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

Cyclosporin A was given to five patients with acute leukaemia in whom graft-versus-host disease (G.V.H.D.) had developed after bone-marrow transplantation from sibling donors. In all instances the acute erythematous skin reaction of G.V.H.D. resolved within two days, but four of the five patients died. Cyclosporin A in high doses produced anorexia, nausea, and a reversible rise in blood-urea. The four patients who died all had liver damage, but the histological changes varied. Cyclosporin A modifies the acute skin reaction of G.V.H.D. In the management of liver and gut G.V.H.D., and in prophylaxis of G.V.H.D., its role needs to be determined.
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PMID:Cyclosporin A for the treatment of graft-versus-host disease in man. 8 37

In a randomised, double-blind trial 20 patients with leukaemia received human recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) and 20 received placebo, for 14 days after allogeneic, matched sibling, bone-marrow transplantation. The neutrophil count recovered to 0.5 x 10(9)/l 3 days earlier in the GM-CSF group than in the placebo group (not significant), and the median neutrophil count at 14 days was significantly higher in the GM-CSF group (1.90 vs 0.46 x 10(9)/l). The lymphocyte count was significantly higher in the GM-CSF than in the placebo group between days 10 and 15 after transplantation, but this difference was not associated with a higher incidence of graft-versus-host disease. There was no evidence that GM-CSF was associated with a greater incidence of leukaemic relapse. The GM-CSF group had lower haemoglobin concentrations and platelet counts and higher plasma urea, creatinine, and bilirubin than the placebo group. The duration of hospital stay was the same for both patient groups. Further studies are now indicated to assess the overall effect of GM-CSF on outcome after allogeneic bone-marrow transplantation.
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PMID:Human recombinant GM-CSF in allogeneic bone-marrow transplantation for leukaemia: double-blind, placebo-controlled trial. 197 80

Cyclosporin A(CyA) is a valuable post graft immunosuppressive agent in allogeneic bone marrow transplantation. The use of CyA is associated with a reduction in severity of graft versus host disease and improved marrow engraftment. A major side effect of CyA is nephrotoxicity. In 33 patients studied during the first 4 weeks of therapy there is a close correlation between trough (12 h) serum cyclosporin A concentrations and plasma creatinine (r = 0.93, P less than 0.001) and urea (r = 0.88, P less than 0.001). Trough CyA serum concentrations of greater than 500 ng/ml are potentially nephrotoxic. Other risk factors for early nephrotoxicity in cyclosporin therapy are the concurrent use of aminoglycoside antibiotics (P = 0.01) and hyperbilirubinaemia (P = 0.01). Early nephrotoxicity can be prevented by maintaining trough CyA levels in the range 100-400 ng/ml. During prolonged CyA therapy, cumulative renal impairment can occur and nephrotoxic episodes associated with microangiopathic peripheral blood changes and hypertension are seen in a minority of patients.
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PMID:Nephrotoxicity in bone marrow transplant recipients treated with cyclosporin A. 634 56

Oral cyclosporin A was used as prophylaxis against graft-versus-host disease in (a) 31 patients with acute leukaemia or aplastic anaemia given transplants of HLA-matched bone marrow and (b) five patients with inborn errors of metabolism given transplants of haplotype-identical (parental) bone marrow. Twenty-six patients survived longer than two months after the operation. Despite the cyclosporin A, 31 patients (86%) suffered an acute form of graft-versus-host disease and 22 (61%) a chronic form. Nevertheless, the disease was usually treatable with immunosuppressive agents and caused the death of only one patient. Cyclosporin A caused renal toxicity in all cases; occasionally this was associated with a "capillary leak" syndrome, fatal in two patients. In children hypertension, fits, and fluid retention were common side effects. Blood concentrations of cyclosporin A correlated with blood urea values and blood pressure but did not predict the occurrence of graft-versus-host disease. Four different dose schedules were used to find the optimum way to administer this drug. Oral cyclosporin A is extremely effective at reducing the severity of graft-versus-host disease, but prevention of the disease is limited by toxicity of the drug and variable absorption. Better results might be achieved with parenteral administration or by using the drug in combination with other methods.
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PMID:Cyclosporin A as prophylaxis against graft-versus-host disease in 36 patients. 680 91

The increase of non specific surgeries in transplanted patients may be related to the better survival achieved by the efficacy of immunosuppressive therapy and improved surgical and intensive care conditions. Therefore, the anaesthetist may be mandated to give anaesthesia in such patients, treated in hospitals which are not involved in transplantation procedures. The ignorance of the main physiologic and pharmacological changes in the new grafted organ as well as the knowledge of high risks of rejection or infection contribute to the anxiety often encountered in front of these patients. The denervated heart is unable to respond to stimulations requiring the integrity of autonomic neural mechanisms. Modulation of cardiac output depends on intrinsic activity (Frank-Starling mechanism) and therefore of end diastolic volume (preload). The denervated transplanted lung shows inability to elicit cough reflex; the latter is totally abolished in case of tracheal anastomosis. These physiologic changes have no deleterious effects on early cardiac and pulmonary functions following transplantation. In the same way, renal, liver or pancreatic functions are restored after respective replacement. However chronic rejection occurs frequently in 50% of patients in a mean time of 5 years following surgery except for liver transplanted patients which seem to be better protected. It results in a progressive decrease in organ function tests. The preoperative assessment requires primary contact with the transplant center. This communication should give precious information about the last biological and functional results as well as about the immunosuppressive therapy. Standard preoperative investigations include measurements of haemoglobin, urea, electrolyte and creatinine concentrations, liver tests, ECG, chest X-ray and coagulation pattern. Previsible difficult intubation should be detected in case of previous pancreas transplantation. Immunosuppressive therapy and other treatments should not be disrupted until surgery. Usual premedication may be used. Previsional peroperative transfusion requires specific packed red blood cells, fresh frozen plasma and platelets in order to reduce CMV contamination and GVH reactions. Locoregional or general anaesthesia may be used with respect to usual contraindications. Special attention should be given in cardiac transplanted patients in order to maintain adequate preload. As atropine is ineffective, bradycardia may be treated by isoprenaline. Patients with lung transplants require a reduction of vascular loading and of hydratation and early postoperative pulmonary physiotherapy. Pancreas transplanted patients often suffer from severe cardiac diseases (coronaropathy). The immunosuppressive therapy modifies the pharmacological behavior of many anaesthetic agents. Ciclosporine enhances mainly the effects of muscle relaxants. Peroperative invasive monitoring requires full aseptic techniques. Invasive monitoring should be discussed in terms of benefit-risk ratio.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Anesthesia for non-specific surgery in a post-transplantation patient]. 833 62

We evaluated the preventive effects of a novel nonpolyglutamatable antifolate, MX-68, on two experimental murine models of systemic lupus erythematosus (SLE); NZBxNZW F1 (BWF1) mice and chronic graft-versus-host disease (GVHD) mice, in comparison with classical antifolate methotrexate (MTX). The oral administration of 2 mg/kg MX-68, three times a week from 12 to 40 or 60 weeks of age, significantly delayed the onset of proteinuria and prolonged the life-span of BWF1 mice. The elevation of serum blood urea nitrogen (BUN) and cholesterol levels resulting from the development of lupus nephritis was also inhibited. However, MX-68 did not suppress the increase of serum anti-DNA or anti-TNP antibodies or total IgG isotype (IgG1, IgG2 and IgG3) levels. In chronic GVHD mice, MX-68 given three times a week from the day of first cell injection, for 9 weeks, dose-dependently delayed the appearance of proteinuria. The elevation of BUN and cholesterol levels was also inhibited. Furthermore, in the 4 mg/kg MX-68 group, the production of IgG anti-DNA and anti-TNP antibodies was significantly inhibited, but this was not observed in the 2 mg/kg MX-68 and the 4 mg/kg MTX groups. These beneficial effects of MX-68 were much greater than those of MTX in both models. These results suggest that MX-68 might be a more useful drug for the treatment of SLE.
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PMID:Preventive effect of a novel antifolate, MX-68, in murine systemic lupus erythematosus (SLE). 927 76

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

A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent currently commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Using the general concept of bioisosteric replacement, variations of the hydroxyglycine central "C" region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. By this way, the malonic derivative 13a was discovered as the first example of a new series of potent immunosuppressive agents encompassing a retro-amide bond linked to the hexyl-guanidino moiety. Structure-activity relationships of this series were studied by synthesizing compounds 13g-i and 13k-s. Variation of the "right-amide" of 13a led to the urea 19a and the carbamates 23 and 27a which proved to be equally active as DSG in our GVHD model. Finally 27a was found to be the most potent derivative, being slightly more active than DSG in a heart allotransplantation model in rats. Due to the absence of chiral center in its structure and to its improved chemical stability compared to DSG, 27a was selected as a candidate for clinical evaluation.
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PMID:Structure-immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 1. Structural modifications of the hydroxyglycine moiety. 992 33

Transplant-related mortality (TRM) following allo- geneic bone marrow transplantation (BMT) remains a major concern and early identification of patients at risk may be clinically relevant. In this study we describe a predictive score based on bilirubin and blood urea nitrogen (BUN) levels on day +7 after BMT. The patient population consisted of 309 consecutive patients who underwent BMT from sibling (n = 263) or unrelated donors (n = 46) for hematologic disorders between December 1990 and December 1996. Of 27 laboratory tests taken on day +7 after BMT, serum bilirubin (P = 0.02) and BUN (P = 0.007) were found to be independent predictors of TRM in multivariate analysis. The median levels of bilirubin (0.9 mg/dl) and of BUN (21 mg/dl) were then used as a cut-off and a score of 1 was given for values equal/greater than the median. There were 216 patients with scores 0-1 (low risk) on day +7 (bilirubin <0.9 and/or BUN <21) and 93 patients with score 2 (high risk) (bilirubin >/=0.9 and BUN >/=21): the latter had more grade III-IV acute graft-versus-host disease (P = 0.03), slower neutrophil (P = 0.02) and slower platelet engraftment (P = 0.002). The actuarial 5 year TRM is 22% for low risk vs44% for high risk patients (P = 0.0003). For HLA-identical siblings TRM is 20% vs35% (P = 0.01), for unrelated donors it is 20% vs 65% (P = 0.01). Day +7 score was highly predictive of TRM on multivariate analysis (hazard ratio 1.9, P < 0.01), after adjustment for year of transplant (P < 0.00001), unrelated vs sibling donors (P = 0.001), patient age (P = 0.01) and diagnosis (P = 0.01). These results were validated on an independent group of 82 allogeneic BMT recipients in a pediatric Unit who showed an actuarial TRM of 16% for low risk vs 46% for high risk patients (P = 0.002). This study suggests that it may be possible to identify patients with different risks of TRM on day +7 after BMT: high risk patients could be eligible for programs designed to intensify prophylaxis of post-transplant complications.
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PMID:Early predictors of transplant-related mortality (TRM) after allogeneic bone marrow transplants (BMT): blood urea nitrogen (BUN) and bilirubin. 1049 Jul 32

We have previously shown that patients at high risk of graft-versus-host disease (GVHD) and transplant-related mortality (TRM) can be identified on day +7 following an allogeneic bone marrow transplant (BMT), based on serum bilirubin and blood urea nitrogen levels. One possible approach to reduce the risk of GVHD and TRM, is pre-emptive treatment with T cell antibodies. We report a pilot study testing the feasibility of this approach in 18 high risk patients, with a median age of 41, 83% of whom had advanced disease, undergoing an alternative donor BMT (family mismatched in five and unrelated in 13). The patients received three doses of rabbit antithymocyte globulin (ATG) (Thymoglobuline; Sangstat) 1.25 mg/kg on alternate days, starting at a median interval of 11 days (range 7-13) after BMT. Controls were 20 historical unrelated donor transplants (median age 35, 63% with advanced disease), with a high score from our original publication in 1999. The actuarial 1 year TRM of the ATG-treated patients was 40% compared to 60% for untreated controls (P = 0.06). Severe grade III-IV aGVHD developed in 27% of the ATG-treated patients, and in 55% of the controls (P = 0.08). This study indicates that early pre-emptive treatment of aGVHD in day +7 high risk patients is feasible and may lead to a reduction of aGVHD and TRM. This approach is being tested in a prospective randomized trial.
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PMID:Pre-emptive therapy of acute graft-versus-host disease: a pilot study with antithymocyte globulin (ATG). 1262 70


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