Published online before print June 12, 2003, doi: 10.1161/01.STR.0000078563.72650.61
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(Stroke. 2003;34:1704.)
© 2003 American Heart Association, Inc.
Original Contributions |
UK-279,276, a Neutrophil Inhibitory Glycoprotein, in Acute Stroke
Tolerability and Pharmacokinetics
From the University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, UK (K.R.L.); Department of Neurology, University Hospital, Essen, Germany (H.C.D.); Department of Medicine, University Hospital, Umea, Sweden (K.A.); and Pfizer Sandwich, Kent, UK (M.K.).
Correspondence to Professor K.R. Lees, University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, G11 6NT, UK. E-mail k.r.lees{at}clinmed.gla.ac.uk
Background and Purpose— UK-279,276, a recombinant glycoprotein, binds selectively to the CD11b/CD18 integrin on neutrophils and has the potential to modulate the neuroinflammation associated with acute stroke. After preclinical evidence of neuroprotection, UK-279,276 has entered clinical development. The purposes of this study were to evaluate the safety and tolerability of UK-279,276 and to examine its pharmacokinetics and pharmacodynamics (binding to neutrophil CD11b) in patients with acute stroke.
Methods— This was a multicenter, double-blind, dose-escalation study in 176 patients randomized to a single intravenous dose of UK-279,276 (6 cohorts: 0.06, 0.1, 0.2, 0.5, 1.0, 1.5 mg/kg) or placebo (3:1 randomization within each cohort) within 12 hours of stroke onset.
Results— Age and stroke severity were well balanced across groups, with a mean age of 70 years (range, 39 to 92 years) and moderate baseline stroke severity (mean Scandinavian Stroke Scale score, 36.5 to 43.2; mean National Institutes of Health Stroke Scale score, 6.3 to 8.5). UK-279,276 was well tolerated at doses up to 1.5 mg/kg. There was no evidence of a relationship between dose of UK-279,276 and adverse events or clinical chemistry or hematology laboratory tests, or of an increased incidence of infection-related adverse events with the study drug. A dose-dependent UK-279,276-specific IgG antibody response was observed in patients treated with the 1.0- and 1.5-mg/kg doses. UK-279,276 displayed nonlinear pharmacokinetics across the dose range investigated. The duration of CD11b saturation was dose dependent, with >80% saturation achieved for at least 7 days after treatment with UK-279,276 1.0 and 1.5 mg/kg.
Conclusions— UK-279,276 was well tolerated in acute stroke patients at single doses up to 1.5 mg/kg. Further clinical investigation of UK-279,276 is ongoing.
Key Words: antigens • neuroprotection • neutrophils • stroke, acute • treatment outcome
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