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)

Considerable advances in the understanding of the immune basis of type I diabetes have encouraged trials of a number of forms of immunotherapy. Preliminary evidence indicates that cyclosporin (Sandimmune) treatment can halt beta cell destruction in about 50% of patients with newly diagnosed type I diabetes. Further studies are necessary to define the toxicity of this and other protocols prior to clinical use. Efforts to define the target antigen in type I diabetes may lead to development of more specific forms of immunotherapy or, possibly, a vaccine.
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PMID:Immunotherapy in type I diabetes. Approaches to prevention and treatment. 355 98

The microemulsion-based formulation of cyclosporin (Neoral; referred to as the microemulsion formulation in this review) is a microemulsion preconcentrate which has been developed to overcome problems associated with the poor and unpredictable absorption of the standard oral formulation of this drug. These include marked intra- and interpatient variability in the extent of absorption, a poor correlation between trough blood concentrations of cyclosporin and total systemic exposure, and the need for regular monitoring of blood cyclosporin concentrations. In healthy volunteers and renal or liver transplant recipients, administration of the microemulsion formulation resulted in cyclosporin absorption which was significantly faster, more extensive and more predictable than that seen with the standard oral formulation. Furthermore, measurement of whole-blood trough cyclosporin concentrations provided a better estimate of systemic drug exposure in renal transplant recipients who received the microemulsion formulation than in those who received the standard formulation. Systemic exposure of cyclosporin delivered by the new formulation appears to be relatively unaffected by food intake. Initial data suggest that drug absorption from the microemulsion formulation is enhanced in comparison with that achieved from the standard formulation in liver transplant recipients undergoing biliary diversion or with cholestasis, although absorption from the new formulation does not appear to be completely independent of bile. Preliminary results from other groups that experience cyclosporin malabsorption from the standard formulation (patients with cystic fibrosis or diabetes, and children) are also encouraging. Clinical trials specifically designed to investigate the relative immunosuppressive efficacy of the microemulsion formulation have not been reported; further data are required to fully establish the relationship between the more rapid and extensive absorption of cyclosporin from the microemulsion formulation and the probability of graft rejection or adverse events (including nephrotoxicity and hypertension). However, no statistically significant differences have been noted between the 2 formulations in the incidence of these events in studies to date. The incidence of rejection in new renal or liver transplant recipients treated for a minimum of 3 months was approximately 31 to 50% in those receiving the microemulsion formulation and approximately 24 to 56% in those receiving the standard formulation. Thus, although confirmation of existing efficacy and tolerability data is required, the characteristic pharmacokinetic properties of the microemulsion formulation make it an attractive option for the oral delivery of cyclosporin in transplant recipients, offering more predictable and more extensive drug absorption than the standard formulation. The microemulsion formulation may be of particular benefit in patients who show poor absorption of cyclosporin from the standard oral formulation, such as liver transplant recipients with biliary diversion or cholestasis.
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PMID:Cyclosporin. A review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (Neoral). 858 33

This follow-up multicenter analysis is based on 362 pancreas allograft recipients at 14 institutions who were given tacrolimus between 1 May 1994 and 15 November 1995. Three groups were studied: (1) recipients given tacrolimus initially for induction and maintenance therapy (n = 250; 215 without, 35 with, a concurrent bone marrow transplant), (2) recipients who converted to tacrolimus for rescue or rejection therapy (n = 89), and (3) recipients who converted to tacrolimus for other reasons (n = 23). Of 215 recipients without a bone marrow transplant in the induction group, 166 (77%) underwent a simultaneous pancreas-kidney transplant (SPK), 29 (14%) a pancreas transplant alone (PTA), and 20 (9%) a pancreas after previous kidney transplant (PAK). Initial antibody therapy was given to 185 (86%) recipients. All 215 received tacrolimus and prednisone; 202 (94%) also received azathioprine (AZA) and 11 (5%) mycophenolate mofetil (MMF). The most common side effects of tacrolimus were neurotoxicity in 21%, nephrotoxicity in 21%, gastrointestinal (GI) toxicity in 13%, and diabetogenicity in 13% of these recipients. No recipient in this group developed new-onset insulin-dependent diabetes mellitus. Of 89 recipients in the rescue group, 71 (79%) had an SPK, 11 (13%) a PTA, and 7 (8%) a PAK. Before conversion, all had been on cyclosporine (CsA)-based immunosuppression; 74% of them had 2 or more rejection episodes previously. The most common side effects were nephrotoxicity in 27%, neurotoxicity in 26%, GI toxicity in 18%, and diabetogenicity in 8% of these recipients. No recipient in this group developed new-onset insulin-dependent diabetes mellitus. In the induction group patient survival at 1 yr was 98% for SPK, 79% for PTA, and 100% for PAK recipients. According to a matched-pair analysis, pancreas graft survival for SPK recipients at 1 yr was 88% with tacrolimus vs. 73% with CsA (p = 0.002); for PTA recipients, 68% vs. 70% (p > 0.35); and for PAK recipients, 85% vs. 65% (p = 0.13). Graft loss from rejection was not different with tacrolimus vs. CsA in all 3 pancreas recipient categories. At 1 yr, 17% of recipients had converted from tacrolimus to CsA for diabetogenicity, nephrotoxicity, or rejection; 23% had converted from AZA to MMF. The incidence of post-transplant lymphoma was < 2%. In the rescue group, patient survival rates at 1 yr were 96% for SPK, 100% for PTA, and 86% for PAK recipients (p < 0.08). Pancreas graft survival at 1 yr was 89% for SPK, 58% for PTA, and 69% for PAK recipients (p = 0.004). Graft loss from rejection was significantly lower for SPK vs. PTA or PAK recipients. At 1 yr, 20% of recipients had reconverted from tacrolimus to CsA for rejection, neurotoxicity, or nephrotoxicity; 19% had converted from AZA to MMF. There were no post-transplant lymphomas in the rescue group. This follow-up multicenter analysis shows that tacrolimus after pancreas transplantation is associated with high graft survival rates when used for induction and with high graft salvage rates when used for rescue therapy. The rate of graft loss from rejection is low in all 3 pancreas recipient categories. The overall incidence of new-onset insulin-dependent diabetes mellitus is < 1%, as is the incidence of post-transplant lymphoma. Converting from tacrolimus to CsA and, in patients on tacrolimus, from AZA to MMF, is safe; interchangeable use of drugs appears to be of immunologic benefit. To determine the best immunosuppressive regimen after pancreas transplantation, a prospective randomized study comparing tacrolimus and MMF vs. Neoral plus MMF is mandatory.
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PMID:Tacrolimus in pancreas transplantation: a multicenter analysis. Tacrolimus Pancreas Transplant Study Group. 926 19

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

Female solid organ recipients with good graft function generally tolerate pregnancy well. However, the combination of mother, fetus, transplanted organ, and immunosuppressive and other medications increases the complexity of management and raises the specter of adverse outcomes. For the mother, considerations include the nature of the original disease (i.e. genetic risk of transmission), co-morbid conditions which increase pregnancy risk (i.e. hypertension, diabetes, renal insufficiency), and long-term maternal prognosis. For the fetus, questions include the adequacy of maternal physiology (cardiac, renal, glycernic control, etc.), exposure to medications, and exposure to infectious agents. The transplanted organ must accommodate the increased workload of pregnancy and the needs of the fetus. The delicate balance between immunosuppression and rejection may be altered by the pregnancy. The impact of pregnancy on recurrent disease can also be an issue. Medication issues include changes in drug pharmacokinetics and the potential for adverse effects on the fetus. These effects could include chromosomal aberrations, structural malformations, organ-specific toxicity, intrauterine growth retardation, and immune system development. For female kidney recipients there are sufficient data to demonstrate a direct relationship between creatinine levels before and during pregnancy and risk of graft loss in the postpartum period. Pregnancy itself does not appear to adversely affect stable graft function. Among liver recipients, those with recurrent viral hepatitis may have deterioration of graft function with subsequent pregnancies. These recipients should be apprised accordingly, as maternal deaths have occurred in this setting. Postpartum depression and potential for medication noncompliance require vigilance. The safety of pregnancy from the NTPR analysis to date has been largely derived from the experience with CsA-based regimens. For recipients on CsA there have been good maternal outcomes without any specific or predominant malformation patterns in the offspring. For the general population, malformations occur in approximately 3% of live births. To date, there is no indication that this incidence has increased despite the complex medical regimens of transplant recipients. Data are accruing with tacrolimus and Neoral. Continuing data entry and continued follow-up of off-spring will allow for further recommendations, especially in light of the new medications and combinations. Recipients should be advised to wait one to 2 years after transplant before considering pregnancy. Those with stable graft function, and with no rejection, graft dysfunction, or deterioration should still be apprised of the high risk of prematurity and low birthweight, although maternal risks appear low. These are high-risk pregnancies, requiring close communication and cooperation between the high-risk obstetrician and the transplant team. The use of the FDA pregnancy categories should not be the sole reason for choosing a particular immunosuppressive drug. Agents such as Neoral and tacrolimus would appear to offer some advantage as blood levels can be measured. At present, no safety guidelines can be given for mycophenolate mofetil, OKT3, or ATG. Identification of prepregnancy factors predictive of higher risks and appropriate counseling and management guidelines are major NTPR goals, and depend on the continued assistance and cooperation of the transplant community.
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PMID:Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. 991 94

The greater and more consistent absorption of cyclosporine from the microemulsion formulation (Neoral; Novartis Pharmaceuticals Ltd., Frimley, UK) when compared with that from the original form (Sandimmune; Novartis Pharmaceuticals Ltd., Frimley, UK) results in greater systemic exposure. Lung transplant recipients could particularly benefit from this enhanced exposure, but not at the expense of excessive cyclosporine toxicity. We compared the pharmacodynamics of Neoral and Sandimmune over the first postoperative year in 50 lung transplant recipients. Twenty-eight patients were randomly selected to receive Neoral and 22 to receive Sandimmune. Nine patients with cystic fibrosis (CF) were randomly selected independently (5, Neoral; 4, Sandimmune). Patients were maintained on similar trough blood cyclosporine concentrations (C0) throughout the 12-month follow-up. A limited blood sampling strategy was adopted to compare the pharmacokinetics of the two formulations at the end of weeks 1 to 4, and of weeks 13, 26, 39, 52. The influence of any difference between the pharmacokinetics of Neoral and Sandimmune on either efficacy or toxicity of the drug was investigated during the follow-up period. Patients in the Neoral and the Sandimmune groups were matched demographically. There were no differences in dose-normalized blood cyclosporine concentrations measured predose (C0) or 6 hours postdose between the two groups. However, the measurement at 2 hours postdose (C2) and the total AUC0-6 were significantly greater in the Neoral group in both CF and non-CF patients at all visits (p < 0.001). Non-CF patients required 9% lower doses of Neoral to achieve comparable C0 measurements to those patients receiving Sandimmune. However, patients with CF required 2 to 3 times the dose of both Neoral and Sandimmune to achieve the same C0 as non-CF patients. The linear rejection rate in the Sandimmune group was 1.87 episodes per patient year, which was similar to the rejection rate of 1.97 episodes per patient year in the Neoral group. Serial lung function, blood biochemistry and hematology, mortality and the incidence of severe renal dysfunction, hypertension, infection, seizures, and new-onset diabetes were all similar in the two groups. Despite equivalent C0, those in the Neoral group were consistently exposed to greater blood cyclosporine concentrations during the dosing interval than those in the Sandimmune group. This did not increase the incidence of serious cyclosporine-associated side effects or influence the rate of acute rejection either. When data from the Neoral and Sandimmune groups were combined, measurements of C0 but not C2 or C6 were associated with the risk of acute lung allograft rejection.
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PMID:Randomized, trough blood cyclosporine concentration-controlled trial to compare the pharmacodynamics of Sandimmune and Neoral in de novo lung transplant recipients. 1005 Oct 50

Post-transplant diabetes mellitus, a complication due to corticosteroids and the calcineurin inhibitors, cyclosporine and tacrolimus (FK506), is commonly regarded as a form of type-2 (adult-onset) diabetes mellitus. Diabetic ketoacidosis, which requires relative insulin deficiency to impair fatty acid metabolism, is a complication of type-1 diabetes mellitus. We report three patients who presented with diabetic ketoacidosis post-transplant. All three patients presented with severe hyperglycemia, significant ketosis and metabolic acidosis of variable severity. One patient was a renal transplant recipient on a cyclosporine-based regimen. The other two patients were liver transplant recipients receiving either cyclosporine or tacrolimus-based immunosuppression. Both of the liver transplant recipients were found to have moderate to high serum levels of calcineurin inhibitors on presentation. The liver recipient on cyclosporine (Neoral) had a 4 hour post-dose level of 388 ng/ml and the patient on tacrolimus was found to have a trough level of 21.2 ng/ml. Our experience suggests that post-transplant diabetes mellitus, in association with calcineurin inhibition, may result in ketoacidosis either secondary to relative beta cell dysfunction, peripheral insulin resistance, or a combination of the two effects. Post-transplant diabetes mellitus can be an atypical form of adult-onset diabetes with features of both type I and type II diabetes mellitus.
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PMID:Post-transplant diabetic ketoacidosis--a possible consequence of immunosuppression with calcineurin inhibiting agents: a case series. 1074 93

Tacrolimus has proven to be superior to cyclosporine-Sandimmune with regard to the prevention of acute rejections, but data comparing tacrolimus with Neoral are scarce. A total of 128 consecutive renal transplant recipients was studied. The patients were treated with Neoral-based (n = 74) or tacrolimus-based (n = 54) immunosuppressive regimens. Survival analyses (Cox regression analysis) were performed on an intention-to-treat basis. Renal function and cardiovascular risk profile were analyzed by means of a repeated-measures analysis of variance (ANOVA) up to 12 months after transplantation. Immunological features were less favorable in the tacrolimus group. Two-year patient and graft survival were comparable. Acute-rejection-free survival was 82 % in the tacrolimus group versus 40 % in the Neoral group (P < 0.0001). The severity of the rejections (1997 Banff classification) was comparable (P = 0.43). Immunological graft loss (3.7 % vs. 12.2 %, P = 0.02) and conversion because of rejection (0 % vs. 28.4 %, P < 0.001) were less in the tacrolimus group. A higher proportion (68.5 % vs. 14.9 %, P < 0.001) was successfully put on monotherapy. Creatinine clearance, proteinuria, and fractional uric acid clearance were similar. In the tacrolimus group mean blood pressure was comparable, but patients needed less anti-hypertensive drugs (P < 0.001) and, even with fewer patients on lipid-lowering drugs, total cholesterol was lower (5.2 vs. 6.0 mmol/l, P = 0.003). Treatment for post-transplant diabetes mellitus was 18.5 % versus 10.8 % (P = 0.22). In both groups, antidiabetic medication could be withdrawn for most patients. This study indicates that tacrolimus is superior to cyclosporine-Neoral in preventing acute rejection with comparable patient and graft survival rates. Because of a lower need for treatment of hypertension and hypercholesterolemia, the cardiovascular risk profile is more favorable. A considerable proportion of patients can be successfully weaned off co-medication and treated with tacrolimus monotherapy.
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PMID:Single-center experience with tacrolimus versus cyclosporine-Neoral in renal transplant recipients. 1179 34

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


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