Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The toxicity of a highly selective, recombinant fusion immunotoxin, DT390anti-CD3sFv, was examined in mice. The protein was expressed from a hybrid gene in which the single chain Fv of the anti-murine CD3 epsilon antibody cDNA was spliced to truncated diphtheria toxin cDNA. DT390anti-CD3sFv, previously shown to have significant anti-GVHD effects when administered to mice given transplants of allogeneic MHC-disparate donor T cells (Vallera et al., Blood 88, 2342-2353, 1996), preferentially localized to kidney and had profound renal toxicity as assessed by histology and serum levels of blood urea nitrogen (BUN), and creatinine. Kidney effects were more severe than liver effects at the maximum tolerated dose (MTD) of 10 microg/day BID given over a six day interval. Toxic injury was attributed in part to the toxin moiety since DT390 administered alone was more toxic than equivalent doses of DT390 given in the context of DT390anti-CD3sFv fusion protein. The presence of anti-CD3sFv ligand reduced toxicity since DT390anti-CD3sFv was twice as toxic to severe combined immunodeficiency disease (scid) mice which do not have CD3epsilon expressing T cells as compared to their normal counterparts. Together, these findings further our understanding of the toxicities limiting the in vivo administration of DT fusion immunotoxins in mice and provide a foundation for future genetic modifications which should be directed at reducing these effects.
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PMID:Renal dysfunction accounts for the dose limiting toxicity of DT390anti-CD3sFv, a potential new recombinant anti-GVHD immunotoxin. 946 72

Cytomegalovirus (CMV) remains a cause of significant morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Ganciclovir prophylaxis, or preemptive treatment based on detection of antigenemia or CMV DNA by PCR, effectively prevents CMV disease during the first 100 days after transplant in allograft recipients. In recipients of T-cell depleted transplant or if severe acute graft-versus-host disease is present, ganciclovir prophylaxis or preemptive treatment should be started with an induction course of ganciclovir (5 mg/kg BID) and given at least 5 days per week and continued until day 100 after transplant. Although prevention of CMV disease before day 100 is highly effective, there is a continued risk of late-onset CMV disease after day 100. In CMV-seropositive recipients, the incidence of late CMV disease may be as high as 17%. Strategies to prevent late CMV infection and disease are needed. In seronegative recipients, seronegative or leukocyte-reduced blood products are effective in preventing acquisition of CMV through blood products. Controversy exists about the optimal strategy of preventing CMV disease in seropositive autologous HSCT recipients. The outcome of CMV pneumonia remains poor despite treatment with ganciclovir in combination with CMV hyperimmune globulin or intravenous immunoglobulin. Owing to continued clinical significance of CMV in the HSCT setting, new and more effective anti-CMV drugs with improved pharmacokinetic properties are urgently needed.
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PMID:Current antiviral strategies for controlling cytomegalovirus in hematopoietic stem cell transplant recipients: prevention and therapy. 1142 87

Conventional preparative regimens for allogeneic stem cell transplantation are associated with excessive regimen-related toxicity (RRT) in some patients because of underlying comorbidities, advanced age, or prior treatment. We studied a preparative regimen designed to reduce RRT, yet allow for adequate engraftment and development of a graft-versus-malignancy effect. Thirty patients (median age, 57 years) were entered on study. Twenty-nine patientsreceived stem cells from HLA-identical siblings and 1 from a sibling mismatched for 1 antigen at the A locus. Sixteen patients had received previous stem cell transplants (6 allogeneic and 10 autologous). The preparative regimen consisted of fludarabine 30 mg/M2 per day IV on day -10 to day -5, busulfan 1 mg/kg per dose PO (n = 6) or 0.8 mg/kg per dose IV (n = 24) for 8 doses every 6 hours on day -6 to day -5, and horse-derived antithymocyte globulin 5 mg/kg per day IV (n = 12) or 15 mg/kg per day IV (n = 18) on day -4 to day -1. GVHD prophylaxis consisted of cyclosporine (CYA) 3 mg/kg BID PO starting on day -3 (n = 13) or CYA and methotrexate 15 mg/m2 IV on day +1 and 10 mg/m2 IV on day +3 and day +6 (n = 17). The median number of CD34 cells transplanted was 3.19 x 10(6)/kg. All patients demonstrated recovery of hematopoietic function. Twenty-six (89%) of 29 evaluable patients achieved greater than 90% donor cell chimerism before day 100. Three patients never achieved greater than 90% donor chimerism, and another 3 patients subsequently lost donor chimerism. All 6 of these patients had autologous reconstitution with progressive disease. RRT was minimal; 7 patients had greater than grade II nonhematologic toxicity and there were no toxic deaths attributable to the conditioning regimen. Transplantation-related mortality was 7% (95% confidence interval [CI], 6%-8%) at 3 months and 28% (95% CI, 23%-34%) at 12 months after transplantation. Non-relapse-related mortality was most often due to infection. Grade II or greater GVHD developed in 56% of evaluable patients, and all patients with disease response developed GVHD. Actuarial estimates of overall and disease-free survival at 12 months were 52% (95% CI, 43%-63%) and 30% (95% CI, 24%-37%), respectively. Although this preparative regimen allowed adequate engraftment with minimal RRT, GVHD and infectious complications caused significant morbidity and mortality. Further study to define appropriate patient populations for this regimen, while limiting GVHD and infection risks, is needed.
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PMID:Phase II study of a moderate-intensity preparative regimen with allogeneic peripheral blood stem cell transplantation for hematologic diseases: the Texas Transplant Consortium experience. 1223 67

A once-daily modified release formulation of oral tacrolimus (Tac QD) has been developed in response to the problem of nonadherence. However, there have been no data available about the efficacy of Tac QD conversion from intravenous Tac (Tac i.v.) in allogeneic hematopoietic stem cell transplantation (allo-SCT). We analyzed the pharmacokinetics (PK) of Tac QD in allo-SCT recipients. A total of 10 patients with hematological malignancies who received allo-SCT from unrelated donors were enrolled. Patients received Tac i.v. at 0.03 mg/kg a day before transplantation. Administration of Tac i.v. was converted to Tac QD at a 1:4 ratio when the patients had recovered from regimen-related gastrointestinal toxicity and could tolerate oral medication. After conversion, six out of 10 patients (60 %) showed a sustained decrease in Tac exposure and required dose adjustment. The conversion from Tac i.v. to Tac QD should be performed under close medical supervision. Area under the curve (AUC) and the trough of Tac QD showed a correlation, and the trough should be maintained above 7.5 ng/ml to provide an adequate AUC. Although four patients received bone marrow from an HLA DRB1 1 antigen-mismatched unrelated donor, no patients developed grade III-IV acute graft-versus-host disease (GVHD). The modification of Tac QD to maintain a whole-blood trough concentration above 7.5 ng/ml may be as effective as Tac BID.
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PMID:Pharmacokinetics for once-daily modified release formulation of tacrolimus hydrate in unrelated hematopoietic stem cell transplantation. 2532 85

Tacrolimus is used in bone marrow transplant patients to prevent graft-versus-host disease. There have been few case reports of tacrolimus toxicity (>30 ng/mL) in solid organ recipients as well as in nontransplant patients. Several case reports suggest phenytoin and rifampin decrease tacrolimus levels in toxicity, but does it actually make a difference? A 60-year-old man with acute myeloblastic leukemia after allogenic stem cell transplant with fever, diarrhea, and abdominal pain was transferred to the intensive care unit for persistent hypotension and acute hypoxic respiratory failure requiring intubation. The following day his tacrolimus level was 8.6 ng/mL and creatinine was 2.2 (baseline = 1.8). The patient inadvertently received 15 mg intravenous tacrolimus instead of his scheduled 0.5 mg intravenous. Four hours later, a random tacrolimus level was 36.4 ng/mL. Tacrolimus was discontinued; phenytoin 200 mg BID was started for 4 doses and rifampin was started for 2 doses at 600 mg. Sixteen hours postinjection, tacrolimus level decreased to 26.4 ng/mL and to 9 ng/mL after 64 hours. Creatinine improved to 1.1 after 30 hours. He was extubated 5 days later without any new neurological findings and his creatinine returned to baseline. Our patient received 30 times his daily dose resulting high tacrolimus levels. Assuming there was sufficient time for distribution, our patient's half-life increased to 34.5 hours compared with the reported half-life of 12 hours. The possibilities for this increase include ineffective or harmful effects of the phenytoin/rifampin combination, change in metabolism kinetics at high levels, or other unidentified patient-specific factors. Further studies should be done to ensure that phenytoin and rifampin are safe to give in tacrolimus toxicity.
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PMID:Phenytoin and Rifampin Do Not Decrease Levels in Acute Tacrolimus Toxicity. 3008 54