Practical considerations in the use of intravenous tacrolimus in hematopoietic stem cell transplantation patients
Bibliographic record
Abstract
Graft-versus-host-disease (GvHD) is the most frequent and important complication after allogeneic hematopoietic stem cell transplantation (HSCT). Despite aggressive immunosuppressive prophylaxis, GvHD can still occur even when the donor is a perfectly matched sibling. Prevention and treatment of GvHD remain a major challenge in allogeneic stem cell transplantation. Most centres use a combination of a calcineurin inhibitor (cyclosporine or tacrolimus) in conjunction with a short course methotrexate as prophylaxis of GvHD. Methylprednisolone in combination with a calcineurin inhibitor is the first-line treatment for acute GvHD. Patients with failure of initial therapy will receive a secondary treatment with tacrolimus, mycophenolate mofetil, sirolimus, anti-thymocyte globulin or monoclonal antibodies among others. Tacrolimus is a macrolide antibiotic isolated from the Streptomyces tsukubaensis. It inhibits calcineurin, resulting in the inhibition of interleukin-2 production and the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection and GvHD. Tacrolimus (Prograft , Astellas Pharma, UK, USA) is commercially available in two different forms: capsules for oral administration and a sterile solution for intravenous (IV) administration. The latter contains the equivalent of 5mg anhydrous tacrolimus in 1mL. Each mL contains polyoxyl 60 hydrogenated castor oil (HCO-60) 200mg, and dehydrated alcohol, USP, 80.0% v/v. Tacrolimus injection must be diluted within the range 0.004–0.02mg/ml with 0.9% sodium chloride or 5% dextrose before administration. In addition, due to the non-commercial availability, many centers prepare an oral tacrolimus suspension. Currently, the recommended method of administration of IV tacrolimus is continuous (24 h) infusion because of high rates of neurologic and renal toxicities seen with rapid or short infusions twice daily. However, when using continuous infusion, a dedicated central venous line is advised and this reduces the number of access ports required for administration of other drugs such as antibiotics or parenteral nutrition. Due to this logistic problem, some centers prefer the intermittent administration of tacrolimus which is considered to be a safe and effective alternative to continuous infusion in children. When administrating tacrolimus intravenously, there are some major concerns. As tacrolimus is prepared and administered with IV tubing, syringes and other equipment containing polyvinylchloride (PVC), it can be absorbed by the PVC. In addition, castor oil, as part of the excipients for the IV tacrolimus solution, may leach phthalates from PVC-phthalate containing equipment. Therefore, it is advised to use PVC-free and phthalate-free containers, tubing and syringes, in order to maintain a consistant blood concentration. Our research question was guided by an allogeneic transplanted patient who received cyclosporine and low-dose methotrexate for the prevention of GvHD as routinely performed in our hospital. Due to an insufficient response (skin rash suggestive for GvHD) in combination with methylprednisolone, cyclosporine was switched to tacrolimus after a few days of treatment. The administration of tacrolimus in continuous infusion was complicated by large fluctuation in blood levels. For this patient, due to absorption problems, the
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.005 |
| 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".