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.

The 1996 Leicestershire Community Stroke & Ethnicity Study: differences and similarities between South Asian and white strokes.

OBJECTIVE: To estimate the number of strokes in Leicestershire and investigate possible differences between South Asian and white patients. DESIGN: Prospective incidence sample survey. SETTING: Leicestershire. PARTICIPANTS: Acute stroke cases occurring in registered populations of 12 'high Asian' and 11 'low Asian' general practices. RESULTS: The age-specific incidence rates of stroke in Leicestershire were similar to those of the Oxford Community Stroke Project. South Asian patients were less likely to be living alone at home before their stroke and they tended to be younger than whites. However, only 12% of South Asian patients with a stroke were not admitted to hospital within 7 days of their stroke compared to 23% of white patients (chi2 = 3.24, d.f. = 1, P = 0.07). Only 21% of South Asian patients died within 28 days of their stroke compared to 33% of white patients (age-adjusted odds ratio = 0.37; 95% CI: 0.14-0.97). CONCLUSIONS: Overlapping case-finding was crucial to finding all 'possible' strokes and this required close collaborative working between general practices, community health services, hospitals and the health authority. Relatively fewer South Asian patients were managed in the community in the first 7 days. Interestingly, South Asian patients were less likely than white patients to die within 28 days. This is an area worthy of further research.

Impaired dexterity of the ipsilateral hand after stroke and the relationship to cognitive deficit.

BACKGROUND AND PURPOSE: Previous research has reported impaired hand function on the "unaffected" side after stroke, but its incidence, origins, and impact on rehabilitation remain unclear. This study investigated whether impairment of ipsilateral dexterity is common early after middle cerebral artery stroke and explored the relationship to cognitive deficit. METHODS: Thirty patients within 1 month of an infarct involving the parietal or posterior frontal lobe (15 left and 15 right hemisphere) used the ipsilateral hand in tests that simulated everyday hand functions. Performance was compared with that of healthy age-matched controls using the same hand. Standardized tests were used to assess apraxia, visuospatial ability, and aphasia. RESULTS: All patients were able to complete the dexterity tests, but video analysis showed that performance was slow and clumsy compared with that of controls (P<0.001). Impairment was most severe after left hemisphere damage, and apraxia was a strong correlate of increased dexterity errors (P<0.01), whereas reduced ipsilateral grip strength correlated with slowing (P<0.05). The pattern of performance was different for patients with right hemisphere damage. Here there was no correlation between grip strength and slowing, while dexterity errors appeared to be due to visuospatial problems. CONCLUSIONS: Subtle impairments in dexterity of the ipsilateral hand are common within 1 month of stroke. Ipsilateral sensorimotor losses may contribute to these impairments, but the major factor appears to be the presence of cognitive deficits affecting perception and control of action. The nature of these deficits varies with side of brain damage. The effect of impaired dexterity on functional outcome is not yet known.

Microvascular skin responses in elderly people with varicose leg ulcers.

The function of cutaneous primary afferent unmyelinated nerves (C-fibres) was assessed by measuring axon reflex vasodilatation in the skin over the arms and feet of 15 elderly patients with chronic venous ulcers using a laser Doppler flowmeter. Dilatation of skin microvasculature in response to nerve-independent stimuli was also assessed. Results were compared with those of control subjects matched for age and sex. The chronic venous ulcer group showed reduced axon reflex vasodilatation in the feet but not the arms. Response to nerve-independent vasodilators was similar in both ulcer patients and controls in arms and feet. Local impairment of C-fibre function may partly explain the increased incidence and resistance to healing of leg ulcers in old people.

Use of rehabilitation apartments for elderly patients.

Sixty-three admissions to rehabilitation apartments were studied. In almost half of patients the actual outcome on discharge disagreed with the occupational therapy assessment after using the apartment. Patients who were placed in the apartment to help them gain insight into their disabilities remained unconvinced--the majority returning home despite advice. Although rehabilitation apartments may improve patient morale they should not be used to predict ability to survive at home or to dissuade patients who seem likely to fail from returning there.