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Biomedical subjects

K W Muir

Publications and source records attributed to K W Muir.

At least 55 records · Page 3Linked to original sources
PubMed1995

Systemic and cerebral hemodynamic responses to the noncompetitive N-methyl-D-aspartate (NMDA) antagonist CNS 1102.

The excitatory amino acid antagonists are being developed as neuroprotective drugs aimed at limiting ischemic neuronal damage. Their hemodynamic and neurologic side effects are important in assessing safety and tolerability. We studied CNS 1102, a high-affinity noncompetitive N-methyl-D-aspartate (NMDA) receptor-channel antagonist, in normal volunteers. The effects of 2 mg CNS 1102 were assessed in a single-blind, placebo-controlled, fixed-dose, cross-over trial comparing administration by intravenous infusion for 15 min or bolus for 2 min in 8 healthy male subjects. Cerebral hemodynamics were studied with carotid and vertebral duplex ultrasound imaging, common carotid artery walltracking, and middle cerebral artery velocity readings. CNS 1102 administration was associated with light-headedness, mild disorientation, perioral and peripheral paresthesias, and flushing. Mean arterial blood pressure (MAP) increased significantly from baseline 1 h after CNS 1102 administration, with a maximal increase of 17 mm Hg over placebo. Pulse rate was unchanged. Common carotid artery pulsatility decreased by 38.4% [8.3-64.5, 95% confidence interval (CI)] and vertebral pulsatility by 43.8% [11.5-74.1], both p < 0.02. No significant differences were detected for other velocity and flow parameters. Middle cerebral artery mean velocity increased by 4.6 cm/s (1.6-7.8 cm/s) and diastolic velocity by 4.6 cm/s (2.4-7.3 cm/s) (both p < 0.01), but systolic velocity was unchanged. The middle cerebral pulsatility index decreased by 11% (3.8-16.1), p < 0.001. CNS 1102 is well tolerated at a fixed dose of 2 mg in normal volunteers. Cerebral arteriolar constriction is inferred from the ultrasound results.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Clinical experience with excitatory amino acid antagonist drugs.

BACKGROUND: Excitotoxic damage due to excess release of neuronal glutamate is hypothesized to play a pivotal role in the pathogenesis of focal cerebral ischemia. Drugs that antagonize excitatory amino acid function are consistently neuroprotective in preclinical models of stroke, and many are now entering clinical trials. SUMMARY: Antagonists of the N-methyl-D-aspartate (NMDA) receptor are furthest advanced in clinical development for stroke. Both noncompetitive (aptiganel hydrochloride, dextrorphan) and competitive (selfotel, d-CPPene) antagonists have undergone tolerability studies in acute stroke and traumatic brain injury. These agents all cause a similar spectrum of neuropsychological symptoms, and several have important cardiovascular effects. Other modulatory sites on the NMDA receptor complex, notably the polyamine and magnesium ion sites, are also the subject of clinical trials. Glycine site antagonists are in early clinical development. Non-NMDA glutamate receptor antagonists remain in preclinical study. Neuroprotection by agents that block glutamate release in vitro may be due to sodium channel blockade in vivo, but some agents (619C89) exhibit neurological effects similar to NMDA antagonists in stroke. The therapeutic index is unknown for different drugs but may be determined by cardiovascular effects, especially hypotension, which may be detrimental after stroke. CONCLUSIONS: Excitatory amino acid antagonists are in advanced development in the treatment of stroke and traumatic brain injury. A similar pattern of side effects is apparent with the majority of agents. However, cardiovascular effects may ultimately define therapeutic index for each drug.

Brain Ischemia↗
PubMed1995

A randomized, double-blind, placebo-controlled pilot trial of intravenous magnesium sulfate in acute stroke.

BACKGROUND AND PURPOSE: Magnesium ions act as endogenous vasodilators of the cerebral circulation and act pharmacologically as noncompetitive antagonists of the N-methyl-D-aspartate receptor by virtue of their role as endogenous voltage-sensitive blockers of the ion channel. The preclinical efficacy of magnesium has been demonstrated in standard models of stroke. METHODS: Sixty patients were randomized to magnesium sulfate (8 mmol IV over 15 minutes and 65 mmol over 24 hours) or placebo within 12 hours of clinically diagnosed middle cerebral artery stroke. Pulse, blood pressure, and serum magnesium levels were monitored. Primary outcome was death or significant functional impairment (Barthel Index score < 60) at 3 months. RESULTS: Magnesium was well tolerated, with no significant adverse effects and no change in blood pressure or pulse rate. Laboratory and electrocardiographic variables did not differ significantly between placebo- and magnesium-treated groups. Serum magnesium rose from 0.76 mmol/L to 1.42 mmol/L over 24 hours and remained significantly higher than in the placebo group at 48 hours. Thirty percent of magnesium-treated and 40% of placebo-treated patients were dead or disabled (Barthel Index score < 60) at 3 months (P = .42). There was a decrease in the number of early deaths in the magnesium-treated group (P = .066, log-rank test). CONCLUSIONS: Magnesium sulfate is well tolerated after acute stroke and has no deleterious hemodynamic effects at this dose. Further trials are required to determine efficacy.

Acute Disease↗
PubMed1995

Lack of association between angiotensin converting enzyme gene insertion/deletion polymorphism and stroke.

AIM: The human angiotensin converting enzyme (ACE) gene is a candidate genetic locus for stroke because of the importance of the renin-angiotensin system to the development of cardiovascular disease. In the present study, the association between ACE gene deletion/insertion (D/I) polymorphism and the presence or absence of ischaemic stroke was evaluated and possible associations between ACE gene polymorphism and certain subgroups of stroke were investigated. MATERIALS AND METHODS: DNA samples from 585 unselected suspected stroke patients admitted to the Acute Stroke Unit, Western Infirmary, Glasgow, and from 188 age- and sex-matched controls were genotyped by polymerase chain reaction. RESULTS: There was no evidence of any association between ACE gene polymorphism and the presence of ischaemic stroke except in the subgroup containing only hypertensive patients, where the odds ratio of a DD genotype for ischaemic stroke was just significantly greater than 1 (odds ratio 2.51, 95% confidence interval 1.06, 5.94). There was no significant association between ACE genotype and the stroke subgroups investigated. CONCLUSION: The DD genotype may not be a risk factor for stroke, particularly in the normotensive population. Further study in a strictly controlled population is required to test for the possibility of an increased risk of stroke in hypertensives with DD homozygotes.

Cerebrovascular Disorders↗
PubMed1994

Poor accuracy of stroke scoring systems for differential clinical diagnosis of intracranial haemorrhage and infarction.

The differentiation of cerebral infarction and cerebral haemorrhage is the most important first step in the management of acute stroke, because clinical management of the two disorders differs substantially. The Guy's Hospital and Siriraj stroke diagnostic scores were developed to aid clinicians in this decision. We have tested the performance of the two scores on a group of 1059 patients admitted to the acute stroke unit (ASU) at the Western Infirmary, Glasgow, with suspected stroke between May, 1990, and December, 1993. The diagnosis was confirmed as stroke by computed tomography (CT) scanning or necropsy (n = 10) in 991 patients. For each clinical score we subjectively identified the cut-off point that maximised sensitivity to cerebral haemorrhage with the smallest loss of specificity. At its optimum cut-off point the Guy's Hospital score had a sensitivity for the diagnosis of haemorrhage of 70% and specificity of 64%. The corresponding figures for the Siriraj score at its optimum cut-off point were 68% sensitivity and 64% specificity. The overall predictive accuracy of both scores was 64%. The greater complexity of the Guy's Hospital score (thirteen variables included) did not result in substantially superior performance to the Siriraj score (five variables). This validation study suggests that neither score is useful for exclusion of haemorrhage before anticoagulant treatment is initiated or as a diagnostic screening procedure for trials of low-risk treatments such as aspirin. Our findings emphasise the need for routine CT scanning in this setting, since this method remains the most accurate for differentiating between haemorrhage and infarction.

Acute Disease↗
PubMed1994

Anticardiolipin antibodies in an unselected stroke population.

A pathogenetic role in thrombotic disease, particularly in young people, has been postulated for anticardiolipin antibody (ACA). We have carried out a prospective controlled study of 262 unselected patients with acute stroke and 226 controls to assess the prevalence and relation to age and vascular risk factors of ACA. Titres of IgG, IgA, or IgM ACA were above the upper normal limit in 38% of patients. The proportions of patients and controls with raised titres did not differ significantly (13 vs 8% IgG, 22 vs 29% IgA, 11 vs 7% IgM). IgG titres were higher among patients than among controls (mean 3.88 vs 2.86 u/mL [95% CI for difference 0.62-0.87], p = 0.0004), whereas IgA and IgM titres were lower in patients than in controls (IgA 4.82 vs 5.98 u/mL [1.12-1.60], p = 0.01; IgM 3.00 vs 3.64 u/mL [1.01-1.45], p = 0.04). However, within age tertiles the only significant difference between patients and controls for IgG ACA was in the oldest tertile. Analysis by number of risk factors for stroke showed a significant difference between the groups only for subjects with one risk factor. IgA and IgM ACA titres were higher among controls only in those with no vascular risk factors. We found no evidence to support the hypothesis that ACA is an independent risk factor for stroke in young people. The increase in IgG titre with age and number of vascular risk factors in stroke patients suggests that ACA may be a non-specific accompaniment of vascular disease. Routine testing for ACA in stroke patients is not justified.

Acute Disease↗
PubMed1994

Aplastic anaemia associated with fenbufen: a report of two cases.

We report two cases of aplastic anaemia occurring in patients after exposure to the NSAID fenbufen. In each case, the patient had not been exposed to other drugs in this class, and was on no concomitant medication which has previously been associated with this complication. Failure of in vitro growth of haemopoietic progenitor cells in clonogenic assays confirmed the diagnosis of aplasia, and also confirmed that aplasia induced by this agent is not due to the presence of any humoral inhibitory factor, but to an intrinsic abnormality in the pluripotent stem cells. Aplastic anaemia is a recognized, but extremely rare, complication of exposure to NSAIDs of any chemical subtype.

Aged↗
PubMed1994

Pharmacological effects of the non-competitive NMDA antagonist CNS 1102 in normal volunteers.

1. Non-competitive antagonists at the glutamatergic N-methyl D-aspartate receptor significantly reduce the volume of ischaemic cerebral infarction in animals and are potential agents for the treatment of acute stroke in humans. 2. CNS 1102, a novel non-competitive NMDA antagonist, was administered as a 15 min intravenous infusion to healthy male volunteers in a double-blind, placebo-controlled, dose-ranging study. This was the first administration to man. 3. Clinically significant sedation, increased mean arterial pressure and pulse rate were seen at doses of 30 micrograms kg-1 and above. Symptoms of sedation and central nervous excitation became unacceptable for conscious individuals at doses of 45 micrograms kg-1 and above. 4. Rapid onset of central nervous system effects after administration is in keeping with rapid distribution of CNS 1102 to brain. Steady state volume of distribution was large (444 l) and terminal elimination half-life from plasma was approximately 4 h. 5. Pharmacokinetic properties are favourable for a potential neuroprotective therapy. The maximum tolerated dose for conscious individuals was 30 micrograms kg-1 given intravenously over 15 min. Further assessment of CNS 1102 should seek methods of drug administration which maximise administered dose with minimal side effects.

Adult↗
PubMed1994

Cardiac tamponade as the initial presentation of malignancy: is it as rare as previously supposed?

Advanced malignant disease frequently involves the heart and pericardium, and pericardial effusion is a common postmortem finding in such patients. Identification of pericardial effusions in life is uncommon, however, even when symptomatic. Cardiac tamponade occurring as the first presentation of malignancy appears to be uncommon. We present five cases of cardiac tamponade due to undiagnosed malignancy which presented to a general medical unit over 18 months. The availability of echocardiography was an important factor in correct diagnosis, since clinical features were non-specific. Bronchial adenocarcinoma was the cause in three of the five cases. Review of the literature confirms adenocarcinomas of the bronchus as the most common cause of this complication. The majority of cases have presented with large volume, haemorrhagic effusions, and cytology (with or without carcinoembryonic antigen measurement) was diagnostic in most patients. Immediate treatment with subxiphoid pericardiotomy is recommended; the role of balloon catheter pericardiotomy remains to be established. Combined chemotherapy and radiotherapy appears to extend survival, which in some cases may be prolonged. We recommend that early echocardiography should be obtained in all patients presenting with apparent cardiac failure, since early treatment of malignant effusions provides symptomatic relief.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1994

Interconversion of stroke scales. Implications for therapeutic trials.

BACKGROUND AND PURPOSE: Stroke scales are intended to measure stroke severity for the purpose of clinical trials. Scores have been used to determine trial entry, to compare patient groups within or between trials, or as a secondary end point. The use of scores as an end point in meta-analysis has not been validated, but such analyses have nevertheless been performed when equivocal results have been obtained using the main outcome measure. The different scale designs suggest that conversion of scores may not be possible. We sought to determine whether scores on different scales could be interconverted. METHODS: A single observer scored 433 consecutive admissions to an acute stroke unit on the Canadian Neurological Scale, the middle cerebral artery Neurological Score (or Orgogozo scale), and the National Institutes of Health stroke scale. Data were separated into training and test sets, and linear regression was used to model conversion between scales. Prediction errors were calculated. Strokes were subdivided according to the Oxfordshire Community Stroke Project classification, and coefficients of determination were calculated for different subtypes. RESULTS: Conversion between Canadian and middle cerebral artery Neurological scales was satisfactory (R2 = 94.7%), and prediction errors were acceptable (absolute prediction error, 5.0 +/- 5). Conversion from the National Institutes of Health scale was worse (R2 = 87.5% to Canadian and 89.0% to Neurological Score), and prediction errors were significantly greater (Neurological Score error, 8.7 +/- 7; Canadian Neurological Scale error, 8.5 +/- 7.3; P < .005 for both). Coefficients of determination for interconversion were significantly worse for dysphasic patients with total anterior circulation strokes than for other stroke types (P < .01). Reweighting the motor component of the National Institutes of Health scale improved coefficients of determination and reduced prediction errors, but prediction error for conversion to the Canadian scale remained significantly greater than other conversions (P = .001). CONCLUSIONS: The Canadian Neurological Scale and the middle cerebral artery Neurological Score may reliably be converted. The National Institutes of Health scale cannot be used to predict these scores reliably, even with reweighting of the motor score. Interconversion is poorest for patients with dysphasia and total anterior circulation strokes. These results suggest that there will be more general difficulty in interconverting scales that use different test items and weighting. Meta-analysis using sequential changes in averaged scores from various stroke scales is not valid.

Adult↗
PubMed1993

A survey of exercise testing practice in Scottish hospitals.

A 1989 survey (unpublished) of exercise testing practice in Scotland suggested that there were important differences in the practice of exercise testing between hospitals. A postal questionnaire was sent to 30 teaching and district general hospitals in 1991 and followed up by telephone questioning of consultants. The numbers of exercise tests performed had increased to 22,012 in 1990, and a greater proportion were performed in district general hospitals. General practitioners had very limited access to the service but hospital doctors of any grade had almost free access. Rationing of early post myocardial infarction testing led to attempts to define "high risk" post infarction patients and this included inappropriate patients in many hospitals. A variety of different protocols was used. Eighteen out of 30 hospitals surveyed discontinued beta blockers but only four hospitals took account of antianginal, antihypertensive or other medication, and all but one exercised patients while on digoxin. In the majority of hospitals decisions regarding drug therapy were taken by individual physicians. A variety of personnel reported tests, many without specialist training in cardiology. Even among consultants there was no concerns on the degree of ST depression which was significant. Exercise tests performed in different hospitals in Scotland are not comparable due to the wide variation in patient selection, test conditions, and interpretation of tests. This problem is likely to be exacerbated by the multiple personnel involved in all aspects of testing. It seems probable that there is a problem throughout the United Kingdom, and that there is a need for guidelines.

Exercise Test↗