title: Leukocyte counts in cerebrospinal fluid and blood following firategrast treatment in subjects with relapsing forms of multiple sclerosis.
abstract: OBJECTIVE
  Firategrast is an orally bioavailable alpha4 beta1/alpha4 beta7 integrin antagonist designed to reduce trafficking of lymphocytes into the central nervous system (CNS). This could decrease multiple sclerosis (MS) activity, but may compromise CNS immune surveillance. We aimed to quantitate the effect of firategrast treatment on cerebrospinal fluid (CSF) lymphocyte count and the extent/speed of recovery after its discontinuation.
  
  
  METHODS
  Forty-six subjects with relapsing forms of MS were treated for up to 24 weeks with open-label firategrast, 900 (females) or 1200 (males) mg twice daily. CSF and blood cell counts, and lymphocyte composition were determined using flow cytometry.
  
  
  RESULTS
  Median (n, range) CSF lymphocyte counts (cells/µl) at weeks 0, 24, 28 and 36 were: 5.3 (44, 0.3-70.2), 3.3 (31, 0.0-99.0), 3.0 (32, 0.0-58.2) and 3.5 (29, 0.0-274.8). CD4+, CD8+ T- and CD19+ B-lymphocyte counts followed a similar pattern. Minimal changes were observed for CD3-CD16+CD56+ natural killer cells. Median CD4 : CD8 ratios were: 2.9 (41, 1.1-10.9), 2.2 (29, 0.6-5.9), 3.8 (28, 1.6-9.0) and 3.8 (21, 2.1-9.4). Blood lymphocyte counts were elevated at weeks 4 and 24, consistent with the mechanism of firategrast, and returned to baseline when firategrast was discontinued. There were minimal changes in CD4 : CD8 ratios.
  
  
  CONCLUSIONS
  Firategrast treatment was associated with modest decreases in median CSF total, CD4, CD8 and CD19 lymphocyte counts. The generally small magnitude of decreases suggests that sufficient numbers of lymphocytes can access the subarachnoid space, preserving CNS immune surveillance.
authors: Neurosciences Clinical Statistics, GlaxoSmithKline, Uxbridge, UK. richard.a.grove@gsk.com
authors: R A
authors: RA
authors: Grove
authors: S
authors: S
authors: Shackelford
authors: S
authors: S
authors: Sopper
authors: S
authors: S
authors: Pirruccello
authors: J
authors: J
authors: Horrigan
authors: E
authors: E
authors: Havrdova
authors: M
authors: M
authors: Gold
authors: O
authors: O
authors: Graff
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000037:antagonists & inhibitors*; D007958:Leukocyte Count; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D039041:Integrin alpha4beta1; D016023:Integrins; C071777:integrin alpha4beta7; C585685:Firategrast