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A study of the haematological and immunological effects of GrobetaT in normal healthy volunteers

Hennessy, Brian James; (2003) A study of the haematological and immunological effects of GrobetaT in normal healthy volunteers. Doctoral thesis (M.D), UCL (University College London). Green open access

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GroβT (SB-251353) is a recombinant N-terminal 4-amino acid truncated form of the human chemokine Groβ. Preclinical data from mice and rhesus monkeys have shown that single doses of GroβT induce a rapid mobilisation of high quality haemopoietic stem cells and neutrophils and have a synergistic effect over G-CSF (granulocyte-colony stimulating factor) alone. Prephase I clinical trials in healthy male volunteers were developed to investigate the effects of GroβT both subcutaneously and intravenously in a placebo controlled, dose escalating manner in humans. The effects on neutrophil count, peripheral blood stem cell (PBSC) [CD34 cell] mobilisation, clonogenic colony growth (granulocyte-macrophage and megakaryocyte), neutrophil activation, neutrophil function and CD4 T helper cell subsets (Th1:Th2) ratios were investigated. GroβT was administered in nine escalating doses intravenously (0.2 to 200 ?g/kg) and eight escalating doses subcutaneously (0.2 to 500 μg/kg). Subjects were dosed in groups of 3 or 4 with either placebo or active compound with up to 16 samples taken per dosing session. A high degree of reproducibility was obtained in the assays used including the more difficult functional asssays (neutrophil function and CD4 subset analysis). Biological variation in response between individuals was observed. Increases in neutrophil count over baseline values and controlled for placebo response of up to 16.3 x 109/1 were seen. Counts increased within 15 minutes of administration with a maximum effect by 45 minutes and lasted up to 8 hours. Although a mild increase in CD34 cells (up to 7.6 cells/?l) was seen, clinically significant mobilisation of PBSCs was not recorded. GroβT did not cause neutrophil activation. Changes in neutrophil function were noted but were variable with dose and individual as were effects on Th1:Th2 ratio. The drug was well tolerated with a low incidence of side effects. GroβT effectively mobilises neutrophils but not PBSCs in the doses and conditions studied.

Type: Thesis (Doctoral)
Qualification: M.D
Title: A study of the haematological and immunological effects of GrobetaT in normal healthy volunteers
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Chemokines
URI: https://discovery.ucl.ac.uk/id/eprint/10101367
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