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.)

Tolerability of the Low-Affinity, Use-Dependent NMDA Antagonist AR-R15896AR in Stroke Patients

Background and Purpose—AR-R15896AR is a use-dependent, low-affinity blocker of the NMDA ion channel with neuroprotective effects in animal models of focal cerebral ischemia. This study aimed to establish the highest safe and tolerated loading and maintenance dosing regimen of AR-R15896AR in acute ischemic stroke patients and to determine the associated plasma concentrations of AR-R15896AR.Methods—This was a 4-part, multicenter, randomized, double-blind, placebo-controlled study in 175 patients (mean age, 69 years) within 24 hours of acute stroke symptom recognition. Ascending 60-minute intravenous infusion loading doses of AR-R15896AR were initially examined (100, 150, 200, 250, or 300 mg or placebo in 3:1 randomization, n=36 treated); in part 2, 250, 275, or 300 mg was compared with placebo (n=33). In part 3, a 250-mg loading dose was followed by 9 maintenance doses of 60, 75, 90, 105, or 120 mg every 8 hours versus placebo in 3:1 randomization (n=59); subsequently, in part 4, maintenance doses of 90, 105, and 120 mg after the 250-mg loading dose were directly randomized against placebo (n=42). Safety, tolerability, and pharmacokinetics were the primary end points; NIHSS at 1 week and Barthel and modified Rankin scores at 1 month were also recorded, but the study was neither designed nor powered to assess efficacy.Results—Rates for mortality and serious adverse events (SAE) were similar in active and placebo groups (9% mortality and 23% SAE for all active combined versus 11% mortality and 33% SAE for placebo). Adverse events associated with AR-R15896AR were dizziness, vomiting, nausea, stupor, and some agitation/hallucination. Withdrawal from treatment occurred only in response to loading doses with AR-R15896AR: placebo, 3 of 46 (7%); 250 mg, 11 of 89 (12%); 275 mg, 1 of 8 (12.5%); and 300 mg, 3 of 15 (20%). No significant difference in outcome was observed between groups. Plasma concentrations of AR-R15896AR were 1524±536 ng/mL at the end of the 250-mg loading infusion and were 1847±478 ng/mL at steady state after the 9 maintenance doses of 120 mg.Conclusions—The maximum tolerated loading infusion of AR-R15896AR in this study was 250 mg over a period of 1 hour. Subsequent maintenance infusions of 120 mg every 8 hours were well tolerated. With these doses, putative neuroprotective concentrations of 1240 ng/mL are attained by the loading dose and are satisfactorily maintained thereafter. The loading dose may be improved further by adjustment on an individual patient basis, but tolerability issues remain

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

Acknowledgments This work was supported by the Stroke Association and British Heart Foundation [grant number TSA BHF 2013/01]. The work of Dr David Dickie and Dr Terry Quinn is funded by the Stroke Association. We would like to thank Christine McAlpine, Ruth Graham, Glasgow Royal Infirmary, UK; Lauren Pearce, Royal United Hospital, UK; Caroline Fornolles, Louise Tate, Frances Justin, Luton and Dunstable University Hospital, UK; Dean Waugh, Leeds Teaching Hospitals NHS Trust, UK; Donal Concannon, Altnagelvin Hospital, UK; Sharon Tysoe, Nina Francia, Nisha Menon, Raji Prabakaran, Southend University Hospital, UK; Amy Ashton, Caroline Watchurst, Marilena Marinescu, Sabaa Obarey, Scheherazade Feerick, University College London NHS Foundation Trust, UK; and Janice Irvine, Sandra Williams, and German Guzman Gutierrez, Aberdeen Royal Infirmary, UK; Caroline Fox and Joanne Topliffe, Broomfield Hospital, Essex, UK.Peer reviewedPublisher PD

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

Gorbachev's economic reforms: Perestroika in crisis

SIGLEAvailable from Bibliothek des Instituts fuer Weltwirtschaft, ZBW, Duesternbrook Weg 120, D-24105 Kiel / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Perindopril reduces blood pressure but not cerebral blood flow in patients with recent cerebral ischemic stroke

Background and Purpose: The relationship between high blood pressure and the incidence of stroke is well established. Currently the effects of lowering blood pressure in patients with established cerebrovascular disease is undetermined, and there is continuing concern regarding the treatment of patients soon after a stroke event. Angiotensin-converting enzyme inhibitors maintain cerebral blood flow despite lowering blood pressure in patients with heart failure and otherwise uncomplicated hypertension. We tested the hypothesis that perindopril, an angiotensin-converting enzyme inhibitor with a gradual onset of action and a minimal first-dose hypotensive effect, lowers blood pressure without adversely affecting cerebral blood flow in patients 2 to 7 days after symptoms of cerebral infarction. Methods: Patients were randomized to receive 15 days of oral perindopril (4 mg) or placebo in a double-blind study. Blood pressure was monitored semiautomatically. Cerebral blood flow was calculated from internal carotid artery and vertebral Doppler ultrasound, supplemented by middle cerebral artery blood velocities. Results: Twenty-four patients completed the protocol; four additional patients were withdrawn for reasons unrelated to treatment. Patients on perindopril had a placebo-corrected reduction in blood pressure of 19/11 mm Hg. Blood pressure remained reduced after 2 weeks of treatment. In contrast, total cerebral blood flow was unaffected by perindopril. Neurological symptoms improved similarly in both groups. Conclusions: Perindopril was well tolerated and effectively reduced blood pressure without reducing carotid territory blood flow in patients with symptoms of recent cerebral ischemia

Tolerability of the low-affinity, use-dependent NMDA antagonist AR-R15896AR in stroke patients: a dose-ranging study

Background and Purpose—AR-R15896AR is a use-dependent, low-affinity blocker of the NMDA ion channel with neuroprotective effects in animal models of focal cerebral ischemia. This study aimed to establish the highest safe and tolerated loading and maintenance dosing regimen of AR-R15896AR in acute ischemic stroke patients and to determine the associated plasma concentrations of AR-R15896AR. Methods—This was a 4-part, multicenter, randomized, double-blind, placebo-controlled study in 175 patients (mean age, 69 years) within 24 hours of acute stroke symptom recognition. Ascending 60-minute intravenous infusion loading doses of AR-R15896AR were initially examined (100, 150, 200, 250, or 300 mg or placebo in 3:1 randomization, n=36 treated); in part 2, 250, 275, or 300 mg was compared with placebo (n=33). In part 3, a 250-mg loading dose was followed by 9 maintenance doses of 60, 75, 90, 105, or 120 mg every 8 hours versus placebo in 3:1 randomization (n=59); subsequently, in part 4, maintenance doses of 90, 105, and 120 mg after the 250-mg loading dose were directly randomized against placebo (n=42). Safety, tolerability, and pharmacokinetics were the primary end points; NIHSS at 1 week and Barthel and modified Rankin scores at 1 month were also recorded, but the study was neither designed nor powered to assess efficacy. Results—Rates for mortality and serious adverse events (SAE) were similar in active and placebo groups (9% mortality and 23% SAE for all active combined versus 11% mortality and 33% SAE for placebo). Adverse events associated with AR-R15896AR were dizziness, vomiting, nausea, stupor, and some agitation/hallucination. Withdrawal from treatment occurred only in response to loading doses with AR-R15896AR: placebo, 3 of 46 (7%); 250 mg, 11 of 89 (12%); 275 mg, 1 of 8 (12.5%); and 300 mg, 3 of 15 (20%). No significant difference in outcome was observed between groups. Plasma concentrations of AR-R15896AR were 1524±536 ng/mL at the end of the 250-mg loading infusion and were 1847±478 ng/mL at steady state after the 9 maintenance doses of 120 mg. Conclusions—The maximum tolerated loading infusion of AR-R15896AR in this study was 250 mg over a period of 1 hour. Subsequent maintenance infusions of 120 mg every 8 hours were well tolerated. With these doses, putative neuroprotective concentrations of 1240 ng/mL are attained by the loading dose and are satisfactorily maintained thereafter. The loading dose may be improved further by adjustment on an individual patient basis, but tolerability issues remain

Tolerability of the Low-Affinity, Use-Dependent NMDA Antagonist AR-R15896AR in Stroke Patients

Background and Purpose—AR-R15896AR is a use-dependent, low-affinity blocker of the NMDA ion channel with neuroprotective effects in animal models of focal cerebral ischemia. This study aimed to establish the highest safe and tolerated loading and maintenance dosing regimen of AR-R15896AR in acute ischemic stroke patients and to determine the associated plasma concentrations of AR-R15896AR. Methods—This was a 4-part, multicenter, randomized, double-blind, placebo-controlled study in 175 patients (mean age, 69 years) within 24 hours of acute stroke symptom recognition. Ascending 60-minute intravenous infusion loading doses of AR-R15896AR were initially examined (100, 150, 200, 250, or 300 mg or placebo in 3:1 randomization, n=36 treated); in part 2, 250, 275, or 300 mg was compared with placebo (n=33). In part 3, a 250-mg loading dose was followed by 9 maintenance doses of 60, 75, 90, 105, or 120 mg every 8 hours versus placebo in 3:1 randomization (n=59); subsequently, in part 4, maintenance doses of 90, 105, and 120 mg after the 250-mg loading dose were directly randomized against placebo (n=42). Safety, tolerability, and pharmacokinetics were the primary end points; NIHSS at 1 week and Barthel and modified Rankin scores at 1 month were also recorded, but the study was neither designed nor powered to assess efficacy. Results—Rates for mortality and serious adverse events (SAE) were similar in active and placebo groups (9% mortality and 23% SAE for all active combined versus 11% mortality and 33% SAE for placebo). Adverse events associated with AR-R15896AR were dizziness, vomiting, nausea, stupor, and some agitation/hallucination. Withdrawal from treatment occurred only in response to loading doses with AR-R15896AR: placebo, 3 of 46 (7%); 250 mg, 11 of 89 (12%); 275 mg, 1 of 8 (12.5%); and 300 mg, 3 of 15 (20%). No significant difference in outcome was observed between groups. Plasma concentrations of AR-R15896AR were 1524±536 ng/mL at the end of the 250-mg loading infusion and were 1847±478 ng/mL at steady state after the 9 maintenance doses of 120 mg. Conclusions—The maximum tolerated loading infusion of AR-R15896AR in this study was 250 mg over a period of 1 hour. Subsequent maintenance infusions of 120 mg every 8 hours were well tolerated. With these doses, putative neuroprotective concentrations of 1240 ng/mL are attained by the loading dose and are satisfactorily maintained thereafter. The loading dose may be improved further by adjustment on an individual patient basis, but tolerability issues remain