Inhibition of Immune Thrombocytopenic Purpura (ITP) by an Orally Bioavailable Inhibitor of Syk Kinase Activity.
Bibliographic record
Abstract
Abstract Immune Thrombocytopenic Purpura (ITP) is an autoimmune disease characterised by the destruction of platelets by pathogenic autoantibodies. Clearance of platelets by phagocytic cells such as macrophages occurs through activating receptors for the Fc portion of IgG (FcγR). A central tyrosine kinase in this activation pathway is Syk, which is required for FcγR-mediated phagocytosis; thus, we questioned whether inhibition of Syk would ameliorate ITP. R406 is an orally bioavailable Syk-kinase inhibitor which is well tolerated by human volunteers. Using a well-described murine model of ITP, we tested the ability of R788 (the prodrug of R406) to ameliorate thrombocytopenia. Mice injected with an antibody directed to integrin αIIβ were profoundly thrombocytopenic when platelets were enumerated 24 hr post injection. However, mice pre-treated with 25 or 40 mg/kg R788 were protected from thrombocytopenia. Mice pre-treated with the vehicle alone displayed no protection. It has been demonstrated that chimeric Syk deficient mice display a bleeding diathesis; it was therefore questioned whether treatment of mice would demonstrate prolonged tail vein bleeding time. In independent experiments, mice treated with the with the bioavailable inhibitor R406 had no significant difference in bleeding time compared to untreated mice or mice treated with vehicle alone. Syk is also involved in collagen-induced platelet secretion and aggregation. To further the potential use of this drug in humans, the ability of platelets derived from human volunteers treated with R788 to respond to in vitro collagen-induced aggregation was analysed. Platelets from volunteers treated with the drug displayed normal collagen (as well as ADP)-induced platelet aggregation compared to untreated volunteers or those treated with the vehicle alone. These data suggest that future investigation of Syk inhibition in autoimmune diseases such as ITP is warranted.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".