Therapeutic Approaches to Stroke: Prevention and Acute Treatment

Dyker, Alexander G (1997) Therapeutic Approaches to Stroke: Prevention and Acute Treatment. MD thesis, University of Glasgow.

Abstract

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.).

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Additional Information: Adviser: K R Lees
• Keywords: Medicine
• Date of Award: 1997
• Depositing User: Enlighten Team
• Unique ID: glathesis:1997-75953
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 17:13
• Last Modified: 19 Nov 2019 17:13
• URI: https://theses.gla.ac.uk/id/eprint/75953