Effect of Clozapine on Neutrophil Kinetics in Rabbits
Bibliographic record
Abstract
Clozapine is an atypical antipsychotic drug effective in the treatment of refractory schizophrenia; however, its use is limited due to its propensity to cause agranulocytosis in some patients. Little is known about the mechanism of idiosyncratic drug-induced agranulocytosis, in part because of the lack of a valid animal model. Clozapine is oxidized by activated human neutrophils and bone marrow cells to a reactive nitrenium ion by the myeloperoxidase-hydrogen peroxide system of neutrophils. This reactive metabolite has been shown in vitro to induce the apoptosis of neutrophils and bone marrow cells. While in vitro studies demonstrated the toxic potential of clozapine upon oxidation, it is not clear if similar conditions occur in vivo. In response to the difficulties encountered with detecting apoptotic neutrophils in vivo, we conducted a series of studies in rabbits using two fluorescent cell-labeling techniques to study the effect of clozapine treatment on neutrophil kinetics, that is, their rates of production and removal from circulation. The fluorescein dye, 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester (CFSE), was used as a general cell label to measure the half-life of neutrophils in blood. In addition, the thymidine analogue, 5-bromo-2-deoxyuridine (BrdU), was used to label dividing cells, thus enabling the measurement of the efflux of neutrophils from the bone marrow. Clozapine, indeed, increased the rate of both the release of neutrophils from the bone marrow and their subsequent disappearance from circulation. Failure of the bone marrow to compensate for a shorter neutrophil half-life could lead to agranulocytosis. Alternatively, the damage to neutrophils caused by clozapine could, in some patients, lead to an immune-mediated response against neutrophils resulting in agranulocytosis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".