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Biomedical subjects

G A Ford

Publications and source records attributed to G A Ford.

At least 19 recordsLinked to original sources
PubMed2007

Intra-arterial thrombolysis for acute stroke in patients 80 and older: a comparison of results in patients younger than 80 years.

BACKGROUND AND PURPOSE: Intra-arterial fibrinolytic therapy is a promising treatment for acute ischemic stroke. Few data are available on its use in elderly patients. The purpose of this study was to compare the baseline characteristics, complications, and outcomes between intra-arterially treated ischemic stroke patients aged > or = 80 years and their younger counterparts. METHODS: Patients aged > or = 80 years (n = 33) were compared retrospectively with contemporaneous patients aged < 80 years (n = 81) from a registry of consecutive patients treated with intra-arterial thrombolysis over a 9-year period. RESULTS: The very elderly and younger cohorts were very similar in baseline characteristics, including pretreatment stroke severity (National Institutes of Health Stroke Scale [NIHSS] 17 versus 16), differing only in history of stroke/transient ischemic attack (42% versus 22%, P = .01) and weight (66.8 versus 75.8 kg; P = .02). Significant differences in recanalization (TIMI 2-3) rates could not be detected between the very elderly and younger patients (79% versus 68%, P = .10). Rates of major symptomatic hemorrhage (7% versus 8%) and any intracerebral hemorrhage (39% versus 37%) did not differ. Outcomes at 90 days showed lower rates of excellent functional outcome (mRS < or = 1, 26% versus 40%, P = .02) and survival (57% versus 80%, P = .01) among the very elderly. CONCLUSIONS: Intra-arterial fibrinolysis in the elderly can be accomplished with recanalization rates and hemorrhage rates equal to that in younger patients. Although mortality rates are higher and good functional outcomes are lower than in younger persons, nondisabling outcomes may be achieved in a quarter of patients. These findings suggest that the investigation and use of intra-arterial thrombolytic treatment in very elderly patients should not be avoided but pursued judiciously.

Adult↗
PubMed2006

Magnesium supplementation for the management of essential hypertension in adults.

BACKGROUND: Epidemiological evidence on the effects of magnesium on blood pressure is inconsistent. Metabolic and experimental studies suggest that magnesium may have a role in the regulation of blood pressure. OBJECTIVES: To evaluate the effects of magnesium supplementation as treatment for primary hypertension in adults. SEARCH STRATEGY: We searched the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, ISI Proceedings, ClinicalTrials.gov, Current Controlled Trials, CAB abstracts, and reference lists of systematic reviews, meta-analyses and randomised controlled trials (RCTs) included in the review. SELECTION CRITERIA: Inclusion criteria were: 1) RCTs of a parallel or crossover design comparing oral magnesium supplementation with placebo, no treatment, or usual care; 2) treatment and follow-up >/=8 weeks; 3) participants over 18 years old, with raised systolic blood pressure (SBP) >/=140 mmHg or diastolic blood pressure (DBP) >/=85 mmHg; 4) SBP and DBP reported at end of follow-up. We excluded trials where: participants were pregnant; received antihypertensive medication which changed during the study; or magnesium supplementation was combined with other interventions. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted data and assessed trial quality. Disagreements were resolved by discussion or a third reviewer. Random effects meta-analyses and sensitivity analyses were conducted. MAIN RESULTS: Twelve RCTs (n=545) with eight to 26 weeks follow-up met our inclusion criteria. The results of the individual trials were heterogeneous. Combining all trials, participants receiving magnesium supplements as compared to control did not significantly reduce SBP (mean difference: -1.3 mmHg, 95% CI: -4.0 to 1.5, I(2)=67%), but did statistically significantly reduce DBP (mean difference: -2.2 mmHg, 95% CI: -3.4 to -0.9, I(2)=47%). Sensitivity analyses excluding poor quality trials yielded similar results. Sub-group analyses and meta-regression indicated that heterogeneity between trials could not be explained by dose of magnesium, baseline blood pressure or the proportion of males among the participants. AUTHORS' CONCLUSIONS: In view of the poor quality of included trials and the heterogeneity between trials, the evidence in favour of a causal association between magnesium supplementation and blood pressure reduction is weak and is probably due to bias. This is because poor quality studies generally tend to over-estimate the effects of treatment. Larger, longer duration and better quality double-blind placebo controlled trials are needed to assess the effect of magnesium supplementation on blood pressure and cardiovascular outcomes.

Adult↗
PubMed2006

Combined calcium, magnesium and potassium supplementation for the management of primary hypertension in adults.

BACKGROUND: Previous research suggests that increasing dietary intakes of calcium, potassium or magnesium separately may reduce BP to a small degree over the short term. It is unclear whether increasing intakes of a combination of these minerals produces a larger reduction in BP. OBJECTIVES: To evaluate the effects of combined mineral supplementation as a treatment for primary hypertension in adults. SEARCH STRATEGY: We searched the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, ISI Proceedings, ClinicalTrials.gov, Current Controlled Trials, CAB abstracts, and reference lists of systematic reviews, meta-analyses and randomised controlled trials (RCTs) included in the review. The search was unrestricted by language or publication status. SELECTION CRITERIA: Inclusion criteria were: 1) RCTs of a parallel or crossover design comparing oral supplements comprising a combination of potassium, and/or calcium, and/or magnesium with placebo, no treatment, or usual care; 2) treatment and follow-up >=8 weeks; 3) participants over 18 years old, with raised systolic blood pressure (SBP) >=140 mmHg or diastolic blood pressure (DBP) >=85 mmHg with no known primary cause; 4) SBP and DBP reported at end of follow-up. We excluded trials where participants were pregnant, or received antihypertensive medication which changed during the study. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. Disagreements were resolved by discussion or a third reviewer. Random effects meta-analyses and sensitivity analyses were conducted. MAIN RESULTS: We included three RCTs (n=277) with between 24 and 28 weeks follow-up. Three combinations of minerals were investigated: potassium & magnesium, calcium & magnesium, and calcium & potassium. One trial investigated combinations of calcium & magnesium and of calcium & potassium, and for each found a statistically non-significant increase in both SBP and DBP. All three trials investigated the combination of potassium & magnesium. None of the trials provided data on mortality or morbidity. The combination of potassium & magnesium compared to control resulted in statistically non-significant reductions in both SBP (mean difference = -4.6 mmHg, 95% CI: -9.9 to 0.7) and DBP (mean difference = -3.8 mmHg, 95% CI: -9.5 to 1.8), although the results were heterogeneous (I(2)=68% and 85% for SBP and DBP respectively).A sensitivity analysis using alternative reported values which accounted for missing data had very little effect on DBP but resulted in a larger, statistically significant reduction in SBP (mean difference = -5.8 mmHg, 95% CI: -10.5 to -1.0). The quality of the trials was not well reported. AUTHORS' CONCLUSIONS: We found no robust evidence that supplements of any combination of potassium, magnesium or calcium reduce mortality, morbidity or BP in adults. More trials are needed to investigate whether the combination of potassium & magnesium is effective.

Adult↗
PubMed2006

Calcium supplementation for the management of primary hypertension in adults.

BACKGROUND: Metabolic studies suggest calcium may have a role in the regulation of blood pressure. Some epidemiological studies have reported that people with a higher intake of calcium tend to have lower blood pressure. Previous systematic reviews and meta-analyses have reached conflicting conclusions about whether oral calcium supplementation can reduce blood pressure. OBJECTIVES: To evaluate the effects of oral calcium supplementation as a treatment for primary hypertension in adults. SEARCH STRATEGY: We searched the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, ISI Proceedings, ClinicalTrials.gov, Current Controlled Trials, CAB abstracts, and reference lists of systematic reviews, meta-analyses and randomised controlled trials (RCTs) included in the review. SELECTION CRITERIA: Inclusion criteria were: 1) RCTs comparing oral calcium supplementation with placebo, no treatment, or usual care; 2) treatment and follow-up >/=8 weeks; 3) participants over 18 years old, with raised systolic blood pressure (SBP) >/=140 mmHg or diastolic blood pressure (DBP) >/=85 mmHg; 4) SBP and DBP reported at end of follow-up. We excluded trials where: participants were pregnant; received antihypertensive medication which changed during the study; or calcium supplementation was combined with other interventions. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted data and assessed trial quality. Disagreements were resolved by discussion or a third reviewer. Random effects meta-analyses and sensitivity analyses were conducted. MAIN RESULTS: We included 13 RCTs (n=485), with between eight and 15 weeks follow-up. The results of the individual trials were heterogeneous. Combining all trials, participants receiving calcium supplementation as compared to control had a statistically significant reduction in SBP (mean difference: -2.5 mmHg, 95% CI: -4.5 to -0.6, I(2 )= 42%), but not DBP (mean difference: -0.8 mmHg, 95% CI: -2.1 to 0.4, I(2) = 48%). Sub-group analyses indicated that heterogeneity between trials could not be explained by dose of calcium or baseline blood pressure. Heterogeneity was reduced when poor quality trials were excluded. The one trial reporting adequate concealment of allocation and the one trial reporting adequate blinding yielded results consistent with the primary meta-analysis. AUTHORS' CONCLUSIONS: In view of the poor quality of included trials and the heterogeneity between trials, the evidence in favour of causal association between calcium supplementation and blood pressure reduction is weak and is probably due to bias. This is because poor quality studies generally tend to over-estimate the effects of treatment. Larger, longer duration and better quality double-blind placebo controlled trials are needed to assess the effect of calcium supplementation on blood pressure and cardiovascular outcomes.

Adult↗
PubMed2006

Factors affecting the use of cumulative sums in the analysis of circadian blood pressure.

The assessment of circadian blood pressure change by ambulatory blood pressure monitoring has potential as a predictor for cardiovascular events, but its evaluation is problematic due to the difficulty in defining day and night periods for individual subjects. The cumulative sums (cusums) method has the advantage of simplicity over mathematical modelling techniques and is reported to give more reproducible results than methods that use time-dependent sleep and wake periods. However, cusum parameters (cusum-derived circadian alteration magnitude (CDCAM) and cusum plot height (CPH)) are affected by the implementation of the method and by the quality of ambulatory blood pressure recordings. This study quantifies the effects of using interval blood pressure values, changing the time used for calculating the cusum plot slope (CPS) and using incomplete data recordings. Significant effects are reported in all cases. Using interval rather than recorded blood pressures causes a mean reduction in CPH and CDCAM of approximately 6%. Altering the CPS time by 1 h (from 6 h) results in a mean change in CDCAM of approximately 7%. In recordings with hourly readings, the coefficient of variation in CPH and CDCAM ranges from 4% (one missing reading) to 13% (five missing readings).

Aged↗
PubMed2005

Intravenous thrombolysis for acute ischaemic stroke: preliminary experience with recombinant tissue plasminogen activator in the UK.

OBJECTIVE: To present the preliminary experience of implementing intravenous thrombolytic therapy for acute ischaemic stroke in three UK stroke centres. BACKGROUND: Recombinant tissue plasminogen activator for ischaemic stroke received approval from UK regulatory authorities in April 2003. Since 1997, a small number of UK centres had used thrombolytic therapy in highly selected stroke patients. We present the early experience of that treatment in Glasgow and Newcastle. DESIGN: Patients were selected and treated in accordance with the American Heart Association guidelines. Additionally, radiologic criteria employed in the European-Australasian Acute Stroke Studies were applied. National Institutes of Health Stroke Scale (NIHSS) scores were measured on admission, and Modified Rankin Scale (MRS) scores were assessed at 3 months for all patients with stroke treated prior to initiation of the Safe Implementation of Thrombolysis in Stroke monitoring program for implementation of thrombolysis in stroke in April 2001. Intracranial and systemic haemorrhagic complications were recorded. RESULTS: 120 patients received thrombolytic treatment (approximately 1% of all admissions with presumed stroke). Mean age was 69 years (range 22-93) and initial median NIHSS score was 17 (range 3-31). In the two centres for which temporal data were available, the mean delay between symptom onset and treatment was 139 min (range 20-185). Sixteen episodes of cerebral haemorrhage or haemorrhagic transformation of any degree occurred, of which 5 (4%) were symptomatic. One patient deteriorated and died before repeat CT imaging could be performed. One non-fatal episode of systemic bleeding occurred. One patient was lost to follow-up. At 3 months, 31% of recipients had achieved good (MRS 0-1) outcome, 22% moderate (MRS 2-3) outcome and 21% (MRS 4-5) poor outcome. Twenty-one per cent died within 3 months of stroke. Observed frequency of bleeding complications and protocol violations (6%) was similar to those reported elsewhere. CONCLUSION: A small proportion of stroke patients received thrombolytic treatment. Patients treated were more severely affected than in other published European and North American series. Outcomes and complications were consistent with experience elsewhere.

Acute Disease↗
PubMed2004

Hippocampal atrophy, whole brain volume, and white matter lesions in older hypertensive subjects.

OBJECTIVE: To determine the potential role of whole brain atrophy, hippocampal atrophy, or both, and small vessel disease/white matter lesions as mechanisms underlying the cognitive impairment associated with hypertension. METHODS: Using MRI scanning the authors determined hippocampal volumes, whole brain volumes, and location and severity of white matter lesions, using Scheltens scale, in 103 hypertensive (166 +/- 8/88 +/- 7 mm Hg, 54 female) and 51 normotensive (132 +/- 12/74 +/- 7 mm Hg, 21 female) subjects age > or = 70 years. RESULTS: Compared to normotensive subjects, older hypertensive subjects had significantly smaller whole brain volumes (887 +/- 109 vs 930 +/- 97 cm3, p = 0.02) and nonsignificantly reduced hippocampal volumes (5.39 +/- 1.60 vs 5.67 +/- 1.80 cm3, p = 0.33). Hypertensive subjects had an increased burden of periventricular lesions: bands (p = 0.03), frontal caps (p = 0.08), occipital caps (p = 0.07), and total periventricular hyperintensities (p = 0.02). They also had higher scores in subcortical areas: frontal (p = 0.04), temporal (p = 0.03), and deep white matter areas (p = 0.05). A correlation was found between whole brain volumes and systolic blood pressure (r = -0.19, p = 0.02). No correlation was seen between whole brain volumes and white matter lesion burden. CONCLUSIONS: Moderate hypertension in non-impaired older subjects is associated with smaller whole brain volume and an increased burden of subcortical and periventricular white matter lesions.

Aged↗
PubMed2004

Agreement between ambulance paramedic- and physician-recorded neurological signs with Face Arm Speech Test (FAST) in acute stroke patients.

BACKGROUND AND PURPOSE: Patients with suspected stroke first assessed by ambulance paramedics require early recognition to facilitate appropriate triage and early treatment. We determined paramedic's accuracy in detecting acute stroke signs by comparing agreement between neurological signs recorded in the Face Arm Speech Test (FAST), a stroke recognition instrument, by paramedics on the scene and by stroke physicians after admission. METHODS: Suspected stroke patients admitted by ambulance paramedics directly to an acute stroke unit through a rapid ambulance protocol were examined by a trainee stroke neurologist or admitting stroke physician over a 1-year period. Recorded neurological signs (facial weakness, arm weakness, speech disturbance) in confirmed acute stroke/transient ischemic attack (TIA) cases were compared between paramedics and the stroke neurologist/physician. RESULTS: Ambulance crews referred 278 suspected stroke patients of whom 217 (78%) had confirmed stroke (n=189) or TIA (n=28); 95% were examined by the stroke neurologist (median 18 hours after paramedic assessment). Recorded signs and agreement between paramedics and stroke physicians in confirmed stroke group were: facial weakness, 68% versus 70% (kappa=0.49; 95% CI: 0.36 to 0.62); arm weakness, 96% versus 95% (kappa=0.77; 95% CI: 0.55 to 0.99); and speech disturbance, 79% versus 77% (kappa=0.69; 95% CI: 0.56 to 0.82). Interrater agreement was complete for arm weakness in 98% cases. CONCLUSIONS: Recognition of neurological deficits by ambulance paramedics using FAST shows good agreement with physician assessment, even allowing for temporal evolution of deficits. The high prevalence and good agreement for arm weakness suggest that this sign may have the greatest usefulness for prehospital ambulance triage and paramedic-based neuroprotective trials.

Acute Disease↗
PubMed2004

Stroke, dementia, and drug delivery.

Stroke and dementia represent a major health burden for elderly subjects as they are associated with significant morbidity and mortality. The rates of stroke and dementia are progressively increasing due to the ageing population in most westernized countries. Therefore, both these conditions represent a major therapeutic target. However, the therapeutic options available for the management of stroke and dementia remain largely unsatisfactory, the main reason being the difficulty in transferring the results obtained in animal and in vitro studies to the clinical setting. This review focuses on the recent advances in pathophysiology and treatment of these conditions and future directions for research. Moreover, the technique of functional magnetic resonance imaging is discussed in detail as a tool to assess the effects of therapeutic agents on the central nervous system and monitor the progression of diseases. Finally, an overview of the issue of drug delivery into the central nervous system is presented.

Anticholesteremic Agents↗
PubMed2003

White matter disease and sleep-disordered breathing after acute stroke.

OBJECTIVE: To assess sleep-disordered breathing (SDB) in patients with acute stroke and its relationship to prestroke cerebrovascular disease, particularly leukoariosis. METHODS: The authors studied SDB and CT evidence of prestroke cerebrovascular disease, nonacute brain infarction, and white matter disease (WMD) in 78 previously independent patients with acute stroke. Subjects underwent respiratory sleep studies to determine the Apnea-Hypopnea Index (AHI) and Desaturation Index (DI) 7 to 14 days following stroke. CT scans were evaluated for severity of acute prestroke cerebrovascular disease and WMD severity. RESULTS: Prestroke cerebrovascular disease was present in 49 (63%) patients and was associated with worse SDB (mean AHI 35 vs 23, p < 0.01; mean DI 28 vs 18, p < 0.05), particularly in men (mean AHI 43 vs 27, p < 0.01). WMD severity correlated with AHI (r = 0.26, p < 0.05) and age (r = 0.56, p < 0.01). WMD severity in frontal and basal ganglia areas showed the strongest association. On multivariate analysis, WMD severity correlated independently with AHI (R(2) = 0.07, p < 0.05). CONCLUSIONS: The presence of prestroke cerebrovascular disease and severity of WMD are associated with worse SDB. These findings suggest that either white matter is particularly vulnerable to the hypoxia and blood pressure variability associated with SDB or that WMD is a major factor exacerbating SDB following stroke.

Acute Disease↗
PubMed2003

Tolerability of NXY-059 at higher target concentrations in patients with acute stroke.

BACKGROUND AND PURPOSE: NXY-059 is a nitrone-based free radical-trapping agent in development for acute stroke. In patients with acute stroke, NXY-059 is well tolerated at concentrations known to be associated with neuroprotection in animal models of transient cerebral ischemia; however, higher target concentrations appear necessary on the basis of animal models of permanent ischemia. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, dose-escalation, multicenter study that evaluated safety, tolerability, and plasma concentrations of 2 NXY-059 dosing regimens within 24 hours of acute stroke. NXY-059 was administered as either 915 mg over 1 hour followed by 420 mg/h for 71 hours or 1820 mg for 1 hour followed by 844 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded for up to 30 days. RESULTS: One hundred thirty-five patients were recruited, of whom 134 received study treatment and completed assessments (844 mg/h, n=39; 420 mg/h, n=48; placebo, n=47). Mean age was 69 years (range, 34 to 92 years), and baseline National Institutes of Health Stroke Scale score was 8.5 (SD, 6.6). Serious adverse events occurred in 3, 17, and 13 patients, respectively, with deaths in 0, 4, and 3 patients and treatment discontinuations because of adverse events in 0, 1, and 3 patients. Good outcome, defined by modified Rankin Scale score of 0 or 1, was seen in 53%, 29% and 40%, respectively. No safety concern was identified in analysis of body temperature, blood pressure, or other laboratory parameters. The unbound plasma concentration at steady state was 260+/-79 micromol/L, exceeding the target of 200 micromol/L in the high-dose group. CONCLUSIONS: NXY-059 was well tolerated in patients with an acute stroke at and above concentrations shown to be neuroprotective in an animal model when initiated 4 hours after onset of permanent focal ischemia.

Adult↗
PubMed2002

Sleep-disordered breathing following acute stroke.

BACKGROUND: The reported prevalence of sleep apnoea following stroke varies between 44% and 72%, but its course and relations are unclear. AIM: To determine the prevalence and course of sleep-disordered breathing in acute stroke in-patients, and its relation to age, stroke subtype, pre-stroke handicap and post-stroke outcome. DESIGN: Prospective uncontrolled observational study. METHODS: Paired respiratory sleep studies were performed at week 2 and week 6-9 following stroke. Pre- and post-stroke handicap (modified Rankin Score) and week 2 and week 6-9 disability (Barthel Score) and impairment (Scandinavian Neurological Stroke Score) were assessed. Pre-stroke sleepiness was determined by Epworth Score. RESULTS: There were 68 patients in the week 2 study, and 50 in the week 6-8 study. Mean week 2 Apnoea Hypopnoea Index (AHI) was 30; 64 patients (94%) had an AHI > or =10. Mean AHI was higher in subjects with lacunar vs. cortical strokes (44 vs. 28, p<0.05), in subjects aged > or =65 years (32 vs. 21, p<0.05) and in those with greater pre-stroke handicap (modified Rankin Score 2 vs. <2) (41 vs. 27, p<0.05). In 50 paired studies, mean AHI fell from 31 to 24 (p<0.01) and the proportion with AHI > or =10 fell from 96% to 72%. Pre-stroke sleepiness was associated with post-stroke neurological impairment (r=-0.325, p<0.05) and disability (r=-0.377, p<0.05). DISCUSSION: Sleep-disordered breathing improves in the first 6-9 weeks following stroke, but remains highly prevalent. Worse sleep-disordered breathing was observed following lacunar stroke, and in older subjects or those with pre-stroke handicap.

Acute Disease↗
PubMed2001

Nitric oxide signaling mechanisms in the forearm vasculature of pregnant women.

During pregnancy, forearm blood flow and constrictor responses to nitric oxide synthase inhibition are enhanced. Responses to brachial artery infusion of N(G)-monomethyl-L -arginine in pregnant women who have normal resting forearm blood flow and in pregnant women who have norepinephrine-induced reduced forearm blood flow were no different. Mechanisms independent of acute flow effects may account for the enhanced vascular nitric oxide activity during pregnancy.

Blood Flow Velocity↗
PubMed2001

Management of older patients with hypertension in primary care: improvement on the rule of halves.

OBJECTIVES: the benefits of treatment of hypertension in older people are well-established but implementation of this knowledge may be sub-optimal. We have determined recent primary care management of older people with hypertension. METHODS: we examined health records (n = 6986) of a 1 in 7 sample of patients aged 65-80 years from a random sample of practices (n = 51) in the former Northern Region of the UK, stratified by health authority, for the previous 6 years. We recorded documented risk factors, diagnosis of hypertension, three most recent blood pressure readings, current drug therapy and previous blood pressure lowering therapy, and presence of coexistent pathology. RESULTS: blood pressure was defined as hypertensive (> or = 160/> or = 90 mmHg; one or both values above these limits), normotensive or undetermined using a validated algorithm. In 30% of patients, blood pressure status was undetermined. Thirty-five percent of subjects were found to be hypertensive. Of these, 70% were receiving antihypertensive treatment but only 30% of treated patients had controlled (< 150 and 90 mmHg) and 13% well controlled (< 140 and 85 mmHg) blood pressure. In all, 14% of older hypertensive patients were detected, treated and had their hypertension controlled. There were significant differences between practices in the proportion of hypertensive patients treated (P < 0.001) and in the proportion of hypertensive patients whose blood pressure was controlled (P < 0.01). CONCLUSIONS: treatment of hypertension in older people in primary care has improved in terms of detection and treatment but in only one-third of patients is high blood pressure controlled. There remain important opportunities for prevention of stroke and myocardial infarction in this age group through achieving improved blood pressure control.

Aged↗
PubMed2001

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.

Aged↗
PubMed2001

Tolerability and pharmacokinetics of the nitrone NXY-059 in patients with acute stroke.

BACKGROUND AND PURPOSE: Increased free radical formation contributes to the damage caused to the brain by acute ischemia. NXY-059 is a nitrone-based free radical trapping agent in development for acute stroke. NXY-059 has neuroprotective efficacy when given 5 hours after onset of transient focal ischemia in the rat. METHODS: This was a randomized, double-blind, placebo-controlled, parallel group, multicenter study that evaluated the safety and tolerability of 2 NXY-059 dosing regimens compared with placebo within 24 hours of acute stroke. NXY-059 was administered as either 250 mg over 1 hour followed by 85 mg/h for 71 hours or 500 mg over 1 hour followed by 170 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded up to 30 days. RESULTS: One hundred fifty patients were recruited, of whom 147 received study treatments and completed assessments (50 placebo, 48 lower-dose NXY-059, 49 higher-dose NXY-059). Mean (+/-SD) age was 68 (+/-10) years, and baseline National Institutes of Health Stroke Scale score was 7.9 (+/-6.2). Serious adverse events occurred in 16%, 23%, and 16% of patients, respectively, with deaths in 0%, 10%, and 4%, largely following the proportions with primary intracerebral hemorrhage (6%, 16%, and 8%). Hyperglycemia, headache, and fever were common but not related to treatment. The mean unbound steady state NXY-059 plasma concentrations were 25 and 45 micromol/L, respectively. Population pharmacokinetic analysis estimated clearance to be 4.6 L/h. CONCLUSIONS: NXY-059 was well tolerated in patients with an acute stroke. The testing of higher doses in future trials may be justified.

Adult↗