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

The development of more selective immunosuppressive agents to mitigate transplant rejection and autoimmune diseases requires effective strategies of blocking signaling pathways in T cells. Current immunosuppressive strategies use cyclosporin A (CsA) or FK506 to inhibit calcineurin, which dephosphorylates and promotes the nuclear import of nuclear factor of activated T cells (NFAT) transcription factors. These nuclear NFATs then transactivate cytokine genes that regulate proliferative responses of T cells. Both CsA and FK506 have debilitating side effects, including nephrotoxicity, hypertension, diabetes, and seizures, that argue for the development of alternative or complementary agents. To this end, we developed cell-based assays for monitoring NFAT dynamics in nonlymphoid cells to identify small molecules that inhibit NFAT nuclear import. Interestingly, we found that the majority of these small molecules suppress NFAT signaling by interfering with "capacitative" or "store-operated" calcium mobilization, thus raising the possibility that such mobilization processes are relevant targets in immunosuppression therapy. Further, these small molecules also show dose-dependent suppression of cytokine gene expression in T cells. Significantly, the IC(50) of CsA in primary T cells was reduced by the addition of suboptimal concentrations of these compounds, suggesting the possibility that such small molecules, in combination with CsA, offer safer means of immunosuppression.
 ...
PMID:Chemical genetics to identify NFAT inhibitors: potential of targeting calcium mobilization in immunosuppression. 1518 84

Cyclosporine and tacrolimus, two calcineurin inhibitors, show different side effects and toxicities. The data concerning their nephrotoxicity are few and conflicting. A retrospective study was performed in 2 groups of renal transplant recipients treated with cyclosporine or tacrolimus to evaluate graft function and side effects. All patients had completed at least 6 months of follow-up before inclusion in the study. Group I included 10 patients who were converted from cyclosporine to tacrolimus, due to cosmetic problems or due to chronic graft dysfunction with creatinine values <3 mg/dL. After conversion, there was a significant reduction in creatinine values (from 2.43 +/- 1.21 to 1.86 +/- 0.72 mg/dL; P =.023) and an improvement in creatinine clearance (from 47.5 +/- 19.2 to 56.1 +/- 18.9 mL/min; P =.047). The lipid profile did not change, but there was a trend to better blood pressure control with less antihypertensive drugs. Group II compared 2 subgroups of patients receiving kidneys from the same donor, one treated with cyclosporine and the other with tacrolimus. Tacrolimus patients showed better renal function; namely, creatinine was 1.15 +/- 0.27 versus 1.44 +/- 0.33 mg/dL (P =.029) and creatinine clearance was 87.7 +/- 27.1 versus 60.3 +/- 25.9 mL/min (P =.043). Lipid and blood pressure values were not different between the 2 subgroups, but tacrolimus patients tended to need a lower number of antihypertensive medications. The incidence of de novo diabetes mellitus was approximately 20% among patients using tacrolimus. We concluded that tacrolimus may be less nephrotoxic than cyclosporine. Tacrolimus patients showed better graft function and easier blood pressure control, but a high incidence of posttransplantation diabetes mellitus.
 ...
PMID:Cyclosporine versus tacrolimus in kidney transplantation: are there differences in nephrotoxicity? 1519

In the control of acute rejection, attention is being focused more and more on the long-term adverse effects of the immunosuppressive agents used. Since cardiovascular disease is the main cause of death in renal transplant recipients, optimal control of cardiovascular risk factors is essential in the long-term management of these patients. Unfortunately, several commonly used immunosuppressive drugs interfere with the cardiovascular system. In this review, the cardiovascular adverse effects of the immunosuppressive agents currently used for maintenance immunosuppression are thoroughly discussed. Optimising immunosuppression means finding a balance between efficacy and safety. Corticosteroids induce endothelial dysfunction, hypertension, hyperlipidaemia and diabetes mellitus, and impair fibrinolysis. The use of corticosteroids in transplant recipients is undesirable, not only because of their cardiovascular effects, but also because they induce such adverse effects as osteoporosis, obesity, and atrophy of the skin and vessel wall. Calcineurin inhibitors are the most powerful agents for maintenance immunosuppression. The calcineurin inhibitor ciclosporin (cyclosporine) not only induces these same adverse effects as corticosteroids but is also nephrotoxic. Tacrolimus has a more favourable cardiovascular risk profile than ciclosporin and is also less nephrotoxic. It has little or no effect on blood pressure and serum lipids; however, its diabetogenic effect is more prominent in the period immediately following transplantation, although at maintenance dosages, the diabetogenic effect appears to be comparable to that of ciclosporin. The diabetogenic effect of tacrolimus can be managed by reducing the dose of tacrolimus and early corticosteroid withdrawal. The effect of tacrolimus on endothelial function has not been completely elucidated. The proliferation inhibitors azathioprine and mycophenolate mofetil (MMF) have little effect on the cardiovascular system. Yet, indirectly, by inducing anaemia, they may lead to left ventricular hypertrophy. MMF is an attractive alternative to azathioprine because of its higher potency and possibly lower risk of malignancies. Sirolimus also induces anaemia, but may be promising because of its antiproliferative features. Whether the hyperlipidaemia induced by sirolimus counteracts its beneficial effects is, as yet, unknown. It may be combined with MMF, however, initial attempts resulted in severe mouth ulcers.
 ...
PMID:Effect of immunosuppressive agents on long-term survival of renal transplant recipients: focus on the cardiovascular risk. 1534 97

With increasing long-term survival rates after orthotopic liver transplantation (OLT), metabolic alterations complicating the clinical course, such as diabetes mellitus (DM), become increasingly important. Liver cirrhosis is associated with severe alterations in glucose metabolism. However, it is currently unclear whether these changes are reversed by successful OLT. We therefore characterized glucose metabolism in patients with liver cirrhosis and normal fasting glucose levels before OLT (cir), in the clinically stable long-term course after OLT (OLT), and control subjects (con) using oral glucose tolerance tests (cir = 100, OLT = 62, con = 32), euglycemic-hyperinsulinemic clamps (cir = 10, OLT = 27, con = 14), and positron emission tomography (PET) scan analysis with 18F-fluorodeoxyglucose (FDG) as a tracer (cir = 7, OLT = 7, con = 5). Fasting insulin and C-peptide levels were significantly elevated in patients with liver cirrhosis compared with both control subjects (P <.001) and patients after OLT (P <.001). After OLT, insulin was normalized, whereas C-peptide remained elevated (P < 0.01). In the patients with liver cirrhosis, 27% had a normal glucose tolerance, 38% had an impaired glucose tolerance (IGT), and 35% were diabetic. After OLT, 34% had a normal glucose tolerance, 29% an IGT, and 37% were diabetic. Comparison of the same patients before and after OLT demonstrated that IGT or diabetes before OLT was the major risk factor for these conditions after OLT, which was independent of either immunosuppression (cyclosporine vs FK506) or low-dose prednisolone. Total glucose uptake was reduced in patients with liver cirrhosis to less than half the values in control subjects (21.2 +/- 2.8 vs 43.7 +/- 2.4 micromol/kg/minute, respectively, P <.001), whereas patients after OLT showed intermediate values (35.7 +/- 1.4 micromol/kg/minute, P < 0.05 vs con, P < 0.01 vs cir). This difference was caused by a reduction in nonoxidative glucose metabolism in patients with liver cirrhosis compared with control subjects (7.4 +/- 1.9 vs 28.7 +/- 1.8 micromol/kg/minute, respectively, P <.01) and patients after OLT (20.1 +/- 1.4 micromol/kg/minute, P < 0.05 vs con and OLT). In the PET study, skeletal muscle glucose uptake was significantly reduced in patients with liver cirrhosis compared with control subjects (3.5 +/- 0.4 vs 11.8 +/- 2.5 micromol/100g/minute, respectively, P <.05). After OLT, muscle glucose uptake improved compared with patients with liver cirrhosis (5.9 +/- 1.0 micromol/100g/minute, P <.05) but remained significantly lower than in control subjects (P <.05). In conclusion, these results demonstrate that preexisting IGT or diabetes are the major risk factors for IGT and diabetes after OLT. This finding was independent of the immunosuppressive medication. The peripheral insulin resistance in cirrhosis is characterized by a decrease in nonoxidative glucose disposal that is improved, but not normalized, after OLT.
 ...
PMID:Alterations in glucose metabolism associated with liver cirrhosis persist in the clinically stable long-term course after liver transplantation. 1539 Mar 30

Evidence suggests that steroid sparing in renal transplantation is associated with good outcomes, although there are limited data regarding steroid sparing in Tacrolimus and Mycophenolate Mofetil (MMF)-based regimes. In this study we describe the use of these agents in 101 consecutive patients undergoing renal transplantation using only a 7-day course of prednisolone. Median follow-up was 33 months (range 18-44). Patient and graft survival at 1 year were 100% and 98%, respectively. The acute rejection rate at both 6 and 12 months was 19%, with two episodes beyond 12 months. Anti-CD25 monoclonal antibody (anti-CD25 mAb) was administered to 25 patients at high immunological risk: a trend toward a lower rejection rate was seen in these patients compared with those at lower risk but not receiving induction therapy (8% vs. 22%; p = 0.11). Two patients experienced recurrent rejection. Of the twenty-three rejection episodes in total, 26% showed vascular involvement. Allograft function was preserved at 12 months with a mean creatinine of 144 micromol/L and mean estimated glomerular filtration rate (GFR) of 55 mL/min. At 12 months, the incidence of post-transplant diabetes mellitus was 3.5%. This steroid-sparing regime is associated with excellent patient and graft outcomes, and a low incidence of side effects.
 ...
PMID:Steroid sparing with tacrolimus and mycophenolate mofetil in renal transplantation. 1547 85

Both tacrolimus and mycophenolate mofetil (MMF) are potent immunosuppressive agents used in combination for prevention of acute rejection in renal transplantation. We studied the efficacy and safety of tacrolimus/MMF-based primary immunosuppression as well as their pharmacokinetics (PK) in Chinese renal transplant recipients. Oral tacrolimus was initiated at about 0.2 mg/kg/d, dose which was adjusted to achieve target trough levels of 10 to 20 ng/mL at 3 months and 5 to 10 ng/mL thereafter. The patients also received MMF (0.5 g bid) and prednisolone. PK profiles were studied at 1 week, and 1, 3, and 6 months posttransplant. Blood samples were taken at 0 (predose), 20, 40, 60, 75, and 90 minutes and 2, 4, 6, 8, 10, and 12 hours postdose for each profile. Plasma MPA and whole blood tacrolimus levels were determined by HPLC and EMIT methods respectively. Eight patients were studied with mean follow-up of 16.1 +/- 2.4 months. One patient (12.5%) experienced a borderline acute rejection episode. Both 1-year graft and patient survival rates were 100%. Posttransplant diabetes, diarrhea, and hand tremor occurred in 12.5%, 12.5%, and 37.5%, respectively. No patient had an opportunistic infection. Tacrolimus trough concentrations showed a fair correlation with AUC(0-12h) (R(2) = 0.587). Mean MPA AUC values at 1, 3, and 6 months were 40.5 +/- 9.4, 44.4 +/- 17.3, and 57.2 +/- 20.7 mug*h/mL, respectively (P = .0486, n = 7). In conclusion, primary immunosuppression with tacrolimus, low-dose MMF (0.5 g bid), and prednisolone is effective and safe with adequate systemic MPA exposure in renal transplant recipients.
 ...
PMID:Primary immunosuppression with tacrolimus and low-dose mycophenolate mofetil in renal transplant recipients. 1551 54

The introduction of new immunosuppressants has prompted trials of steroid withdrawal. However, several groups have reported a higher incidence of rejection. We conducted a randomized two-arm, parallel-group, open-label, prospective study to compare steroid withdrawal (at 6 months posttransplant) from the regimens of tacrolimus + mycophenolate mofetil (MMF) (FK group) versus cyclosporine + MMF (CSA group). The entry criteria were recipients of first living donor transplants with no diabetes mellitus (DM), congestive heart failure, chronic liver disease, or acute rejection within 6 months posttransplant. The primary endpoint was a biopsy-proven acute rejection episode or treatment failure within 1 year posttransplant. While 87 recipients were assigned to FK (n = 43) and CSA groups (n = 44) before transplantation, 76 recipients (FK 39, CSA 37) could be tapered off steroids at 6 months posttransplant, since 11 were excluded due to acute rejection within 6 months posttransplant (FK two, CSA three) or protocol violations (FK two, CSA four). After steroid withdrawal, the incidence of acute rejection episodes was 0% in the FK group and 13.5% in the CSA group (P < .05). Other results at 12 months posttransplantation were comparable: the incidences of DM 7.8% versus 0% (FK group vs CSA group), hypercholesterolemia 41.0% versus 59.5%, hypertensives 48.7% versus 59.6% as well as the levels of plasma creatinine 1.21 +/- 0.24 versus 1.31 +/- 0.50 mg/dL (P > .05 in every variable). These data suggest that steroid withdrawal is successful in first living donor renal transplant recipients. Tacrolimus may be significantly more effective than cyclosporine to prevent acute rejection after steroid withdrawal.
 ...
PMID:Randomized trial of tacrolimus versus cyclosporine in steroid withdrawal in living donor renal transplant recipients. 1551 59

Tacrolimus-based immunosuppression is currently accepted as mainstream therapy in many transplant centers worldwide due to its potent immunosuppressive activity compared to cyclosporine. A tacrolimus-based regimen has been successfully used for our living donor liver transplantation (LDLT) recipients. Adverse effects such as neurotoxicity, nephrotoxicity, and new-onset diabetes mellitus, however, have limited its clinical application. In deceased donor liver transplantation, cyclosporine rescue therapy is valuable for such complications, but few reports have described a strategy for conversion in LDLT. Herein, we present our experience of conversion from tacrolimus to cyclosporine therapy in adult LDLT recipients. Among 203 recipients, 37 patients (18%) required conversion, primarily for neurotoxicity (41%), diabetes mellitus (16%), hematopoietic disorder (16%), and gastrointestinal intolerance (11%). Primary adverse events resolved within 2 months after conversion in 35/37 (94%) of the patients. For LDLT recipients unable to maintain effective immunosuppression with tacrolimus, conversion to cyclosporine is an effective option.
 ...
PMID:Conversion to cyclosporine provides valuable rescue therapy for living donor adult liver transplant patients intolerant to tacrolimus: A single-center experience at the University of Tokyo. 1568 38

Liver transplant recipients are at risk of chronic renal failure (CRF), customarily considered to be secondary to CsA/FK506 nephrotoxicity. We have examined renal biopsies from 26 liver transplant recipients with CRF. Before OLT, 5 patients had CRF, 8 were diabetic and 9 hypertensive. Renal biopsies were performed at a mean of 5 years after liver transplantation. Mean SCr was then 212 micromol/L, proteinuria was 1 g/24 h. Twelve patients were diabetic and 25 hypertensive. Histology revealed impressive renal destruction, with a mean of 45% interstitial fibrosis and 45% glomerular sclerosis. All biopsies showed severe arteriosclerosis. CRF can be attributed to four associated primary lesions: (i) specific chronic CsA/FK506 arteriolopathy; (ii) typical diabetic nephropathy; (iii) acute or chronic thrombotic microangiopathy attributed to CsA/FK506 or alpha-IFN and (iv) tubular changes related to administration of hydroxyethylstarch. At the end of the follow-up, after a mean of 6.4 years, 12 patients required dialysis, 13 had CRF and only 1 had normal renal function. Thus, CRF in OLT recipients is more complex than originally thought and should not be classified as anti-calcineurin nephrotoxicity without further investigations, including renal histology. These investigations have therapeutic potential, that is, they may lead to a more aggressive treatment of hypertension and/or diabetes.
 ...
PMID:Renal histopathological lesions after orthotopic liver transplantation (OLT). 1581 74

Increased risk of cardiovascular disease contributes significantly to the higher rate of mortality seen in kidney transplant patients compared to the general population. New-onset diabetes mellitus (NODM) is a major risk factor for cardiovascular disease, as well as being associated with significantly increased graft loss and higher health care costs compared to the nondiabetic transplant population. Evidence from large-scale analyses of registry databases has shown that the calcineurin inhibitor, tacrolimus, is associated with approximately a 50% increase in the risk of NODM compared to the microemulsion formulation of cyclosporine (CsA); but to date, little robust evidence is available from clinical trials. The DIRECT (Diabetes Incidence after REnal transplantation: Neoral C2 monitoring versus Tacrolimus) study will be the first prospective trial to compare directly the impact of tacrolimus and CsA microemulsion on glucose metabolism in kidney transplant recipients. DIRECT is a 6-month, parallel-group, open-label, randomized trial for which approximately 700 patients will be recruited at around 70 transplant centers worldwide. Patients will be randomized to tacrolimus or CsA microemulsion (using C2 monitoring), with mycophenolate mofetil or enteric-coated mycophenolic acid, steroids, and basiliximab. Primary endpoints are: (a) a composite of NODM or impaired fasting glucose among patients who are nondiabetic at time of transplantation; and (b) combined incidence of biopsy-proven acute rejection, graft loss, or death with CsA microemulsion C2 monitoring compared to tacrolimus trough monitoring . Full results are expected in 2006, with interim results available by the end of 2004, and will be awaited with interest by the transplant community.
 ...
PMID:Rationale and design of the DIRECT study: a comparative assessment of the hyperglycemic effects of tacrolimus and cyclosporine following renal transplantation. 1583 49


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>