Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tacrolimus was used as the primary immunosuppressive agent in 69 pediatric renal transplantations between December 17, 1989, and June 30, 1995. Children undergoing concomitant or prior liver and/or intestinal transplantation were excluded from analysis. The mean recipient age was 10.3+/-5.0 years (range, 0.7-17.5 years). Seventeen (24.6%) children were undergoing retransplantation, and six (8.7%) had a panel reactive antibody level of 40% or higher. Thirty-nine (57%) cases were with cadaveric kidneys, and 30 (43%) were with living donors. The mean donor age was 28.0+/-14.7 years (range, 1.0-50.0 years), and the mean cold ischemia time for the cadaveric kidneys was 27.0+/-9.4 hr. The antigen match was 2.7+/-1.2, and the mismatch was 3.1+/-1.2. All patients received tacrolimus and steroids, without antibody induction, and 26% received azathioprine as well. The mean follow-up was 32+/-20 months. One- and 4-year actuarial patient survival rates were 100% and 95%. One- and 4-year actuarial graft survival rates were 99% and 85%. The mean serum creatinine level was 1.2+/-0.8 mg/dl, and the calculated creatinine clearance was 82+/-26 ml/min/1.73 m2. The mean tacrolimus dose was 0.22+/-0.14 mg/ kg/day, and the level was 9.5+/-4.8 ng/ml. The mean prednisone dose was 2.1+/-4.9 mg/day (0.07+/-0.17 mg/kg/day), and 73% of successfully transplanted children were off prednisone. Seventy-nine percent were not taking any antihypertensive medications. The mean serum cholesterol level was 158+/-54 mg/dl. The incidence of delayed graft function was 4.3%. The incidence of rejection was 49%, and the incidence of steroid-resistant rejection was 6%. The incidence of rejection decreased to 27% in the most recent 26 cases (January 1994 through June 1995). The incidence of new-onset diabetes was 10.1%; six of the seven affected children were able to be weaned off insulin. The incidence of cytomegalovirus disease was 13%, and that of posttransplant lymphoproliferative disorder was 10%; the incidence of posttransplant lymphoproliferative disorder in the last 40 transplants was 5% (two cases). All of the children who developed posttransplant lymphoproliferative disorder are alive and have functioning allografts. Based on this data, we believe that tacrolimus is a superior immunosuppressive agent in pediatric renal transplant patients, with excellent short- and medium-term patient and graft survival, an ability to withdraw steroids in the majority of patients, and, with more experience, a decreasing rate of rejection and viral complications.
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PMID:Tacrolimus in pediatric renal transplantation. 899 Mar 56

Immunosuppressive agents increase the risk of death due to coronary disease or stroke by their ability to cause 3 different adverse effects: dyslipidaemia, hypertension and hyperglycaemia. Post-transplant diabetes mellitus has emerged as a major adverse effect of immunosuppressants. As recipients of organ transplants survive longer, the secondary complications of diabetes mellitus have assumed greater importance. There is a need for a precise definition of post-transplant diabetes mellitus to facilitate inter-centre comparison and to study the natural history of post-transplant diabetes mellitus. We recommend broad criteria to define hyperglycaemia, as a fasting blood glucose level of > 400 mg/dl at any point or > 200 mg/dl for 2 weeks, or a need for insulin treatment for at least 2 weeks. We also recommend serial measurements of HbA1c. Cyclosporin and tacrolimus cause post-transplant diabetes mellitus by a number of mechanisms, including decreased insulin secretion, increased insulin resistance or a direct toxic effect on the beta cell. For corticosteroids, the induction of insulin resistance seems to be the predominant factor. However, few studies have examined the mechanism of diabetogenicity at the molecular level. This may hold the key for pharmacological manipulation of current immunosuppressive regimens which may result in decreased metabolic complications. Corticosteroid sparing regimens have been shown to reduce the metabolic complications of immunosuppressants including post-transplant diabetes mellitus. However, their use should be balanced against the increased incidence of transplant rejections. Post-transplant diabetes mellitus may be organ-specific irrespective of the immunosuppressant used. Tacrolimus causes a high incidence of post-transplant diabetes mellitus in recipients of kidney transplants (upto 20% in some reports); the diabetogenicity of cyclosporin-based regimens is comparable with that of tacrolimus-based regimens in recipients of liver transplants. A few clinical studies in which attempts were made to discontinue cyclosporin resulted in an unacceptable loss of the transplant. In the case of tacrolimus, complete withdrawal of immunosuppression may be possible in selected patients with liver transplants. However, post-transplant recipients who may benefit from this approach are difficult to identify. In some early series, patients received doses of tacrolimus that were approximately 2 to 3 times higher than those currently used, which may have resulted in a higher incidence of post-transplant diabetes mellitus. More recently, it has been shown that tacrolimus was successful in salvaging whole pancreatic grafts which were maintained on cyclosporin. Tacrolimus-based immunosuppression as primary therapy was also used with remarkable success in solitary whole pancreas transplants. Strategies to reduce the metabolic complications of immunosuppressants should be pursued aggressively as this will directly lead to a decrease in long term cardiovascular adverse effects.
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PMID:Post-transplant diabetes mellitus. The role of immunosuppression. 911 92

Tacrolimus (FK 506) has been evaluated as immunosuppressive therapy in patients with a variety of solid organ and other transplants. Extensive data have now confirmed its efficacy as primary or rescue therapy in renal and hepatic transplantation. In prospective and historically controlled studies of primary therapy, tacrolimus generally demonstrated greater efficacy than the conventional formulation of cyclosporin for preventing episodes of acute rejection and allowed reduction of corticosteroid use. Chronic rejection rates were also significantly lower with tacrolimus in a large randomised liver transplantation trial. However, patient and graft survival rates were similar in both treatment groups (although numerically larger in adults with liver transplants). In children, rejection rates and corticosteroid requirements were usually lower with tacrolimus and patient and graft survival were generally similar with the 2 immunosuppressants. The finding of reduced corticosteroid requirements with tacrolimus may be of particular benefit in prepubertal children, who are still growing. A small amount of evidence has also accumulated regarding the use of tacrolimus as primary therapy in patients who have undergone bone marrow or heart and/or lung transplantation. Data are not conclusive, particularly in children, but tacrolimus appears to be useful for treating patients who have undergone these organ transplantations and may be associated with a lower incidence of obliterative bronchiolitis than cyclosporin in the latter group. Potential efficacy has also been shown in a limited number of patients with pancreas or pancreas-kidney, pancreatic islet and intestinal or multivisceral transplants, and in children who have undergone heart or heart-lung transplantation. Tacrolimus also has a use as rescue therapy in bone marrow, heart, lung and pancreatic transplantation, but data are currently insufficient for conclusions to be made. However, these results support the need for further study in these populations. Adverse effects occurring during tacrolimus therapy are generally of the type common to all immunosuppressive regimens. However, diabetes mellitus, neurotoxicity and nephrotoxicity are more common in tacrolimus than cyclosporin recipients. Hyperlipidaemia, hypertension, hirsutism and gingival hyperplasia are more common with cyclosporin. In 2 large multicentre clinical trials (US liver and European renal), tacrolimus was discontinued more frequently during the first year because of adverse events. However, the tolerability of tacrolimus appears related to dosage, improving as the dose is reduced. Tacrolimus should be considered an effective primary immunosuppressant in renal and hepatic transplantation. The drug is also a useful agent for rescue therapy in patients experiencing rejection or poor tolerability to cyclosporin. Thus, tacrolimus provides the clinician with an effective option for patients requiring immunosuppression and, with a different tolerability and efficacy profile to cyclosporin, it will better allow the tailoring of therapy to meet the needs of individual patients.
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PMID:Tacrolimus. An update of its pharmacology and clinical efficacy in the management of organ transplantation. 942 97

Tacrolimus (FK 506) is a new macrocyclic lactone immunosuppressant which possesses similar but more potent immunosuppressive properties compared with cyclosporin. It is able to inhibit T cell proliferation and the production of interleukine 2 (and other growth promoting cytokines). A major interest of tacrolimus is that it can be used as a rescue therapy since clinical trials have demonstrated its ability to be effective in some patients who develop rejection episodes refractory to current regimens, including corticosteroids. Tacrolimus is highly bound to erythrocytes and is largely metabolized, primarily in the liver, by Cyt P450 3A4. Its excretion pathway concerns the bile almost exclusively. Like cyclosporin, the drug is associated with a range of adverse effects including nephrotoxicity, neurotoxicity and diabetes. Tacrolimus also exhibits a large inter- and intra-individual variability of its pharmacokinetics. Because of this variability and the narrow therapeutic index of tacrolimus, monitoring of tacrolimus blood concentrations would be useful for optimization of therapy. However, even if we know that by maintaining the residual blood concentration under 15 micrograms/l it is possible to reduce dramatically the occurrence of adverse effects, we still have not determined the threshold value of clinical efficacy. This will be important for current and future clinical pharmacology investigations with tacrolimus.
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PMID:[Clinical pharmacokinetics and therapeutic monitoring of tacrolimus]. 943 90

Immunosuppressive efficacy of Neoral and Prograf following primary hepatic transplantation was comparable. Incidence of rejection episodes, infectious complications, hypertension, and postoperative diabetes mellitus was comparable. Although clinical use of both immunosuppressants was associated with early compromise in renal function, no progressive renal dysfunction was observed.
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PMID:Renal function in primary liver transplant recipients receiving neoral (cyclosporine) versus prograf (tacrolimus). 963 66

Following primary liver transplantation, immunosuppressive efficacy of Neoral and Prograf was similar and superior to that of Sandimmune. Rejection incidence was statistically increased with Sandimmune therapy. Incidence of hypertension, posttransplant diabetes mellitus, and infectious complications was not statistically different. Although early compromise in renal function was associated with Sandimmune, Neoral, and Prograf immunosuppression, no progressive renal dysfunction was identified.
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PMID:Impact of Sandimmune, Neoral, and Prograf on rejection incidence and renal function in primary liver transplant recipients. 972 99

A 54-year-old man undergoing hemodialysis because of end-stage renal failure was transplanted with a cadaver kidney in November 1997. He had no history of diabetes. Tacrolimus was used as the primary immunosuppressant. Three weeks after transplantation, he developed insulin-requiring diabetes mellitus. Anti-glutamic acid decarboxylase antibody was not detected on the third post-operative day, but appeared 4 weeks after transplantation. The recipient had DNA haplotypes that indicated susceptibility to Type 1 diabetes in Japanese subjects. Immunosuppressive therapy was changed from tacrolimus to cyclosporin. Thereafter, titer of anti-glutamic acid decarboxylase antibody disappeared and the patient's insulin requirement was notably reduced. The mechanism underlying the development of diabetes in this case appears to be, in part, direct beta-cell toxicity due to tacrolimus therapy, resulting in secondary beta-cell autoimmunity. This case suggests that tacrolimus therapy after transplantation should be used with caution in patients with genetic susceptibility to Type 1 diabetes.
Diabetes Res Clin Pract 1998 Nov
PMID:Post-transplant diabetes with anti-glutamic acid decarboxylase antibody during tacrolimus therapy. 988 44

Tacrolimus is a T cell-specific immunosuppressive agent that has been used in a relatively small number of pediatric kidney transplant recipients. It has been used as a primary immunosuppressive agent, with patient survival rates of over 95%, and graft survival rates of over 90%. In the largest series reported, some two-thirds of the successfully transplanted recipients have been taken off steroids, with substantial catch-up growth, and over 80% have been taken off antihypertensive medications. Important complications have included EBV-related post-transplant lymphoproliferative disorder and post-transplant diabetes mellitus, both reversible. Tacrolimus has also been used to rescue patients with refractory acute rejection, with a success rate of 70%-75%. This review summarizes the current world experience with tacrolimus in pediatric renal transplantation, and describes the details of tacrolimus dosing and the treatment of tacrolimus-related complications. On balance, tacrolimus is an effective immunosuppressive agent and offers important advantages in the management of pediatric renal transplant recipients.
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PMID:Tacrolimus in pediatric renal transplantation: a review. 1008 28

Tacrolimus is a very potent drug for preventing all types of acute rejection after renal transplantation. The decrease of vascular rejection may have important long-term implications. This is demonstrated in the 3-year data of the U.S. multicentre trial, where a significant decrease of graft loss was observed in the tacrolimus patients compared to cyclosporine patients. Safety profiles of both drugs are the same, but there are some major differences in side effects. Hyperglycemia is more common during tacrolimus, but generally the induction of hyperglycemia is a dose-dependent reversible process, which leads generally to diabetes mellitus during high systemic exposure, in certain races and prediabetics. Gum hyperplasia and hirsutism are not seen during tacrolimus therapy and there is a more favorable cardiovascular risk profile during tacrolimus as compared to cyclosporine based immunosuppression.
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PMID:Use of tacrolimus in renal transplantation. 1061 83

A multicenter, prospective, open-label trial was performed to assess the efficacy and safety of tacrolimus for primary immunosuppression in renal transplantation. Twenty patients were evaluated after receiving cadaveric and living, related or unrelated kidney transplants and were monitored for 6 months for patient and graft survival, incidence of acute rejection, and incidence of adverse events. Tacrolimus at a final mean dose of 0.11 mg/kg per day was 100% effective in preventing acute rejection in this Mexican population. Treatment was associated with a low incidence (10%) of posttransplant diabetes mellitus.
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PMID:Primary immunosuppression with tacrolimus in renal transplantation: a multicenter, open-label study. 1091 96


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