UMLS:C0011849 - FACTA Search

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A retrospective survey was performed to establish patient and graft outcome for all 41 patients at our centre receiving sirolimus (SRL) in combination with calcineurin inhibition (CNI) as primary therapy for the 6 years prior to March 2002. Patient mortality [12%; n = 5 (TTP, lymphoma, mucormycosis, and small bowel perforation] was significantly higher at 3 months compared with those not receiving SRL, but not thereafter. 12.8% had delayed graft function and 33% had one or more episodes of rejection in the first 6 months. Mean GFR at 12 months was significantly lower (47.3 mL/min) in the SRL group compared with those not receiving SRL (51.3 mL/min). Twenty-two patients had a 12-month protocol biopsy; CNI toxicity was present in 36%. SRL was associated with significant hyperlipidaemia (serum cholesterol, 5.2 +/- 1.4 at baseline vs 7.3 +/- 1.7 mmol/L at 3 months, P <.001; triglycerides, 2.3 +/- 1.4 at baseline vs 2.7 +/- 1.1 mmol/L at 3 months, P <.05). Mild thrombocytopenia occurred in 23% but was not associated with haemorrhagic events. LDH increased by 62%, remaining elevated out to 2 years post engraftment. Seven patients developed insulin requiring diabetes mellitus, similar to the rate observed in our general transplant population.Thus, in this early experience, SRL in combination with CNI was associated with significant mortality and morbidity including CNI toxicity, presumably a reflection of a heavy burden of immunosuppression. However, 1-year graft survival on SRL was similar to the mean Australia-wide graft survival regardless of immunosuppression. The future use of SRL may center around CNI sparing and avoidance type protocols.
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PMID:Sirolimus: a single center experience in combination with calcineurin inhibitors. 1274 76

This study sought to determine 1) the incidence and costs of new onset diabetes mellitus (NODM) associated with maintenance immunosuppression regimens following renal transplantation and 2) whether the mode of dialysis pretransplant or the type of calcineurin inhibition used for maintenance immunosuppression affected either the incidence or cost of NODM. The study examined the United States Renal Data System's clinical and financial records from 1994 to 1998 of all adult, first, single-organ, renal transplantations in either 1996 or 1997 with adequate financial records. It used the second diagnosis of diabetes in previously nondiabetic patients to identify NODM. While NODM had an incidence of approximately 6% per year among wait-listed dialysis patients, NODM over the first 2 years post-transplant had an incidence of almost 18% and 30% among patients receiving cyclosporine and tacrolimus, respectively. By 2 years post-transplant, Medicare paid an extra $21 500 per newly diabetic patient. We estimated the cost of diabetes attributable to maintenance immunosuppression regimens to be $2025 and $3308 for each tacrolimus patient and $1137 and $1611 for each cyclosporine patient at 1 and 2 years post-transplant, respectively.
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PMID:Incidence and cost of new onset diabetes mellitus among U.S. wait-listed and transplanted renal allograft recipients. 1275 5

FTY720, a synthetic analogue of myriocin (ISP-1), is derived from culture filtrates of the fungus Isaria sinclairii. As a sphingosine analogue, FTY720 appears to undergo phosphorylation and thereby interact with specific G-protein-linked receptors. In vivo, FTY720 causes emigration of lymphocytes from peripheral blood to secondary lymphoid structures. Thus, the drug is the archetype of a new class of agents that alter cellular homing patterns: the adhesion-migration paradigm. Since FTY720 seems to spare nonspecific elements of host resistance, it may address the not infrequent complications of infections associated with existing therapies. In experimental rodent, canine and non-human primate models, FTY720 produces lymphopenia and immunosuppression, prolonging the survival of allografts. Because of synergistic interactions, it promotes the immunosuppressive effects not only of calcineurin antagonists, but also of proliferation signal inhibitors. These interactions proffer the possibility of large reductions in exposure to and mitigated toxicity of existing drugs. In humans, FTY720 causes dose-dependent peripheral blood lymphopenia, a reduced incidence of acute rejection episodes and only one apparent adverse reaction - a negative chronotropic effect - particularly after the loading dose. While the clinical utility of FTY720 is difficult to predict before completion of Phase III studies that elucidate its benefits versus unanticipated side effects, the initial data suggest several potential advantages: it does not produce hyperlipidaemia, diabetes mellitus, nephrotoxicity, neurotoxicity or myelosuppression, which are characteristic of other immunosuppressants. Furthermore, it displays high oral bioavailability and a low interindividual coefficient of variation. Clearly, structural analogues, as well as other agents that alter the balance of chemokines or affect cellular adhesion to activated endothelium, will represent important components of future regimens.
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PMID:FTY720: A new kid on the block for transplant immunosuppression. 1283 71

It is estimated that there are greater than 100000 kidney transplant recipients with a functioning graft in the United States. Recent advances in immunosuppression have improved short-term graft survival rates and decreased early mortality by decreasing the incidence and therapy for acute rejection episodes. For those accepted on the waiting list, transplant prolongs patient survival compared with remaining on dialysis. During the 1990s, 3 new immunosuppressive drugs were introduced in clinical kidney transplantation. All were approved for use by the Food and Drug Administration after large, controlled, randomized trials. Mycophenolate mofetil (MMF), when combined with cyclosporine (CSA) and prednisone, lowered acute rejection rates by nearly 50% compared with control. Tacrolimus compared with CSA also significantly reduced acute rejection rates in kidney transplant recipients, but was associated with a significant increase in posttransplant diabetes mellitus (PTDM) in the early trials. When evaluated in combination with MMF, the incidence of PTDM was much lower. At the end of the decade, sirolimus was shown in several randomized trials to lower acute rejection rates and is believed to be less nephrotoxic compared with calcineurin inhibitors. All of the randomized trials were not statistically powered to assess long-term superiority. Registry analyses have been performed that appear to show some long-term benefit of immunosuppressive therapy with MMF. Other outcome assessments in kidney transplant recipients include risk factors for chronic allograft nephropathy, hypertension, hyperlipidemia, and bone disease. Although there are few randomized trials, understanding of the significance of these common complications has progressed and strategies for therapy and intervention have been developed. This article focuses on the randomized trials of immunosuppressive therapy and complications associated with use of these drugs. In addition, we review the current management and intervention for the comorbidities associated with the long-term clinical management of the kidney transplant recipient.
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PMID:Outcomes in kidney transplantation. 1283 99

Recently, new calcineurin inhibitors, such as tacrolimus (FK-506) and microemulsion cyclosporin, have been approved for maintenance immunosuppression in renal transplant recipients and short-term outcomes have been accumulating. In the majority of patients, these calcineurin inhibitors have been used in combination with new immunosuppressive drugs, such as mycophenolate mofetil (MMF) or sirolimus. Under these circumstances, a comparison of cyclosporin and tacrolimus provides the answer to a very important controversial issue. Which drug should we choose in individual patients? In an attempt to answer this question, this review compared the use of tacrolimus and cyclosporin in modern immunosuppressive regimens, which have already been published in well designed clinical studies, and discusses how immunosuppression should be individualised in renal transplant patients.Overall, short-term patient and graft survival with cyclosporin microemulsion and tacrolimus is almost identical. The incidence of acute rejection is generally lower in tacrolimus/azathioprine- than in cyclosporin/azathioprine-treated patients. However, in conjunction with MMF, the difference in the incidence of acute rejection between tacrolimus- and cyclosporin-treated patients became smaller. Adverse events, such as hypertension, hyperlipidaemia and cosmetic changes (gum hypertrophy, hirsutism) seem to be less frequent in tacrolimus-treated than in cyclosporin-treated patients. Recent randomised studies showed that the incidence of post-transplant diabetes mellitus was almost identical between low-dose tacrolimus- and cyclosporin-treated patients. According to the data discussed in this review, the recommendation on the choice of calcineurin inhibitors at this moment is that either cyclosporin or tacrolimus can be used safely and effectively for patients without any risk factors. However, at our centre, we prefer tacrolimus to cyclosporin in patients with a high risk for rejection, such as those with ABO-incompatibility, delayed graft function, sensitisation, and African American race and some other risk factors, such as hypertension and hyperlipidaemia. Moreover, tacrolimus may be preferable to cyclosporin for women because of hirsutism and for children because of the steroid-sparing effect. We consider that cyclosporin should be chosen when patients experience tacrolimus-related adverse events, such as severe chest pain, tremor, gastrointestinal symptoms and encephalopathy. In conclusion, well tolerated and effective immunosuppression is feasible with both cyclosporin and tacrolimus. In the current immunosuppressive regimens, a calcineurin inhibitor, either tacrolimus or cyclosporin, is the essential basic standard immunosuppressant. Clinicians need to decide the best means of optimising therapy for individual patients, based on various risk factors, such as risk of rejection, i.e. sensitisation, delayed graft function and ABO-incompatibility, and some adverse events, such as hypertension, hyperlipidaemia and cosmetic changes.
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PMID:Calcineurin inhibitors in renal transplantation: what is the best option? 1288 61

Diabetes mellitus, a frequent metabolic complication in liver transplant recipients, may be produced by the diabetogenic effect of calcineurin inhibitors cyclosporine and tacrolimus. The aim of this study was to investigate the safety and metabolic effects of a gradual switch from cyclosporine or tacrolimus to mycophenolate mofetil among 12 diabetic liver transplant recipients. One patient was withdrawn from the study due to gastrointestinal side effects. Of the 11 remaining patients, cyclosporine or tacrolimus was completely withdrawn in five patients. Two patients developed suspected acute rejection episodes that were controlled by increasing the tacrolimus dosage. Glycosylated hemoglobin A1C and C-peptide levels were significantly lower at 3 and 6 months after the initiation of mycophenolate mofetil (P<.03 in all cases). Furthermore, urea and uric acid levels were significantly reduced after the change of treatment. In conclusion, a switch from cyclosporine/tacrolimus to mycophenolate mofetil may produce beneficial metabolic effects in diabetic liver transplant recipients, but poses a risk of graft rejection.
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PMID:Conversion from calcineurin inhibitors to mycophenolate mofetil in liver transplant recipients with diabetes mellitus. 1296 32

Tacrolimus (Tac), which blocks T- and B-cell proliferation by inhibiting calcineurin, was first used for immunosuppression following heart transplant (HT) in 1989. Two multicenter randomized trials have compared Tac to the oil-based cyclosporine (CsA) formulation (both combined with azathioprine and steroids) in HT patients. The two drugs displayed similar patient survival rates and incidences of rejection, nephrotoxicity, diabetes, and infections. The Tac group however, showed a lower incidence of arterial hypertension (and, in one study, of dyslipidemia). A pilot study of Tac in combination with mycophenolate mofetil (MMF) and steroids suggested that maintenance of serum mycophenolic acid levels at 2.5 to 4.5 microg/mL yields lower rejection rates without greater toxicity than previous regimens. Currently, a European multicenter randomized trial is comparing Tac with Neoral CsA, both used in combination with MMF, steroids, and induction antibodies. For patients undergoing primary immunosuppression with CsA, Tac has proved effective for rescue from steroid-resistant acute rejection. It also has tentatively been used without other drugs in selected patients. It is a valid alternative to CsA in current immunosuppressive regimens, because it does not cause gingival hyperplasia or hirsutism and, thus, may improve the quality of life and treatment compliance of female and pediatric patients. It may be preferable to CsA for patients with arterial hypertension or intractable dyslipidemia. Current and future studies will clarify the efficacy and safety of regimens combining Tac with MMF or rapamycin.
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PMID:Tacrolimus in heart transplantation. 1296 69

The anti-interleukin-2 receptor (anti-IL-2R) antibody therapy is an exciting approach to the prevention of acute rejection after renal allograft transplantation whereby immunosuppression is exerted by a selective and competitive inhibition of IL-2-induced T cell proliferation, a critical pathway of allorecognition. The anti-IL-2R antibodies specifically block the alpha-subunit of the IL-2R on activated T cells, and prevent T cell proliferation and activation of the effector arms of the immune system. The anti-IL-2R antibodies are used as induction therapy, immediately after renal transplantation, for prevention of acute cellular rejection in children and adults. During acute rejection, the IL-2Ralpha chain is no longer expressed on T cells; thus, the antibodies cannot be used to treat an existing acute rejection. Two anti-IL-2R monoclonal antibodies are currently in clinical use: daclizumab and basiliximab. In placebo-controlled phase III clinical trials in adults, daclizumab and basiliximab in combination with calcineurin inhibitor-based immunosuppression, significantly reduced the incidence of acute rejection and corticosteroid-resistant acute rejection without increasing the risk of infectious or malignant complications, and neither antibody was associated with the cytokine-release syndrome. Children who receive calcineurin inhibitors and corticosteroids for maintenance immunosuppression, as well as children who receive augmented immunosuppression to treat acute rejection, are at increased risk of growth impairment, hypertension, hyperlipidemia, lymphoproliferative disorders, diabetes mellitus, and cosmetic changes. In older children, the cosmetic adverse effects frequently reduce compliance with the treatment, and subsequently increase the risk of allograft loss. Being effective and well tolerated in children, the anti-IL-2R antibodies reduce the need for calcineurin inhibitors while maintaining the overall efficacy of the regimen; thus, the anti-IL-2R antibodies increase the safety margin (less toxicity, fewer adverse effects) of the baseline immunosuppression. Secondly, the anti-IL-2R antibodies decrease the need for corticosteroids and muromonab CD3 (OKT3) in children as a result of decreased incidence of acute rejection. The recommended pediatric dose of daclizumab is 1 mg/kg intravenously every 14 days for five doses, with the first dose administered within 24 hours pre-transplantation. This administration regimen maintains daclizumab levels necessary to completely saturate the IL-2Ralpha (5-10 microg/mL) in children for at least 12 weeks.The recommended pediatric dose of basiliximab for recipients <35 kg is 10 mg, and 20 mg for recipients > or =35 kg, intravenously on days 0 and 4 post-transplantation. This administration regimen maintains basiliximab levels necessary to completely saturate the IL-2Ralpha (>0.2 microg/mL) in children for at least 3 weeks.
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PMID:Anti-interleukin-2 receptor antibodies for the prevention of rejection in pediatric renal transplant patients: current status. 1451 Jun 27

Calcineurin (CaN), a calmodulin-dependent heterodimer, is, together with NAF-T, involved in the regulation of the Ca++ pump and in the transmission of the activation signal of the immune response. The CaN inhibitor drugs, such as cyclosporin A (CyA), carried by cyclophillin, and tacrolimus, carried by FK-binding protein-12 (FKBP-12), inhibit the binding with the regulatory subunit CaNB. A meta-analysis, comparing tacrolimus with cyclosporin A, has evidenced that tacrolimus significantly increases the diabetes prevalence one year after renal transplant. The diabetogenic effect is due to a direct effect of both drugs on the beta pancreatic cell, in particular on intracellular Ca++ metabolism, which is involved in the insulin secretion and in the reduction of the number of the secretor granules. Some immunological-hystochemical studies, performed on murine pancreas, have evidenced that the FKBP-12 content is higher in beta cells than in alpha cells. This fact allows a high intracellular store of tacrolimus, and a consequently more toxic effect, inside the insulin secreting structures. On the contrary, the low FKBP-12 content of alpha cells involves a higher content of calcineurin and a higher resistance to toxic effects. Finally, an increased incidence of islet cell antibodies (ICA) has been evidenced in patients treated with tacrolimus, as opposed to those treated with CyA.
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PMID:[Calcineurin inhibitors and mechanisms that are responsible for the appearance of post-transplant diabetes mellitus]. 1452 7

The incidence of diabetes in kidney transplant recipients is between 4 and 20% in patients previously not affected by this pathology. This difference is partially due to the immunosuppressive therapy administered. The incidence of diabetes is very high during the first quarter after the transplant, and it becomes stable during the following quarters. The presence of diabetes - evaluated by postprandial glycemia and glycated hemoglobin - should be checked quarterly during the first year after the transplant, every six months during the second year, and yearly starting from the third year. The immunosuppressive therapy (calcineurin inhibitors and steroids), familial history, age, race, and weight (BMI) are among the risk factors of diabetes post-transplant. An increased risk of rejection seems to be among the principal consequences of diabetes in transplant recipients. Moreover, these patients are more prone to infections, cardiovascular disease, and the degenerative complications of diabetes. These facts increase the risk of organ insufficiency, morbidity, and mortality. To manage diabetes in transplant recipients it is necessary to identify at-risk patients before the transplantation, thus avoiding complicated and hazardous examinations after the transplant. After the transplantation, the modifiable risk factors, such as the immunosuppressant drugs used and the control of body weight, must be checked. The control of hypertension is important as well.
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PMID:[The incidence, clinical implications, and risk factors of diabetes mellitus]. 1452 6

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