the results suggest that putative neuroprotective concentrations can be achieved in patients with good tolerability. We observed a hitherto unrecognised effect on liver function. These observations lead to further toxicology studies. The results of the study and pharmacokinetic analysis have been utilised in the design of a phase III clinical efficacy study. (Abstract shortened by ProQuest.)

1-Benzyl-3-(1,2-diphenyl­ethen­yl)-1H-indole

In the title compound, C29H23N, the planar [maximum deviation from the least squares plane = 0.056 (1) Å] indole ring makes dihedral angles of 83.4 (4), 69.9 (1) and 59.9 (1)°, with the least-squares planes of three benzene rings. The mol­ecular packing is stabilized by weak inter­molecular C—H⋯π inter­actions

Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): a multicentre, double-blinded, randomised, placebo-controlled trial

BACKGROUND: People who experience an ischaemic stroke are at risk of recurrent vascular events, progression of cerebrovascular disease, and cognitive decline. We assessed whether allopurinol, a xanthine oxidase inhibitor, reduced white matter hyperintensity (WMH) progression and blood pressure (BP) following ischaemic stroke or transient ischaemic attack (TIA). METHODS: In this multicentre, prospective, randomised, double-blinded, placebo-controlled trial conducted in 22 stroke units in the United Kingdom, we randomly assigned participants within 30-days of ischaemic stroke or TIA to receive oral allopurinol 300 mg twice daily or placebo for 104 weeks. All participants had brain MRI performed at baseline and week 104 and ambulatory blood pressure monitoring at baseline, week 4 and week 104. The primary outcome was the WMH Rotterdam Progression Score (RPS) at week 104. Analyses were by intention to treat. Participants who received at least one dose of allopurinol or placebo were included in the safety analysis. This trial is registered with ClinicalTrials.gov, NCT02122718. FINDINGS: Between 25th May 2015 and the 29th November 2018, 464 participants were enrolled (232 per group). A total of 372 (189 with placebo and 183 with allopurinol) attended for week 104 MRI and were included in analysis of the primary outcome. The RPS at week 104 was 1.3 (SD 1.8) with allopurinol and 1.5 (SD 1.9) with placebo (between group difference −0.17, 95% CI −0.52 to 0.17, p = 0.33). Serious adverse events were reported in 73 (32%) participants with allopurinol and in 64 (28%) with placebo. There was one potentially treatment related death in the allopurinol group. INTERPRETATION: Allopurinol use did not reduce WMH progression in people with recent ischaemic stroke or TIA and is unlikely to reduce the risk of stroke in unselected people. FUNDING: The British Heart Foundation and the UK Stroke Association

Definitive hypofractionated radiotherapy for early glottic carcinoma: experience of 55Gy in 20 fractions

Introduction: A wide variety of fractionation schedules have been employed for the treatment of early glottic cancer. The aim is to report our 10-year experience of using hypofractionated radiotherapy with 55Gy in 20 fractions at 2.75Gy per fraction. Methods: Patients treated between 2004 and 2013 with definitive radiotherapy to a dose of 55Gy in 20 fractions over 4 weeks for T1/2 N0 squamous cell carcinoma of the glottis were retrospectively identified. Patients with prior therapeutic minor surgery (eg. laser stripping, cordotomy) were included. The probabilities of local control, ultimate local control (including salvage surgery), regional control, cause specific survival (CSS) and overall survival (OS) were calculated. Results: One hundred thirty-two patients were identified. Median age was 65 years (range 33–89). Median follow up was 72 months (range 7–124). 50 (38 %), 18 (14 %) and 64 (48 %) of patients had T1a, T1b and T2 disease respectively. Five year local control and ultimate local control rates were: overall - 85.6 % and 97.3 % respectively, T1a - 91.8 % and 100 %, T1b - 81.6 and 93.8 %, and T2 - 80.9 % and 95.8 %. Five year regional control, CSS and OS rates were 95.4 %, 95.7 % and 78.8 % respectively. There were no significant associations of covariates (e.g. T-stage, extent of laryngeal extension, histological grade) with local control on univariate analysis. Only increasing age and transglottic extension in T2 disease were significantly associated with overall survival (both p <0.01). Second primary cancers developed in 17 % of patients. 13 (9.8 %) of patients required enteral tube feeding support during radiotherapy; no patients required long term enteral nutrition. One patient required a tracheostomy due to a non-functioning larynx on long term follow up. Conclusions: Hypofractionated radiation therapy with a dose of 55Gy in 20 fractions for early stage glottic cancer provides high rates of local control with acceptable toxicity

Allylic Oxidation of Alkenes Catalyzed by a Copper−Aluminum Mixed Oxide

A strategy for the allylic oxidation of cyclic alkenes with a copper−aluminum mixed oxide as catalyst is presented. The reaction involves the treatment of an alkene with a carboxylic acid employing tert-butyl hydroperoxide as the oxidant. In all cases, the corresponding allylic esters are obtained. When L-proline is employed, the allylic alcohol or ketone is obtained. The oxidation of cyclohexene and valencene has been optimized by design of experiments (DoE) statistical methodology

Status Update and Interim Results from the Asymptomatic Carotid Surgery Trial-2 (ACST-2)

Objectives: ACST-2 is currently the largest trial ever conducted to compare carotid artery stenting (CAS) with carotid endarterectomy (CEA) in patients with severe asymptomatic carotid stenosis requiring revascularization. Methods: Patients are entered into ACST-2 when revascularization is felt to be clearly indicated, when CEA and CAS are both possible, but where there is substantial uncertainty as to which is most appropriate. Trial surgeons and interventionalists are expected to use their usual techniques and CE-approved devices. We report baseline characteristics and blinded combined interim results for 30-day mortality and major morbidity for 986 patients in the ongoing trial up to September 2012. Results: A total of 986 patients (687 men, 299 women), mean age 68.7 years (SD ± 8.1) were randomized equally to CEA or CAS. Most (96%) had ipsilateral stenosis of 70-99% (median 80%) with contralateral stenoses of 50-99% in 30% and contralateral occlusion in 8%. Patients were on appropriate medical treatment. For 691 patients undergoing intervention with at least 1-month follow-up and Rankin scoring at 6 months for any stroke, the overall serious cardiovascular event rate of periprocedural (within 30 days) disabling stroke, fatal myocardial infarction, and death at 30 days was 1.0%. Conclusions: Early ACST-2 results suggest contemporary carotid intervention for asymptomatic stenosis has a low risk of serious morbidity and mortality, on par with other recent trials. The trial continues to recruit, to monitor periprocedural events and all types of stroke, aiming to randomize up to 5,000 patients to determine any differential outcomes between interventions. Clinical trial: ISRCTN21144362. © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved