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)

Tacrolimus (Prograf, FK506, Fujisawa Healthcare) is a widely used immunosuppressive agent that is used both for the prevention and treatment of solid organ transplant rejection as well as for the prevention and treatment of graft-versus-host disease after allogeneic blood and marrow transplant. Oral preparations of tacrolimus are commercially available in 0.5, 1 and 5 mg gelatin capsules. Previously, only a 0.5 mg/ml oral suspension has been demonstrated to be stable for use in pediatric patients. On our bone marrow transplant service, we found that using this concentration of tacrolimus led to confusion, with patients and their caregivers confusing milligrams and milliliters, thus increasing errors with this formulation. We postulated that a 1 mg/ml oral formulation of tacrolimus would decrease the potential for medication errors. Our findings support new stability information of approximately 4 months for an extemporaneous oral suspension of tacrolimus at a concentration of 1 mg/ml.
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PMID:Long-term stability of a patient-convenient 1 mg/ml suspension of tacrolimus for accurate maintenance of stable therapeutic levels. 1651 28

Thrombotic microangiopathy (TMA) impairs long-term survival after allogeneic hematopoietic stem cell transplantation (HSCT). As the allogeneic HSCT procedure has developed, addressing risk factors for TMA has become more complicated. The aim of this study was to investigate the impact of transplant-associated factors on TMA incidence in patients who have undergone HSCT in various settings. One hundred twenty-three consecutive allogeneic HSCT patients with hematologic diseases receiving myeloablative and reduced-intensity conditioning were evaluated retrospectively. Of 123 patients, 22 (17.9%) developed TMA after HSCT. Multivariate analysis showed the significance of GVHD grade II-IV, and the use of FK506 and the use of high-dose busulfan (Bu) (16 mg/kg) persisted. The hazard ratios of the use of FK506, the use of high-dose Bu (16 mg/kg), and GVHD grade II-IV for TMA were 8.7 (95% CI 2.0-37), 5.7 (95% CI 1.5-21), and 3.4 (95% CI 1.3-9.1), respectively. In the present study, reduced-intensity conditioning did not have an advantage over myeloablative conditioning in decreasing the incidence of TMA after HSCT. Our results also showed that high-dose Bu (16 mg/kg) for the conditioning and FK506 for the prophylaxis of GVHD might contribute more significantly to TMA onset after HSCT than other agents.
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PMID:Risk factor analysis for thrombotic microangiopathy after reduced-intensity or myeloablative allogeneic hematopoietic stem cell transplantation. 1675 59

The establishment of a high-level of chimerism may be the most stable strategy for donor-specific tolerance. The purpose of this study was to evaluate the efficacy of a new protocol using cyclophosphamide (CYP) and granulocyte colony-stimulation factor (G-CSF) to induce high-level chimerism following rat whole-limb allotransplantation. Seventy-three whole-limb allotransplants from LacZ transgenic rats to LEW rats were performed. CYP was injected at day 2, and G-CSF was given from day 0 to 3. Nontreated limb allografts were rejected after 4.2 days. In FK506-treated group for 28 days, the survival time was prolonged to 64 days. In the group treated with CYP/G-CSF, limb allografts were rejected after 5.4 days and 5 of 15 recipients showed acute lethal graft-versus-host disease (GVHD). Polymerase chain reaction (PCR) study showed a high level of chimerism even within 1 week after transplantation. Fourteen of 30 recipients given CYP/G-CSF/FK506 died within 2 weeks. The limb survival was significantly prolonged, however, with three grafts surviving more than 300 days. Seven recipients (24%) showed chronic GVHD. A high-level of chimerism was maintained when limb allografts were not rejected by recipients. Limb allografting could function as a vascularized carrier for bone marrow transplantation, provide a continuous source of donor cells and contribute to a high level of chimerism in the recipient. Pretransplant CYP followed by G-CSF and FK506 treatment significantly prolonged the survival of limb allografts but frequently caused chronic GVHD in the recipients.
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PMID:The role of cyclophosphamide and granulocyte colony-stimulation factor in achieving high-level chimerism in allotransplanted limbs. 1694 71

We evaluated the efficacy of a new protocol using cyclophosphamide (CYP), granulocyte colony-stimulation factor (G-CSF) and FK506 to induce high level chimerism following rat whole-limb allotransplantation. The present study investigated the dose requirement and toxicity of CYP monotherapy in inducing stable bone marrow chimerism. Fifty-six whole-limb allotransplants from LacZ transgenic rats to LEW rats were performed. CYP at a dose of 100 mg to 200 mg/kg was injected 2 days before transplantation and G-CSF of 25 microg/kg/day was given for 4 days. FK506 was used for 28 days at 1 mg/kg/day. The level of chimerism was evaluated by semi-quantitative polymerase chain reaction. The survival of limb allografts in recipients treated with CYP of 150 mg/kg was significantly prolonged to 107 days. The onset of rejection was more prolonged to 158 days in recipients with CYP of 200 mg/kg, with two of eight grafts surviving >1 year and three recipients (38%) showed chronic, nonlethal GVHD with a high level of bone marrow chimerism. Limb allografting could contribute to chimerism in the recipient. Pretreatment with CYP had the dose-dependent effects of prolonging the survival of limb allografts. A CYP dose of 200 mg/kg appears to significantly prolong limb graft survival but frequently causes chronic nonlethal GVHD in the longer surviving recipients.
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PMID:Prolonged survival of rat whole-limb allografts treated with cyclophosphamide, granulocyte colony-stimulation factor and FK506. 1696 77

Dendritic cells (DC) are the most potent antigen-presenting cells (APC) and are pivotal for initiating allograft immunity. Recently, particular DC subsets have been implicated also in allogeneic T cell hyporesponsiveness. Alemtuzumab (anti-CD52, Campath-1H) is a novel T cell depleting antibody that is currently under investigation for the use in allogeneic organ transplantation. While recent studies demonstrated a conspicuous effect of alemtuzumab on peripheral DC in clinical graft-versus-host disease, its efficiency in patients receiving allogeneic organ transplants is still undefined. In the present study we assessed the peripheral DC repertoire in kidney transplant recipients after either alemtuzumab induction therapy followed by FK506 monotherapy or after conventional immunosuppression (FK506, mycophenolate mofetil and steroids) without any induction agent. Induction with alemtuzumab caused a strong and sustained reduction of the total number of peripheral DC and a significant shift from myeloid to plasmacytoid DC subsets (mDC/pDC ratio) as early as 1 month post-transplantation. These data show that alemtuzumab induction targets the peripheral DC repertoire, which might add another mechanism allowing immunosuppressive drug minimization. Further studies are warranted to further elucidate the functional significance of these finding in the setting of allogeneic organ transplantation.
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PMID:Alemtuzumab (Campath-1H) induction therapy and dendritic cells: Impact on peripheral dendritic cell repertoire in renal allograft recipients. 1713 63

Thrombotic microangiopathy (TMA) is one of the severe complications after stem cell transplantation (SCT) and is associated with graft-versus-host disease (GVHD) prophylaxis including FK506. In this study, we experimented on rats using FK506 to demonstrate the occurrence of intestinal TMA. FK506 was administrated into Wistar/ST rats intraperitoneally for 7 days. Rats were examined histopathologically after FK506 injection using light and electron microscopy and immunohistochemistry. FK506 concentrations in whole blood were measured by enzyme immunoassay. In the acute phase, hemorrhagic lesions with multifocal erosions and crypt loss were found in the small intestines of all treated rats. Capillary vessels were dilated, and a few platelet thrombi were found. Electron microscopy demonstrated degenerative swelling of endothelial cells and platelet aggregates adhering to the vessel walls. In the later phase, epithelial regenerative failure, characterized by crypt ghosts, was found in the affected mucosa. Apoptotic epithelial cells were increased in number. The extent of intestinal injury was proportional to the whole blood levels of FK506. The intestinal lesions in rats were consistent with TMA and induced by the injection of FK506 alone. Apoptotic enteropathy was also observed and similar to intestinal GVHD. In this study, we established an intestinal TMA model induced by immunosuppressant (Tacrolimus) only without irradiation.
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PMID:Intestinal thrombotic microangiopathy induced by FK506 in rats. 1727 91

Nasal natural killer (NK)/T cell lymphoma is a rare entity of non-Hodgkin's lymphoma which mostly occurs in East Asian countries. The advanced disease above clinical stage III is often refractory to the radiation and chemotherapies, remission is transient even if achieved, and median survival is about 12 months. Thus the prognosis of advanced NK/T cell lymphoma is generally poor, however, the promising results of allogeneic hematopoietic stem cell transplantation for advanced NK/T cell lymphoma have been recently reported. In most of these cases, stem cell sources were human leukocyte antigen (HLA) matched donors and alternative sources were seldom used. We report here a case of a 36-year-old woman who was diagnosed as having an extranodal NK/T cell lymphoma, nasal type. The patient achieved a complete remission after 2 cycles of chemotherapy including Carboplatin, Etoposide, Ifosfamide, and Dexamethasone, but 3-months later relapsed during the search for HLA-matched unrelated donors. She received unrelated cord blood transplantation (CBT) in the second remission achieved by a regimen containing L-asparaginase. The conditioning regimen was 12 Gy of total body irradiation, high-dose cytarabin and cyclophosphamide. FK506 and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. GVHD involving the intestine and the oral mucosa was observed, but improved without additional immunosuppressive therapies. The patient remains in remission 33 months after CBT. Cord blood thus could be an appropriate stem cell source for patients with advanced NK/T lymphoma who have no HLA matched donors.
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PMID:Successful treatment of advanced extranodal NK/T cell lymphoma with unrelated cord blood transplantation. 1740 80

We retrospectively evaluated the efficacy of mycophenolate mofetil (MMF) in the treatment of steroid-resistant acute and chronic graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation. Thirteen patients, ten men and three women, consisted of 5 cases of acute myelogenous leukemia, 2 of acute lymphoblastic leukemia, 2 of chronic myelogenous leukemia, 2 of lymphoblastic lymphoma, and 1 case each of adult T-cell leukemia and peripheral T-cell lymphoma. The transfusions consisted of 5 peripheral blood, 7 bone marrow and 1 cord blood from 3 mothers, 4 siblings and 6 unrelated donors with conditioning treatments, including 8 total-body irradiation-based regimens, and 2 busulfan plus cyclophosphamide and 2 reduced-intensity regimens. GVHD prophylaxis included FK506 plus methotrexate (MTX) and/or antithymocyte globulin for 9 patients, and cyclosporine and MTX for 4 patients. All patients were treated with second-line MMF for steroid-refractory acute and/or chronic GVHD, and 11 patients improved. The adverse events were tolerable except for one patient in whom grade 3 neutropenia forced discontinuation of treatment. No case of non-relapse mortality occurred. We consider that MMF is beneficial and well tolerated for treatment of steroid-refractory GVHD.
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PMID:[Benefits of mycophenolate mofetil for refractory graft-versus-host disease]. 1786 98

Transplantation of haemopoietic stem cells containing immunocompetent cells invariably leads to the development of graft versus host disease (GVHD) in the recipients unless immunosuppressive prophylaxis is administered for approximately 6 months. Despite the availability of immunosuppressive drugs such as cyclosporin, GVHD remains the most important cause of morbidity and mortality in haemopoietic stem recipients. Tacrolimus (FK506), a macrolide lactone isolated from the fermentation broth of Streptomyces tsukubiensis, has been introduced as an agent with greater activity than cyclosporin for GVHD prophylaxis. Several pilot studies using tacrolimus for prophylaxis of acute GVHD have shown promising results leading to 3 major pivotal trials. These studies were nonblinded randomised trials comparing the combination of tacrolimus and methotrexate with cyclosporin and methotrexate in both matched sibling and unrelated donor transplants for the prevention of acute GVHD. All 3 trials showed a significantly lower incidence of acute GVHD in the tacrolimus arm when compared to the cyclosporin arm. The overall and disease-free survival of patients with non-advanced malignancies was similar between the 2 groups. In one matched sibling study, the overall and disease-free survival in high-risk advanced disease patients who received tacrolimus was poorer than in the cyclosporin recipients. However, a recent matched case controlled study using the International Bone Marrow Transplant Registry database confirmed that the poorer survival outcome of the tacrolimus recipients was due to adverse influence of baseline prognostic factors in the tacrolimus group. The toxicity profile of tacrolimus is similar to that of cyclosporin with the exception that the incidence of hirsutism and hypertension is less frequent in tacrolimus recipients. The nephrotoxicity associated with tacrolimus is dose related. Logistic regression analysis indicated that whole blood tacrolimus concentrations greater than 20 ng/ml were associated with significant nephrotoxicity. The current recommended therapeutic concentration range in whole blood is 10 to 20 ng/ml. Some studies found equal efficacy with a therapeutic range of 5 to 15 ng/ml. This review addresses many details on the practical management of adverse effects, dosage and drug interactions.
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PMID:Optimum use of tacrolimus in the prophylaxis of graft versus host disease. 1803 Nov 44

The induction of a high-level of chimerism (macrochimerism) may be the most reliable strategy for achieving donor-specific tolerance. The purpose of this study was to evaluate the efficacy of a new protocol using total-body irradiation (TBI) and granulocyte-colony stimulation factor (G-CSF) to induce high-level chimerism following rat whole-limb allotransplantation. In this study, we investigated whether the timing of TBI influenced the period of graft survival. In total, 50 whole-limb allotransplants from LacZ transgenic rats to LEW rats were performed. TBI was performed at days 0 and 14, and G-CSF was given for 4 days after TBI. FK506 was given for 28 days after transplant. Nontreated limb allografts were rejected after 4.2 days. The survival time was prolonged to 64 days in the FK506 monotherapy group. In the group receiving TBI at day 14, limb allograft survival was significantly prolonged to 81 days. In the group receiving TBI at day 0, 26% of recipients died but in the surviving recipients the grafts survived for longer than 1 year without lethal graft-versus-host disease (GVHD). Polymerase chain reaction (PCR) analysis revealed a high level of intrabone marrow chimerism in the recipient, thus demonstrating successful induction of macrochimerism. A new protocol of pretransplant TBI followed by treatment with G-CSF and FK506 was found to induce a high level of chimerism and to significantly prolong the survival of limb allografts in recipients without lethal GVHD.
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PMID:Prolonged survival of experimental extremity allografts: a new protocol with total body irradiation, granulocyte-colony stimulation factor, and FK506. 1987 87


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