Cyclosporine Blood Levels Research Articles

Cyclosporine - a treatment and a rare complication: Raynaud's phenomenon

Cyclosporine - a treatment and a rare complication: Raynaud's phenomenon

Blood Cyclosporine Level Soon After Kidney Transplantation is a Major Determinant of Rejection: Insights From the Mycophenolate Steroid-Sparing Trial

Target organs express antigens directly recognized by antigen-specific T cells, thereby precipitating rejection. When early T-cell activation is inhibited, there is a low risk of rejection. We sought to determine the predictive values of serial posttransplant blood cyclosporine trough (C 0) concentrations to minimize the risk for a first rejection episode compared with 2-hour postdose (C 2) drug concentrations. The final aim of the study was to identify a concentration range for the best predictive pharmacokinetic parameter that should be targeted to reduce the risk of rejection. This possibility was explored in 334 de novo kidney transplant recipients who participated in the prospective, multicenter Mycophenolate Steroid-Sparing Trial. Among measurements performed during the first 6 months postsurgery, cyclosporine C 0 levels measured early after transplantation were the strongest predictor of acute graft rejection. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while patients with levels lower than 300 ng/mL showed a more than double risk. Cyclosporine trough values predicted allograft rejection with an accuracy of 74%, while C 2 levels had no predictive value. These findings underline the need to target cyclosporine therapy early posttransplant to modulate T-cell activation.

Rosiglitazone is a safe and effective treatment option of new-onset diabetes mellitus after renal transplantation

The purpose of this study was to assess the safety and efficacy of the insulin sensitizer rosiglitazone in patients with new-onset diabetes mellitus (NODM) after renal transplantation. Twenty-two patients with NODM after renal transplantation were selected to receive rosiglitazone therapy. All patients received prednisone, 15 patients were treated with tacrolimus and seven patients received cyclosporine A. For 16 of the 22 patients treatment with rosiglitazone therapy was successful and mean fasting blood glucose decreased from 182 +/- 17 to 127 +/- 7 mg/dl. Six patients were not treated successfully with rosiglitazone alone, one patient needed a second oral antidiabetic agent and four patients insulin therapy. In one patient rosiglitazone was stopped because of edema after 5 days. There were no changes either in serum creatinine concentrations, or cyclosporine and tacrolimus blood levels respectively. Treatment with rosiglitazone appears to be safe and effective in patients with NODM after renal transplantation.

Switchover to generic cyclosporine in stable renal transplant recipients: A single unit experience

The introduction of the immunosuppressant cyclosporine has significantly improved renal transplant survival. It is an expensive drug and generic alternatives may offer cost advantages. However, generic alternatives must be shown to provide equivalent therapeutic efficacy and safety. This study reports our experience of a switch from the microemulsion formulation of cyclosporine, Neoral (Novartis), to the generic equivalent, Cysporin (Mayne Pharma). A two-period, single-sequence, cross-over study was done to compare cyclosporine blood levels and the area under the curve (AUC) of Neoral with Cysporin 2 weeks after a 1:1 dose switch. cyclosporine blood levels were measured at time points 0, 2, 4 and 8 h (C0, C2, C4, C8) after the switch. The cyclosporine AUC at 0-4 h and 0-12 h were calculated using the trapezoidal method. The two formulations were considered to result in equivalent blood levels if the 95% confidence interval (CI) of the ratio of the two levels was within 0.8-1.25. A total of 38 stable renal transplant patients aged 49.79 +/- 11.38 years (mean +/- SD), who were 7.84 +/- 3.97 years postrenal transplantation, were studied. The Neoral dose at the time of the switch was 2.38 +/- 1.21 mg per kg bodyweight. At all measured time points the 95% CI for the cyclosporine drug level ratio was between 0.9 and 1.15. There were no significant adverse events during the period of study. We conclude that the generic formulation of cylosporin, Cysporin, after a 1:1 switch from Neoral results in equivalent blood levels in stable renal transplant recipients. After switchover cyclosporine levels at C0 or C2 can continue to be monitored as per the institution's current monitoring practice.

Rapid Cyclosporine Tapering and Isotretinoin Usage after Unrelated Donor Hematopoietic Stem Cell Transplantation in Juvenile Myelomonocytic Leukemia.

Juvenile myelomonocytic leukemia (JMML) is a rare type of childhood leukemias, and allogeneic hematopoietic stem cell transplantation (HSCT) is known to be the only way to cure the disease. Unfortunately, relapse is still the most frequent cause of treatment failure after transplant in JMML. We investigated the feasibility of inducing graft versus leukemia (GVL) effect and the use of a differentiating agent even after unrelated HSCT in children with JMML. Seven consecutive patients with JMML underwent unrelated HSCT at a median age of 17 months. The sources of grafts were bone marrows (n=3) or HLA 1- or 2-antigen mismatched cord bloods (n=4). Only 3 of the 7 patients were in complete remission before transplantation. Intravenous busulfan, cyclophosphamide, and etoposide were used as preparative agents except in one who was conditioned with TBI-based regimen. Cyclosporine was used universally for GVHD prophylaxis with additional use of short-term methotrexate in bone marrow transplants and of methyl-prednisolone in cord blood transplants. Cyclosporine was tapered rapidly from around 1 month post-HSCT and isotretinoin (75–100 mg/m2/day) was used in selected patients who have any risk factors of relapse. Cyclosporine blood levels were 247.8±91.1, 146.6±104.2, and 88.8±52.6 ng/mL at 1, 2, and 3 months post-transplant, respectively. There was no grade 3 or 4 acute GVHD and only 2 patients developed grade 2 acute GVHD which was improved without additional treatment. Chronic GVHD was developed in 3 (1 limited, 2 extensive) of the evaluable 5 patents, which was all resolved after combined use of immune suppressive agents. Initial chimeric status analysis at 1 month revealed complete donor chimerism (CC) in 4 patients, mixed chimerism (MC) in 2 and autologous recovery (AR) in one. One of the patients with MC and the one with AR were in disease-free status. One patient whose chimeric status changed from CC to MC eventually relapsed. One patient with initial MC with residual disease turned to CC with complete remission. Another patient with initial MC but with no evidence of disease is on treatment with isotretinoin without relapse for 3 months even with persistent MC. The patient with AR relapsed early after transplant. Five patients are alive relapse-free and disease-free with a median follow-up of 16 months after transplant. The Kaplan-Meier probability of event-free survival was 66.7%. We suggest that GVL induction strategy with concomittant use of a differentiating agent might have a role to suppress leukemic relapse in JMML.

Identifying cyclosporine blood levels associated with the prevention of renal transplant rejection: A single-center, randomized prospective study

Multiple-drug therapy may allow reduced individual drug doses with fewer side effects. Blood levels of cyclosporine (CsA) necessary to avoid rejection may vary with different drug combinations. Fifty-eight kidney transplant patients were randomized into two groups: 25 subjects were assigned to the 4-hour area under the curve (AUC 0–4) Cohort—the “high arm” (4500 to 5500 ng · h/mL)—1 and 33 to the AUC 0–4 “low arm” (2400 to 3400 ng · h/mL). After CsA introduction, AUC 0–4 was drawn on days 4, 7, 14, 21, 28, 42, 56, 70, 84, 90. We compared the proportion of rejection versus rejection-free patients, according to the CsA exposure. Logistic regression analysis showed that an AUC 0–4 of ≥4000 ng · h/mL or a 2-hour cyclosporine level (C 2) of ≥1450 ng/mL predicted a rejection-free course among patients not receiving induction therapy. When either basiliximab or thymoglobulin was administered, a C 2 and AUC 0–4 of 1043 ± 151 ng/mL or 3146 ± 262 ng · h/mL, respectively, were associated with a rejection-free course. Our findings confirm the need for different CsA levels to prevent rejection according to induction therapy. Induction with either basiliximab or thymoglobulin allows reduced CsA levels during the first 3 months after renal transplantation.

Update on liver transplantation using cyclosporine

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.

P‐71 Successful therapy of sebaceous adenitis with topical cyclosporine in 20 dogs

Sebaceous adenitis was diagnosed in 20 dogs on the basis of histopathology and compatible clinical signs. Affected dogs included standard poodles (3), akitas (3), English springer spaniels (3), and chow chows (3). Fungal cultures, skin scrapings and thyroid function tests were unremarkable. Multiple biopsies were taken from all animals. Initial therapy included essential fatty acid supplementation with a total gamma linolenic acid dose of 10–20 mg/kg once daily and an antiseborrhoeic shampoo twice weekly. All animals were assessed at 3 weeks. An improvement in coat condition was noted at this time, but there was no evidence of hair regrowth. Treatment was started with topical cyclosporine. Twenty‐five millilitres of cyclosporine (Neoral oral solution, 100 mg/mL) made up to a total volume of 250 mL of liquid with sterile water was applied to the coat once daily followed by an emollient spray. At a 6‐week recheck, further improvement was noted. In some cases, new hair regrowth was apparent. In six dogs, blood samples were taken at 9 weeks to measure blood levels of cyclosporine. In no case could cyclosporine be detected. Therapy was successful in every case, but was deemed too labour intensive by the owners of some dogs. Despite good initial improvement in their dog's skin condition, they were lost to follow‐up. In all other cases, once hair had regrown after 8–12 weeks, the frequency of application could be reduced to once or twice weekly. Funding: Self‐funded.

ROSIGLITAZONE IS EFFECTIVE AND SAFE IN THE TREATMENT OF POSTTRANSPLANT DIABETES MELLITUS AFTER RENAL TRANSPLANTATION

P302 Aims: It was the purpose of this study to assess the safety and efficacy of rosiglitazone in patients with posttransplantat diabetes mellitus after renal transplantation.. Methods: Patients receiving rosiglitazone for the treatment of posttransplant diabetes mellitus (PTDM) were retrospectively collected from our transplantat database. The diagnostic criteria for diabetes mellitus as recommended by the “expert committee on the diagnosis and classification of diabetes mellitus” were used. 22 patients (11 male, 11 female, age: 55 ± 13 years, median time of diagnosis after transplantation 3 months) were included into the study. 15 patients were treated with tacrolimus (mean trough level 10 ± 5 ng/ml), 7 patients received cyclosporine A (mean trough level 153 ± 54 ng/ml n = 5, C2-level 1350 ± 350 ng/ml n = 2). All patients received prednison (10 ± 5 mg/day). In addition, mycophenolate mofetil and sirolimus was administered to 7 and 3 patients, respectively. Results: Fasting blood glucose decreased from 188 ± 62 mg/dl to 145 ± 46 mg/dl after treatment with rosiglitazone has been started. 4/22 patients had to be treated with insuline as rosiglitazone was not effective in controlling hyperglycemia and 2/22 patients received additional therapy with a second oral agent. One patient had to stop the rosiglitazone medication because of edema and weight gain after 5 days. There were no increases in serum creatinine levels (1.6 ± 0.4 mg/dl vs. 1.6 ± 0.3 mg/dl). Cyclosporine and tacrolimus blood levels were stable, changes of dosage attributable to the rosiglitazone medication were not necessary. Conclusions: Treatment with rosiglitazone seems to be safe and effective in patients with PTDM after renal transplantation.

Cyclosporin Nanoparticulate Lipospheres for Oral Administration

Cyclosporin is a first line immunosuppressive drug used to prevent transplant rejection and to treat autoimmune diseases. It is a hydrophobic cyclic peptide built from nonmammalian amino acids with low oral bioavailability. The aim of this study was to develop an oral delivery system for cyclosporin A (CyA) and investigate the effect of composition and particle size of the CyA lipid nanoparticles (lipospheres) on the oral bioavailability of this drug. Dispersible concentrated oil formulations that upon mixing in water spontaneously form a nanodispersion were developed. The concentrated oil formulations were clear solutions composed of the drug, a solid triglyceride, a water miscible organic solvent, and a mixture of surfactants and emulsifiers. The activity of the formulated cyclosporin was determined in vitro following the effect on the proliferation of T cells. The oral bioavailability was determined on humans following the cyclosporin blood levels after oral intake of formulated cyclosporin. Cyclosporin dispersion systems resulting in particle size of 25 to 400nm were prepared from acceptable pharmceutical components. The composition of the surfactants and emulsifiers, the lipid core component, and the amount and type of the water miscible organic solvent N-methylpyrrolidone (NMP) and alcohols had a strong effect on the particle size of the dispersions. All formulations were reproducible and stable at room temperature for at least 6 months, with full activity of cyclosporin retained. Human oral bioavaiability study indicated a correlation between the AUC and Cmax and the particle size of the dispersion. A Cmax of ∼1300 ng/mL was found after 2h of oral intake of four capsules, each loaded with 50mg cyclosporin. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1264–1270, 2004

Rosiglitazone treatment of diabetes mellitus after solid organ transplantation.

Diabetes mellitus is a common clinical problem after solid organ transplantation. Whether patients have preexisting diabetes or develop posttransplant diabetes, insulin therapy is usually required. Achieving excellent diabetic control is an important target in reducing the incidence of cardiovascular disease after transplantation. The authors treated 18 patients with type 2 diabetes after transplantation with rosiglitazone. Eleven patients had preexisting type 2 diabetes and seven patients developed posttransplant diabetes. Rosiglitazone was added to insulin or glyburide to improve elevated hemoglobin Hb A1C levels in patients with preexisting diabetes or was used to try to avoid insulin therapy in posttransplant diabetics. Blood levels of cyclosporine, tacrolimus, creatinine, and HbA1C were followed for a mean of 381 days (range, 133-718 days). The addition of rosiglitazone did not cause any significant changes in serum creatinine, cyclosporine, or tacrolimus. There were no significant changes in cyclosporine or tacrolimus doses. Mean HbA1C improved from 8.1+/-1.5% to 6.9+/-1.3% (P =0.01) in the 18 patients and from 8.6+/-1.5% to 6.7+/-0.5% (P =0.035) in the 7 patients with posttransplant diabetes. All patients with posttransplant diabetes were well controlled without insulin therapy. Rosiglitazone is a safe and effective oral agent for the treatment of diabetes mellitus after solid organ transplantation. It is the first agent to allow successful oral therapy for patients with posttransplant diabetes, and is a well-tolerated alternative to insulin for these patients.

Conversion from tacrolimus to cyclosporine microemulsion therapy in liver transplant recipients

The calcineurin inhibitors cyclosporine and tacrolimus have distinct advantages and drawbacks. Therefore it is important to tailor their use to the patient's tolerance. In some patients, the need to ameliorate the adverse effects of tacrolimus may necessitate a switch to cyclosporine-based therapy. Rescue therapy with a cyclosporine microemulsion (Neoral)-based regimen for transplant patients intolerant of tacrolimus has been evaluated to assess the best method of switching and determine the initial and maintenance doses of Neoral in children and adults. Our aims were to evaluate not only these facets, but also the pharmacokinetics of Neoral in stable patients, including target 2-hour postdose blood concentrations (C 2) of cyclosporine in liver transplant recipients. Eighteen liver transplant patients switched from tacrolimus to Neoral underwent a program of cyclosporine blood level monitoring. The conversions were conducted safely; the incidence of acute rejection episodes was low (11.1%). Statistical analysis showed that the C 2 correlated with the area under the time-blood concentration curve of cyclosporine for 0 to 4 hours after dosing (R = 0.970). We determined the maintenance doses of Neoral for pediatric and adult patients as well as the feasibility of C 2 quantitated monitoring in liver transplantation.

In renal transplantation blood cyclosporine levels soon after surgery act as a major determinant of rejection: Insights from the MY.S.S. Trial

Target organs express antigens recognized directly by antigen-specific T cells, and their recognition is crucial to precipitate rejection. Then, the earliest T-cell activation is inhibited by cyclosporine A (CsA), the lowest would be the risk of rejection. Here, we aimed to assess this possibility in a large cohort of de novo kidney transplant recipients participating in an ongoing clinical trial, the Mycophenolate Steroid-Sparing (MY.S.S.) Trial. Three-hundred-thirty-four patients entered the prospective, multicenter MY.S.S. trial. The main aim of the study was to assess the predictive value of serial evaluation of blood CsA trough concentration (C0) and 2-hour postdose drug (C2) levels alone or in combination, and to identify which is the critical posttransplant measurement to target CsA therapy in order to minimize the risk of acute rejection. A very large number of CsA trough (N= 2236) and C2 (N= 2128) measurements during the first 6 months postsurgery were available for analysis. Patients with delayed graft function were excluded. CsA trough levels measured at day 2 posttransplant were the strongest predictor of acute graft rejection over 6-month follow-up. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while for levels lower than 300 ng/mL, the risk of acute rejection was more than doubled. Higher levels failed to provide any further protection from graft rejection. CsA trough values predicted allograft rejection with an accuracy of 74%, while C2 levels considered alone had no predictive values at all. Findings that among serial daily measurements posttransplant those taken as early as at day 2 have by far the highest capacity to predict rejection episodes, underline the need of targeting CsA therapy very early posttransplant with the goal to modulate early enough T-cell activation at the interface between the recipient's blood and the graft where alloimmune response actually initiates.

Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis

Background & Aims : Cyclosporine A is highly effective in severe attacks of ulcerative colitis (UC) but is associated with important adverse effects that are mainly dose dependent. Our single center, randomized, double-blind, controlled trial aimed to evaluate the additional clinical benefit of 4 mg/kg over 2 mg/kg IV cyclosporine in the acute treatment of severe UC. Methods : Primary end point was the proportion of patients with a clinical response. Secondary end points included time to response, colectomy rate, and adverse effects. Results : Seventy-three patients were included. Day-8 response rates were 84.2% (32 of 38, 4 mg/kg) and 85.7% (32 of 35, 2 mg/kg) after a median of 4 days in both groups. Short-term colectomy rates were 13.1% (4 mg/kg) and 8.6% (2 mg/kg). Mean cyclosporine blood levels were 237 ± 33 in the 2-mg/kg group and 332 ± 43 ng/mL in the 4-mg/kg group. Active smoking was inversely correlated with clinical response (odds ratio, 0.06), but concomitant azathioprine or steroids were not predictive. A trend toward a higher incidence of hypertension was observed in the 4-mg/kg group (23.7% vs. 8.6%, 2 mg/kg, P < 0.08). Conclusions : High-dose IV cyclosporine has no additional clinical benefit over low dose in the treatment of severe UC. Although we did not observe differences in adverse effects on the short term, the use of 2 mg/kg IV cyclosporine should provide an improved toxicity profile for medical treatment of severe UC.

Blood cyclosporine C 0 and C 2 concentrations and cytomegalovirus infections following lung transplantation

The aim of this study was to determine whether cyclosporine levels predose (C 0) and at two hours postdose (C 2) were higher among patients presenting with cytomegalovirus (CMV) infection or disease. Between days 40 and 365 posttransplantation serial C 0 and C 2 levels were measured in 15 lung transplant recipients. Nine developed 13 episodes of CMV infection or disease. Both C 0 and C 2 levels were higher during CMV infection or disease episodes. Eleven of the 13 CMV episodes (84%) displayed C 0 >220 ng/mL and none had C 0 <200 ng/mL. For C 2, 11 of 13 CMV episodes (84%) showed C 2 >1200 ng/mL and none had C 2 <1000 ng/mL. Among determinations that did not coincide with a CMV episode, 7 of 21 (33%) showed C 0 >220 and 9 of 21 (42%) showed C 2 >1200, respectively ( P < .05). In conclusion, cyclosporine blood levels are higher among patients presenting with CMV infection or disease.

Cyclosporine blood level monitoring: Cross-reactivity of anti-Cyclosporine A monoclonal with its sulphate metabolite: an in vitro study

Cyclosporine is metabolized in the liver by the Cytochrom P450 system. Many of the metabolites have been identified and thoroughly studied. However the sulphate metabolite is the least known. The metabolite is hydrophilic and thus it is not easily detectable by HPLC and it is not available in pure form for analysis. We have isolated the metabolite from transplant patients receiving CYA as part of their immunosuppressive therapy. The amino acid sequence was determined and the molecule was synthesised in our laboratories. We have tested the molecule in vitro using cell culture to determine its activity. 1/2 ml of blood+1/2 ml of RPMI was incubated with the following concentration of either CSA or CSS: 0, 25, 50, 100, 250, 500, 750, 1000, 1250, 1500, 2000 ng/ml. for 2 and 1/2 h at 37 °C with 5% CO 2. The blood was then stimulated with Ionomycine and PMA (phorpol 12 myristate 13-acetate) for additional 2 h. Supernatant was collected and assayed for the concentration of the following cytokines: IL-1a, IL-2, Interferon (IFNa), IL-6, IL-12, TNFa. The cells were used to evaluate the expression of cell activation marker CD69. Blood was assayed for CYA concentration using Abbott TDx assay. Results the level of the metabolite was actually higher than the parent compound indicating that the monoclonal antibodies detected the S form preferentially. The results with other CYA monoclonal was also similar. These results suggest that blood level monitoring of CYA many not be accurate as all the monoclonal antibodies currently used cross react with the metabolites.

Comparison of peak and trough level monitoring of cyclosporine treatment using two modern cyclosporine preparations

AimsDetermination of the peak cyclosporine blood level instead of the trough level promises to represent an improvement in cyclosporine therapy monitoring due to better correlation with the AUC. In kidney transplant recipients we investigated whether this conclusion applies also to a new dispersion formulation of cyclosporine (Cicloral). Patients42 stable kidney transplant recipients were converted from Sandimmun Neoral (NEO) to Cicloral (CIC) in a 1:1 dose relation. MethodsOn the last day of NEO administration and 14 days after conversion to CIC a full 12 h cyclosporine AUC was performed using blood samples obtained prior to and at serial times after dosing. The correlations between cyclosporine levels at these time points and the AUC were determined for NEO and CIC. For each measurement, a predicted AUC was calculated by regression analysis. The prediction error for each sampling time was calculated separately for NEO and CIC. ResultsThe cyclosporine trough levels showed the poorest correlation with AUC for both preparations (NEO: r = 0.187 vs CIC: r = 0.554). The best correlation was observed for samples obtained at three hours after intake of either CIC (r = 0.807) or NEO (r = 0.611). The number of 2 hours measurements that lead to an unacceptable estimate from the real AUC was somewhat lower for CIC (8/40 vs 11/41 with NEO). ConclusionsTwo- or three-hour cyclosporine level monitoring with the newer cyclosporine preparation Cicloral has at least the same precision as that of the original Neoral®. In this study, the newer preparation even showed a tendency towards superior monitoring properties.

Effect of folate administration on heart allograft atherosclerosis one year after transplant: a prospective randomized study

or detection of a new coronary lesion after a mean observation period of 2.8 1.0 years. A multivariate analysis (backward logistic regression) was performed including potential risk factors for CAVD (see below). Patients on dialysis were excluded. Results: Initially plasma homocysteine levels were elevated in the entire cohort (mean 19.3 8.3 mol/L) and ranged from 6.6 to 56.4 mol/L. A total number of 106 patients (57,9%) presented with CAVD at first angiography and progression was detected in 51 transplant recipients (28%). Patients with progressive CAVD presented with significantly higher plasma homocysteine levels (21.7 6.3 mol/L) at baseline investigation as compared to those with a stable course (17.4 7.7 mol/L) (p 0.001). These results were independent of parameters like gender, age, time after transplantation, dyslipoproteinemia, cyclosporine blood levels, initial indication for transplantation and severity of CAVD at baseline examination. Conclusions: Progress of cardiac allograft vasculopathy is strongly associated with elevated plasma homocysteine levels. The intervals of routine surveillance angiography should be shortened in patients with hyperhomocysteinemia and medical treatment to lower elevated homocysteine is recommended in these patients.

Increased cyclosporine blood levels after nisoldipine administration in a renal transplant recipient

Transplant InternationalVolume 15, Issue 11 p. 586-588 Free Access Increased cyclosporine blood levels after nisoldipine administration in a renal transplant recipient Costas Fourtounas, Corresponding Author Costas Fourtounas Department of Nephrology, Aretaieon University Hospital, Vas Sofias 76, 11528 Athens, GreeceE-mail: cfourt@usa.net Tel.: +30-1-7226225Search for more papers by this authorIoannis Kopelias, Ioannis Kopelias Department of Nephrology, Aretaieon University Hospital, Vas Sofias 76, 11528 Athens, GreeceSearch for more papers by this authorDespina Kiriaki, Despina Kiriaki Department of Nuclear Medicine, Laikon General Hospital, Athens, GreeceSearch for more papers by this authorBasil Agroyannis, Basil Agroyannis Department of Nephrology, Aretaieon University Hospital, Vas Sofias 76, 11528 Athens, GreeceSearch for more papers by this author Costas Fourtounas, Corresponding Author Costas Fourtounas Department of Nephrology, Aretaieon University Hospital, Vas Sofias 76, 11528 Athens, GreeceE-mail: cfourt@usa.net Tel.: +30-1-7226225Search for more papers by this authorIoannis Kopelias, Ioannis Kopelias Department of Nephrology, Aretaieon University Hospital, Vas Sofias 76, 11528 Athens, GreeceSearch for more papers by this authorDespina Kiriaki, Despina Kiriaki Department of Nuclear Medicine, Laikon General Hospital, Athens, GreeceSearch for more papers by this authorBasil Agroyannis, Basil Agroyannis Department of Nephrology, Aretaieon University Hospital, Vas Sofias 76, 11528 Athens, GreeceSearch for more papers by this author First published: 11 March 2005 https://doi.org/10.1111/j.1432-2277.2002.tb00113.xCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume15, Issue11November 2002Pages 586-588 ReferencesRelatedInformation

Minimal effect of ketoconazole on cyclosporine (SangCyA) oral absorption and first-pass metabolism in rats: evidence of a significant vehicle effect on SangCyA absorption.

The current work evaluated the effect of the CYP3A inhibitor ketoconazole on the oral absorption and first-pass metabolism of cyclosporine administered as the SangCyA formulation. Groups of 6 male Sprague-Dawley rats were administered SangCyA (5 and 15 mg/kg) by oral gavage alone and with ketoconazole (30 mg/kg). Blood cyclosporine levels were measured over 6 h, encompassing the cyclosporine absorption window. A significant vehicle effect on SangCyA absorption was observed. Comparing a 15 mg/kg dose, cyclosporine C(max) (mean+/-SD 1.12+/-0.16 microg/ml) and AUC(0-6) (5.34+/-0.71 microg h/ml) were 50% lower when propylene glycol was used as gavage vehicle instead of saline (2.19+/-0.94 microg/ml and 9.52+/-2.52 microg h/ml, respectively). Coefficients-of-variation for these parameters were halved in the propylene glycol vehicle however T(max) was unaffected. Ketoconazole increased cyclosporine C(max) and AUC(0-6) by 50-60%, regardless of the vehicle or the cyclosporine dose, without altering T(max) (2-3 h). The small effect of ketoconazole suggests that CYP3A-mediated intestinal and first-pass hepatic metabolism are minor determinants of cyclosporine oral bioavailability in rats.