Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the approval of cyclosporine in 1983, only 3 drugs, mycophenolate mofetil, tacrolimus, and sirolimus, have been approved for maintenance immunosuppression in renal transplant recipients. All 3 agents decrease the incidence of early acute allograft rejection. An increase in intermediate and long-term graft survival has not been shown. However, survival data from these clinical trials should be interpreted with caution because the studies were not designed for this purpose. All 3 drugs have significant, albeit different, safety profiles. It remains to be seen whether, the lower incidence of hypertension and hyperlipidemia seen in tacrolimus-treated patients will reduce the incidence and severity of the cardiovascular disease experienced by renal transplant recipients. Sirolimus causes severe hyperlipidemia, and the long-term consequences both on the pathogenesis of cardiovascular disease and on lipid-associated renal injury have yet to be determined. Tacrolimus and mycophenolate mofetil appear to increase graft survival in pancreas-kidney recipients but their efficacy in another high-risk group, African-American recipients, has not yet been clearly shown. However, the trend toward improved graft survival in African-American recipients treated with tacrolimus is encouraging. Steroid-withdrawal remains a goal in the posttransplant period. The available data from steroid-withdrawal and steroid-avoidance clinical trials are mixed. Steroid withdrawal can be achieved in about 50% of patients on a cyclosporine-based immunosuppression regimen. Steroid-withdrawal under coverage of tacrolimus, mycophenolate mofetil or Neoral (Novartis Pharmaceuticals, East Hanover, NJ) may be more successful than that achieved in patients receiving Sandimmune (Novartis Pharmaceuticals). Further studies are needed in this area.
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PMID:Maintenance immunosuppression: new agents and persistent dilemmas. 1078 29

CyA is the core immunosuppressant of choice for the majority of transplant patients. The introduction of Neoral, a new microemulsion formulation of CyA. and more recently a range of adjunctive immunosuppressants have further enhanced the efficacy and tolerability of CyA-based immunosuppression. In the first year following transplantation the major causes of morbidity and death are graft failure, acute rejection, and systemic infection. Patients with deteriorated pulmonary circulation before transplantation are at increased risk of early postoperative death. Risk factors for early acute rejection include female donor sex, young donor age, and multiple HLA-DR mismatches. The principal cause of death in the long term is graft vasculopathy which accounted for 40% of all deaths. Risk factors that have been hypothesized to play a role in the pathogenesis of graft vasculopathy include hyperlipidemia, recipient age and gender, donor age, the number of HLA AB and DR mismatches, and CMV infection. Strategies proposed to reduce the risk of graft vasculopathy include aggressive use of lipid-lowering agents, avoidance of low CyA doses, and the use of adjunctive rapamycin or RAD therapy. Rejection surveillance therefore relies on routine serial endomyocardial biopsy. Recent research suggests that a more accurate assessment of the state of the graft can be obtained by considering the results across a number of biopsy samples obtained from different parts of the heart, rather than basing clinical judgment on the worst single result obtained. New molecular markers such as granzyme A mRNA are likely to improve the power of histology to diagnose and predict rejection. Neoral pharmacokinetics give greater bioavailability and less intrapatient variability than Sandimmune. In the keynote OLN 351 study comparing Neoral with Sandimmune in de novo heart transplant recipients, fewer Neoral patients needed antilymphocyte therapy to treat rejection, fewer female patients had rejection episodes in the Neoral group, the tolerability of the two formulations was equivalent, and there was a lower incidence of infections in the Neoral group. The clinical impact of Neoral in comparison with Sandimmune in de novo heart transplant patients has been investigated in a number of additional trials, including long-term studies, which have confirmed that Neoral is associated with: Lower CyA doses than Sandimmune. Equal or greater antirejection efficacy than Sandimmune. Comparable tolerability to Sandimmune. During the administration of intravenous CyA as an induction therapy in the days immediately following transplantation, there is evidence to suggest that a 6-hour infusion given twice daily, which mimics the pharmacokinetic profile of oral dosing, may be clinically more effective than a continuous 24-hour infusion. Milligram-for-milligram dose conversion from Sandimmune to Neoral is feasible. Following conversion, a reduction in the CyA dose may be required in the majority of patients to maintain target levels. In pediatric patients, the rate of elimination of CyA is greater and bioavailability increases with increasing age. Younger patients (less than 8 years of age) may be managed more effectively with a 3-times-daily, rather than a twice-daily dosing schedule. A number of studies have compared the clinical effects of Sandimmune and Neoral in maintenance therapy for cardiac transplant patients. As with de novo patients, these studies have found the new formulation of CyA to be associated with lower rates of acute rejection, lower therapeutic doses, and comparable tolerability. Milligram-to-milligram conversion from the old to the new CyA formulation is generally well tolerated, although in a minority of patients there is a significant increase in CyA levels. These may be associated with a transient increase in side effects which resolve on dose reduction. There is a dose-sparing effect with Neoral. Routine monitoring of both CyA and serum creatinine levels are adv
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PMID:Neoral use in the cardiac transplant recipient. 1081 48

A microemulsion formulation of cyclosporin (Neoral) has been developed to overcome the problems of poor and variable absorption of cyclosporin. Neoral is a potent immunosuppressive agent that is highly bound in the plasma. It has been proposed that low-density lipoprotein (LDL) delivers cyclosporin (CsA) to T-lymphocytes via the LDL receptor pathway, where it produces its therapeutic effects. Herein, we report a case of minimal change nephrotic syndrome with type 2 diabetes mellitus treated by Neoral and fluvastatin. A 65-year-old male with a 10-year history of type 2 diabetes mellitus suddenly developed nephrotic syndrome. The potential causative drugs, such as NSAIDs and antibiotics, had not been administered. The laboratory findings were as follows: proteinuria 23 g/day, serum albumin 1.9 g/dl, total cholesterol 629 mg/dl, LDL-Cho 1,930 mg/dl. Renal biopsy was normal on light microscopy, and immunofluorescence demonstrated no staining. Due to the risk of deterioration of diabetes by administering prednisolone, he was given Neoral at 2.0 mg/kg/day. He was also given fluvastatin (40 mg/day) for hyperlipidemia after the renal biopsy. At four weeks after the start of Neoral and fluvastatin, his nephrosis continued, but his LDL-Cho and total cholesterol decreased. At six weeks after treatment, proteinuria gradually reduced. At eight weeks after treatment, the proteinuria had disappeared. Nephrotic syndrome is often associated with abnormal lipid metabolism, and many patients with nephrotic syndrome show high levels of LDL-Cho. It has been reported recently that LDL apheresis is effective against nephrotic syndrome. However, in the present case, it can be speculated that the improvement of hyperlipidemia by fluvastatin probably augmented the effect of Neoral, presumably through the increased cellular uptake of Neoral. This suggests that fluvastatin may be considered as the treatment of choice for the disturbed lipoprotein profile in patients with nephrotic syndrome.
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PMID:[Complete remission of minimal change nephrotic syndrome with type 2 diabetes mellitus treated by microemulsion formulation of cyclosporin and fluvastatin]. 1197 50

Calcineurin inhibitors (CIs) contribute to cardiovascular risk (CR) in renal transplant (RT) patients. However, the CR profile in RT patients without preexistent diabetes is not well known. We compared CR factors in 191 nondiabetic RT recipients with functioning grafts beyond 1 year, receivingly either CsA (Neoral; n=100) or tacrolimus (Tac; n= 91). Clinical data and pretransplant CR profiles were similar in both groups. There were no differences in acute rejection episodes and graft survival rates during follow-up. The overall proportions of posttransplant diabetes (9% versus 6%), and of hypertension (73% vs 63%) were similar in both groups. Hyperlipidemia was more frequent in the CsA group (58% vs 31%; P=.0001). The cholesterol levels in the CsA group showed at 3 months (232+/-47 vs 202+/-42 m/dL; P=.0001), 6 months (232+/-49 vs 205+/-41 mg/dL; P=.0001), and 12 months (217+/-50 vs 202+/-40 mg/dL; P=.028), despite receiving a greater proportion of lipid-lowering drugs (49% vs 15%; P=.0001). Logistic regression analysis showed that CsA was an independent predictor of posttransplant hyperlipidemia (OR: 5.8, CI 95%; 3.3-10.7; P=.0001) as were age, female gender, pretransplant dyslipidemia, and body mass index (BMI). Interestingly, an interaction was observed between pretransplant BMI and CIs: Among pretransplant normal weight patients (BMI <25 kg/m2), CsA produced a greater incidence of hyperlipidemia than tacrolimus (58% vs 23%; P=.0001) while not among patients who were overweight (BMI >25 kg/m2: pretransplant 58% vs 42%; P=.341). In conclusion, CsA confers a higher risk of hyperlipidemia after RT in nondiabetic patients, particularly those with normal pretransplant weight.
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PMID:Cardiovascular risk profile in nondiabetic renal transplant patients: cyclosporine versus tacrolimus. 1296 73

Cyclosporine (CsA) is currently the basis of most immunosuppressive protocols after solid organ transplantation. The introduction of Neoral, a new microemulsion formulation of CsA, and more recently a range of adjunctive immunosuppressants have further enhanced short-term efficacy and tolerability of CsA-based immunosuppression. In addition, Neoral C2 monitoring has been shown to have advantages not only in the early posttransplant period, but also for maintenance transplant patients. The major long-term disadvantage associated with CsA is the development of nephrotoxicity and chronic allograft nephropathy (CAN), which is the second major cause of graft failure. Thus, strategies to reduce the risk of CAN include CsA-sparing protocols, use of C2 level monitoring, introduction of non-nephrotoxic adjunctive immunosuppressants, and optimal management of additional risk factors. Other important side effects related to CsA-based immunosuppression include hypertension, diabetes, and hyperlipidemia. Optimal management of these conditions may lead to significant reduction of cardiovascular-related morbidity and mortality following solid organ transplantation.
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PMID:Experience with cyclosporine in the Canary Islands. 1504 20

As liver transplantation is now being performed with an excellent 5-year survival rate of approximately 70% at selected centers, attention has been shifted to reduce long-term complications of calcineurin inhibitors including diabetes, hypertension, and hyperlipidemia, which have a major effect on morbidity and mortality within the transplant setting. Cyclosporine (CsA) monitoring has been performed traditionally by measurement of predose "trough" blood concentrations (C0). Recent development of 2 hour postdose CsA (C2) monitoring strategy has emerged as a much more sensitive approach for assessing the pharmacokinetics and providing greater precision in the optimization of Neoral dosing than C0 measurements. Furthermore, a reduction of risk factors for atherosclerotic vascular disease and in the incidence and severity of acute cellular rejection have been associated with the adoption of C2 monitoring. However, further data from multicenter trials are required to evaluate the long-term benefits of this new therapeutic monitoring strategy.
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PMID:Future directions in immunosuppression. 1504 8

The use of calcineurin inhibitors (CNIs; cyclosporine and tacrolimus) has dramatically increased medium-term life expectancy after heart transplantation but has had only limited impact on long-term outcomes for heart transplant recipients. The original oil-based formulation of cyclosporine has been superceded by a microemulsion formulation (Neoral), which has more predictable pharmacokinetics and allows more precise dose-tailoring. Cyclosporine microemulsion and tacrolimus (Prograf) have a similar efficacy in the prevention of acute rejection of heart transplants, but their use is accompanied by nephrotoxicity and by cardiovascular side effects. The efficacy of immunosuppression can be improved by adjunctive therapy, such as azathioprine, mycophenolate mofetil (MMF; Cellcept), corticosteroids, and induction therapy. One of the most important predictors of patient mortality at >5 years after heart transplantation is cardiac allograft vasculopathy (CAV)/late graft failure, which accounts for 31% of deaths. Neither cyclosporine nor tacrolimus have been shown to prevent the development of CAV. In terms of efficacy, MMF provides a modest advantage over azathioprine in preventing CAV, and the combination of cyclosporine plus MMF results in significantly lower mortality than cyclosporine plus azathioprine. Overall, CNIs have multiple cardiovascular side effects, such as hypertension, hyperlipidemia and new-onset diabetes after transplantation, although cyclosporine and tacrolimus have somewhat different cardiovascular side-effect profiles. The challenge in choosing the best immunosuppressive regimen is to balance efficacy and safety to optimize graft and patient survival over the course of many decades. Because cyclosporine and tacrolimus have similar efficacy against acute rejection the choice of CNI for heart transplant recipients should be based on the relative risk of cardiovascular and renal side effects.
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PMID:Calcineurin inhibitors in heart transplantation. 1509 6

After the introduction of cyclosporine into liver transplantation in 1983, 1-year patient survival more than doubled. Later, with the improved microemulsified formulation of cyclosporine (Neoral) more stable pharmacokinetics were achieved. Today, C(2) monitoring of cyclosporine blood levels allows a more accurate estimation of the area under the concentration-versus-time curve as the single best indicator of cyclosporine exposure. As a consequence, with better control of side effects as well as desired effects the results of cyclosporine in liver transplantation have been further improved. The introduction of mycophenolate mofetil and basiliximab/daclizumab combination therapy has provided new options for the prevention of allograft rejection. The safety profile of individual immunosuppressive regimens comes more into focus since acute allograft rejection may be controlled successfully with competing strategies. As the focus in liver transplantation is shifting toward greatly improved long-term results, late posttransplant mortality with a functioning graft is a major concern. Prevention of long-term complications associated with highly effective immunosuppressants--posttransplant lymphoproliferative disease, cytomegalovirus infection, diabetes, hypertension, and hyperlipidemia-gains importance. Technical advances in living-related and cadaveric split-liver transplantation have lead to increasing use of segmental liver transplantation with the need to consider the effects of immunosuppression on liver regeneration and metabolism. The individualized orchestration of immunosuppression taking into account the underlying liver disease as well as other individual predispositions remains a future challenge.
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PMID:Update on liver transplantation using cyclosporine. 1562 Oct 81

Innovations in immunosuppressant therapy often transfer from renal transplantation to heart transplantation. Accordingly, there is growing interest in calcineurin inhibitor (CNI)- and steroid-sparing regimens for heart transplant patients. The novel proliferation signal inhibitor, Certican (everolimus), has been shown to allow reduced CNI exposure in renal transplant recipients without loss of efficacy. It has also demonstrated efficacy for reducing biopsy-proven acute rejection (BPAR) and cardiac allograft vasculopathy (CAV) in de novo heart transplantation. The present study reports early clinical experience of introducing everolimus as maintenance immunosuppression in heart transplant recipients whose previous regimen had failed. A 58-year-old woman received an organ from a 56-year-old female donor. She was prescribed cyclosporine for micromemulsion (CsA; Neoral), azathioprine, prednisolone and atorvastatin. After 3 months, azathioprine was switched to mycophenolate mofetil (MMF). At Month 27, the patient experienced Grade 3A BPAR, had a left ventricular ejection fraction (LVEF) of 20%, and compromised renal function. After steroid boluses to control BPAR, everolimus 3.0 mg/day was prescribed, while CsA and prednisolone doses were reduced. One month later, the patient contracted herpes labialis and pneumonia, and creatinine was elevated; CsA was stopped, everolimus dose was reduced to 1.5 mg/day and prednisolone reduced further. After another month, LVEF recovered to 50% and creatinine was 1.29 mg/dl. There was evidence of hyperlipidemia, which responded to atorvastatin 10 mg. For maintenance immunosuppression after heart transplantation, everolimus may allow CsA dose reduction and could be efficacious in combination with MMF. Further studies are required to confirm its efficacy and effects on CAV.
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PMID:Clinical experience with Certican (everolimus) in maintenance heart transplant patients at the Medical University of Vienna. 1577 24

Drugs used for immunosuppression have been implicated in causing numerous long-term side effects including nephrotoxicity, glucose intolerance, and hyperlipidemia. In this study, we reviewed our pediatric liver transplant recipients in terms of glomerular filtration rate (GFR) as well as fasting glucose and lipid profiles. To date, 79 pediatric liver transplantations have been performed at our center: 24 transplantations of at least 5 months to a maximum of 7.3 years posttransplant are reviewed herein. The mean time posttransplantation was 2.1 years. Nine boys and 15 girls showed a distribution of 19 mixed race, 3 black, and 2 white patients. The mean age at the time of transplantation was 6.6 years (0.8-13.3 years) with 8 cases under the age of 3 years. All recipients started with Cyclosporine Neoral (CSA) as first line, but, at the time of testing, immunosuppression included 5 children on CSA and 19 on Tacrolimus. Radionuclide 51 Cr-EDTA Glomerular Filtration Rates (GFR) showed a range from 21 to 220 mL/min/1.73 m2 (mean 96.1, median 89.8). Seven cases had a GFR less than 75 mL/min/1.73 m2. Twenty-one children were on antihypertensives agents: 15 children on 1 agent and 6 children on 2 agents. On full fasting lipid profiles, the total cholesterol ranged from 2 to 7.9 mmol/L (mean 4.4). Only 1 child is currently on statin therapy. Fasting glucose ranged from 3.2 to 5.9 mmol/L (mean 4.1) No difference was observed in glucose values between CsA and Tacrolimus. Thus, immunosuppressive therapies, such as the calcineurin inhibitors, are known to cause nephrotoxicity, which is of concern in pediatric liver transplant recipients. Almost all our patients currently require antihypertensive therapy. At present, the renal function is adequate in the majority of the group, but this study needs to be extended to other pediatric liver transplant recipients with particular emphasis on those who are more than 5 years posttransplantation.
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PMID:Nephrotoxic effects of immunosuppressant therapy in pediatric liver transplant recipients. 1584 75


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