Stable Heart Transplant Patients Research Articles

(505) - Does dd-cf DNA Correlates with CAV in Stable Heart Transplant Patients?

(505) - Does dd-cf DNA Correlates with CAV in Stable Heart Transplant Patients?

Global longitudinal strain in heart transplantation recipients using different vendors: reliability and validity in a tertiary hospital in Colombia.

Global Longitudinal Strain (GLS) is a useful tool to follow-up heart transplant (HT) recipients. Important inter-vendor variability of GLS measurements has been reported in healthy subjects and different conditions, but there is still limited evidence among HT patients. We assessed the reliability and validity of GLS using two vendors (General Electric and Philips) in a group of consecutive and stable adult HT recipients. Patients underwent two concurrent GLS analyses during their echocardiographic follow-up. We evaluated GLS inter-vendor reliability using Bland-Altman's limits of agreement (LOA) plots, computing its coverage probability (CP) and the intraclass correlation coefficient (ICC). Validity was assessed though receiver operating characteristics (ROC) curves, predictive values, sensitivity and specificity of GLS for each vendor to detect a normal left ventricle function. 78 pairs of GLS studies in 53 stable HT patients were analyzed. We observed a modest inter-vendor reliability with a broad LOA (less than 50% of values falling out our CP of 2% and an ICC of 0.49). ROC analyses (areas under the curve of 0.824 Vs. 0.631, p < 0.05) and diagnosis test indices (Sensitivity of 0.73 Vs. 0.64; and Specificity of 0.79 Vs. 0.50) favored GE over Philips. Inter-vendor variability for GLS analysis exceeded clinically acceptable limits in HT recipients. GLS from GE software seemed to show higher validity as compared to Philips'. The present study provides evidence to consider caution for the interpretation of GLS for clinical management in the follow-up of HT patients, especially when GLS is measured by different vendors.

Corticosteroid Weaning in Stable Heart Transplant Patients: Guidance by Serum Cortisol Level.

Background Despite earlier studies describing the feasibility of steroid weaning in heart transplant patients, the majority of patients are maintained on steroid therapy for life. We examined a strategy based on a single morning serum cortisol measurement. Methods We assigned stable posttransplant patients, who were maintained on tacrolimus, mycophenolate mofetil, and corticosteroids, into one of two groups based on a screening morning cortisol level. Patients with a cortisol < 8 micrograms/deciliter were assigned to a “maintenance” group and the others were assigned to the weaning group and steroids were tapered off over 4–6 weeks. Patients were monitored on subsequent office visits for adrenal insufficiency and allograft rejection. Results Thirty-one patients were enrolled (6 patients in the maintenance group and 25 in the steroid-weaning group). Mean follow-up was 10.2 ± 4 years for the weaning group and 9.0 ± 4.9 years in the maintenance group (p = 0.6). No cases of rejection were noted, nor did any patient resume steroid treatment following discontinuation. Conclusion Steroids can be safely discontinued in stable heart transplant patients with an AM serum cortisol ≥ 8 micrograms/deciliter with appropriate outpatient follow-up. In this study, no patient suffered late rejection or clinically noted adrenal insufficiency.

Stable heart transplant patients benefit from high-intensity interval training

Stable heart transplant patients benefit from high-intensity interval training

Pharmacokinetics in stable heart transplant recipients after conversion from twice-daily to once-daily tacrolimus formulations

A prolonged-release formulation of tacrolimus for once-daily administration (tacrolimus QD) has been developed. This phase II, open-label, multicenter, prospective single-arm study compared the pharmacokinetics (PK) of tacrolimus in stable heart transplant patients before and after conversion from twice-daily tacrolimus (tacrolimus BID) to tacrolimus QD. Heart transplant recipients (≥6 months after transplant), previously maintained on tacrolimus BID-based therapy, received tacrolimus BID from Days 1 to 7 and were converted on a 1:1 (mg/mg) basis to tacrolimus QD. Five 24-hour PK profiles were collected (Days 1, 7, 8, 14, 21). Safety parameters were also evaluated. Of 85 patients, 45 (50.6%) completed all 5 evaluable PK profiles. Steady-state tacrolimus area under the curve, 0 to 24 hours (AUC(0-24)) and minimum concentration (C(min)) were comparable for both formulations, with treatment ratio means of 90.5% (90% confidence intervals [CI], 86.4%-94.6%) and 87.4% (95% CI, 82.9%-92.0%), respectively (acceptance interval, 80%-125%). There was good correlation between AUC(0-24) and C(min) for tacrolimus QD (r = 0.94) and BID (r = 0.91). The relationship between these 2 parameters was also similar. This study provides evidence for successful conversion from tacrolimus BID to QD on a 1:1 (mg/mg) total daily dose basis. Approximately one-third of patients may require dose adjustments. Both formulations were well tolerated, with stable renal function during the study. Adverse events were reported by approximately one-tenth of patients receiving tacrolimus BID and a quarter of those who received QD.

Reduced systemic arterial compliance in stable heart transplant patients

Reduced systemic arterial compliance in stable heart transplant patients

431: A Prospective Trial of Steroid Discontinuation in Stable Heart Transplant Patients as Guided by Serum Cortisol Measurement

Heart transplant patients (pts) are typically treated with steroids. Chronic steroid use is associated with a myriad of problems. However, clinicians are often concerned about withdrawing steroids from stable patients. Previous reports of steroid weaning have been retrospective and predictors of success have not been described. A prospective trial of steroid weaning guided by the AM Serum Cortisol (SC) measurement was conducted.

Epstein-Barr virus load in whole blood is associated with immunosuppression, but not with post-transplant lymphoproliferative disease in stable adult heart transplant patients

Development of Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is a serious complication following heart transplantation (HTX). This study investigates EBV DNA load in adult heart transplant recipients, its association with immunosuppression, and its potential as a marker for development of PTLD. EBV DNA load was measured prospectively by quantitative real-time polymerase chain reaction (PCR) in 172 stable HTX patients. Sixty-seven patients (39.0% of total) had a positive EBV PCR at initial examination [median 4.9 (range 1.1-16.9) years post-HTX]. In follow-up testing of 67 positive patients 6 months later, 36 patients continued to have a positive EBV PCR. Overall incidence of EBV DNA was significantly associated with calcineurin inihibitors, azathioprine medication, and with the absence of mycophenolate mofetil (MMF) treatment. In patients with positive EBV DNA levels at initial examination and negative levels at retesting, cyclosporine A levels were found to be significantly higher at initial examination (148.4 +/- 70.2 vs. 119.6 +/- 53.5 ng/ml, P < 0.05). Three patients (1.7%, 3/172) were diagnosed with PTLD during the course of the study (mean follow up 4.0 years). EBV DNA viral load determination does not appear to be useful for risk prediction or early diagnosis of PTLD in adults after HTX, but an association of EBV DNA load with qualitative and quantitative immunosuppression is demonstrated.

Lymphocyte activation and correlation with IMPDH activity under therapy with mycophenolate mofetil

Background In an attempt to monitor the pharmacodynamics of mycophenolate mofetil (MMF) we investigated the association of inosine monophosphate dehydrogenase (IMPDH) activity in peripheral blood mononuclear cells with the expression of lymphocyte activation markers in stable cardiac transplant recipients treated with MMF. Methods Twenty-four study patients were switched from azathioprine to MMF 7.2 ± 4.1 years after heart transplantation. Results While the MPA trough level remained unchanged, the mean activity of IMPDH declined from 890 to 462 pmol/10 6PBMC/h three months after onset of MMF therapy, was almost completely inhibited at six months and partially restored to 160 pmol/10 6PBMC/h 12 months after switch to MMF ( p < .0001). We detected also significant changes in a number of activated lymphocyte subsets: CD4 +/25 +, CD8 +/38 +, CD19 +/69 +, CD3 +/16 +/56 +, natural killer (NK) cells, and monocytes. Moreover, the IMPDH activity profile correlated positively with the number of CD8 +/38 + T cells (correlation coefficient (CC) + 0.53), and inversely with NK cells (CC − 0.52) and CD19 +/69 + cells (CC − 0.61). Conclusions We revealed a close association of IMPDH baseline activity in mononuclear cells with the expression of lymphocyte activation markers in stable heart transplant patients after introduction of MMF therapy. This supports the assumption of a rather immunomodulatory than immunosuppressive effect of MMF.

420: Modulation of Acute and Chronic Allograft Rejection Via Oral Application of Alloantigen Coding DNA

Purpose: Post transplant hyperlipidaemia is associated with the development of coronary graft vasculopathy (CGV). Statins are frequently used in this context, with evidence showing that they reduce the burden of CGV. In addition to lipid lowering properties, statins also have pleiotropic properties including anti inflammatory effects and beneficial immunomodulatory effects on cytotoxic T cells. However, their effect on T regulatory cells (Tregs) which induce transplant tolerance, has yet to be elucidated. Methods and Materials: 96 stable heart transplant patients undergoing routine venesection were prospectively studied. Pravastatin use in each patient was determined by clinical necessity as judged by the caring physician. Flow cytometry and software generated gating strategies were used to identify subdivisions of circulating lymphocytes. Results: 45 patients received Pravastatin, with the remaining 51 patients used as controls. There were no differences in clinical or demographic characteristics between the two groups. For patients taking Pravastatin, the numbers of Tregs were significantly reduced in comparison to controls. These included CD25 cells (P 0.004), CD4 CD25 cells (P 0.002) and CTLA-4CD25 cells (P 0.002). The number of circulating CD4 cells without regulatory markers did not differ between groups. As the dose of Pravastatin increased, the number of Treg cells decreased (CD25; P 0.046, CD4 CD25; P 0.04, CTLA-4 CD25; P 0.04). Conclusions: Pravastatin was associated with lower numbers of circulating Treg cells in patients following heart transplantation. This might alter recipient immune responses to graft tissue, as Treg cells suppress allospecific CD4 T cell responses.

26: Three year outcome of a randomized trial comparing C 0 against C 2 monitoring in stable heart transplant patients

Purpose: We have previously shown that Cyclosporine A monitoring using C2 allows a significant dose reduction at 6 months without compromising patient outcome. We now report the 3 year outcome in stable heart transplant patients randomized to either C0 or C2 monitoring.

Peripheral Blood Leukocyte Counts in Cytomegalovirus Infected Heart Transplant Patients: Impact of Acute Disease Versus Subclinical Infection

Cytomegalovirus (CMV)-associated leucopenia in heart transplant patients is poorly characterized. We conducted a retrospective analysis of timing, degree, and type of leukopenia in four groups of patients: cases (n=20); controls (n=20); subclinical early infection (n=21), and subclinical late infection (n=22). In the cases, white blood cells (WBC) count at diagnosis was compared to prediagnosis; and cases were compared to controls. Subclinical cases (early and late) were identified by measurement of CMV DNA in peripheral blood mononucleocytes, and WBC was compared to those of the cases and controls. First, in human heart transplant recipients the total leukocyte count decreased prior to the time of diagnosis of CMV disease: cases: 5.4+/-2.1 x 10/microL vs. 3.7+/-2.1x10/muL (P<0.01); subclinical early: 8.1+/-4.1 x 10/microL vs. 6.9+/-1.6 x 10/microL (P<0.01). Second, the leukocyte populations most reduced during CMV disease are the neutrophils: 4.4 x 10/microL (78%) to 2.5 x 10/microL (69%) (P<0.05), and monocytes 0.6 x 10/microL (11%) to 0.3 x 10/microL (7.5%) (P<0.05). Third, the reduction in leukocyte count that occurs during CMV disease appears to be independent of immunosuppressive therapy (using cyclosporine A, mycophenolate mofetil, or azathioprine and prednisone). Finally, subclinical CMV infection in stable long-term heart transplant patients without disease is unassociated with a reduction in the leukocyte count. Aside from implications for early diagnosis, CMV-associated decrease in monocytes is important because viral infections like Epstein-Barr virus cause monocytosis. The absence of leucopenia in subclinical late infections is a new important finding.

A comparison of measured trough levels and abbreviated AUC estimation by limited sampling strategies for monitoring mycophenolic acid exposure in stable heart transplant patients receiving cyclosporin A—Containing and cyclosporin A—Free immunosuppressive regimens

Mycophenolate mofetil (NIMF) pharmacokinetics vary widely, and enterohepatic recirculation of the drug and its metabolites may be altered by concurrently administered immunosuppressants, including the widely used agent cyclosporin A (CsA). A reliable method of achieving effective and well-tolerated levels of NIMF-based immunosuppression would be of eminent interest. This study compared the use of measured mycophenolic acid (MPA) trough levels (C0) and abbreviated AUC estimation by limited-sampling strategies for monitoring MPA exposure in stable heart transplant recipients (>1 year after transplantation) receiving a CsA-containing or CsA-free immunosuppressive regimen. The treatment groups were receiving chronic maintenance immunosuppressive regimens consisting of either CsA/MMF or rapamycin (RAPA)/MMF. An additional subgroup of patients was switched from the CsA-containing regimen to the RAPA-containing regimen. Fasting venous blood samples were obtained before dosing and at 40, 75, 120, and 240 minutes after administration of the morning dose of MME The validated Emit assay was used to measure MPA plasma concentrations. Dose adjustment of AUCs was performed by dividing the AUC by the morning NIMF dose in grams. Cmax after administration of the morning dose was determined from available MPA data points using curve-fitting analysis. The increase to Cmax (Cmax-C0) was calculated, and dose adjustment was performed as before. Abbreviated 12-hour MPA AUCs were estimated using a limited-sampling strategy (before dosing and 30 and 120 minutes after dosing) based on high-performance liquid chromatography data. Adverse events were monitored during routine follow-up visits. The study included 47 patients receiving CsA/MMF, 15 receiving RAPA/MMF, and 9 who were switched from CsA/MMF to RAPA/MME The population included 55 men and 7 women, with a mean age of 58.94 years and a mean weight of 81.85 kg. The only significant differences in baseline clinical characteristics between groups were the mean number of years since heart transplantation (3.62 CsA/MMF vs 8.53 RAPA/MMF; P<0.01) and the proportions of patients still receiving corticosteroids (44.7% vs 13.3%, respectively; P<0.01). Reported adverse events were generally mild, including leukopenia (8.1%), diarrhea (6.5%), and abdominal pain (4.8%), and did not require drug discontinuation. In patients receiving CsA/MMF, MPA AUCs ranged from 19.67 to 81.80 mg/h.L (mean [SD], 41.92 [14.14] mg/h.L). MPA Co levels were poorly correlated with total AUC (r2=0.36). MPA Co levels of 0.5 and 1.6 mg/L were correlated with AUCs of <30 and <40 mg/h.L, respectively. In patients receiving RAPA/MMF, MPA AUCs ranged from 34.40 to 87.60 mg/h.L (mean, 51.07 [15.80] mg/h.L). The correlation between Co and total AUC was better than in the CsA/MMF group (r2=0.61). MPA C0 levels of 1.0 and 2.3 mg/L were correlated with AUCs of 30 and 40 mg/h.L, respectively. Statistically significant differences between RAPA/MMF and CsA/MMF were noted in the mean MMF dosage (1.90 [0.71] vs 2.87 [0.78] g/d, respectively; P<0.001), the mean dose-adjusted MPA AUC (60.95 [27.42] vs 31.92 [16.12] mg/h.L.g MMF; P<0.001), and mean dose-adjusted MPA C0 levels (5.10 [3.41] vs 1.41 [0.95] mg/L.g; P<0.001). The dose-adjusted increase to Cmax after morning dosing was comparable between groups, and there was no difference in the frequency distribution of Cmax. In the group switched from the CsA-containing regimen to the RAPA-containing regimen, the changes in MMF dose, dose-adjusted AUC, and MPA C0 levels were similar to those in the CsA/MMF and RAPA/MMF groups. In this comparison of measured MPA C0 levels and 12-hour MPA AUCs estimated by a limited-sampling strategy in stable heart transplant patients receiving chronic maintenance immunosuppressive therapy with CsA/MMF or RAPA/MMF, abbreviated AUC estimation predicted drug exposure more accurately than did measured C0 levels. Thus, MPA AUCs obtained by limited sampling may be useful in guiding clinical management and dosing. However, further study is required, including validation of these findings in clinical outcome studies.

Monitoring of cyclosporine levels in transplant recipients using self‐administered fingerprick sampling

Use of C(2) monitoring for cyclosporine A (CsA) microemulsion results in improved clinical outcomes vs. trough (C(0)) monitoring. Logistical issues include accurate timing of the C(2) sample; requirement for sample dilution with most standard assay techniques; and inconvenience for patients. Recently, it has been shown that CsA concentrations in capillary blood correlate closely with levels in venepuncture samples, and that liquid chromatography tandem mass spectrometry (LC-MS/MS) can analyse CsA concentration using undiluted capillary blood from fingerprick samples. In a study to assess the feasibility of CsA monitoring, 52 stable heart transplant patients were provided with kits to take fingerprick trough and C(2) blood samples at home, returning them to the laboratory by post for LC-MS/MS analysis. In total, 225 samples were provided, of which 14 (6%) were unsuitable for analysis because of clotting (n = 10) or insufficient volume (n = 4). Discomfort was not a problem and initial difficulties that some patients reported in taking the samples resolved with experience. All samples were returned by the postal system in a timely manner. Use of fingerprick assays could allow transplant physicians to have access to C(2) levels when patients visit the clinic for review, and avoids the need for patients to attend the clinic or local healthcare centre solely for venepuncture. A barrier to more widespread introduction of fingerprick testing is likely to be lack of suitable MS facilities and trained personnel. In conclusion, self-administered fingerprick testing for CsA blood levels is practical to implement and highly convenient for patients and offers advantages for the transplant team.

A Randomized, Controlled Trial of C 0- Vs C 2-guided Therapeutic Drug Monitoring of Cyclosporine in Stable Heart Transplant Patients

Cyclosporine monitoring using 2-hour post-dose samples (C2) is thought to be more efficacious than using pre-dose levels (C0) in managing immunosuppression for transplant patients. We evaluated the effect of C2 monitoring on cyclosporine dose and clinical parameters in stable heart transplant patients. 125 stable heart transplant patients were randomized to C0 or C2 monitoring of cyclosporine levels for a period of six months. All patients had both C0 and C2 samples taken, and clinicians were blinded to one of the samples depending on randomization. The primary endpoint was the relative change in cyclosporine (Neoral) dose during the study period and secondary endpoints were change in creatine clearance, mortality, infection, and acute rejection. There was a significant decrease in the cyclosporine dose for the C2 group as compared with the C0 group (-11 mg/day and -26 mg/day respectively, p = 0.0025). No proven rejection episodes occurred in either group and there was no significant difference in the incidence of infection (C0 6, C2 10; p = 0.14), the change in renal function (change in creatine clearance C(0) +0.54 ml/min; C2 -0.16 ml/min; p = 0.61), the number of blood tests or dose adjustments between groups over the study period. Analysis of the blinded samples revealed that the reduction of cyclosporine dose in the C2 group could not be accounted for by reduced immunosuppression . C2 monitoring allows a significant cyclosporine dose reduction without compromising patient outcome in stable heart transplant patients. Further studies are required to ascertain whether this dose reduction can be translated into clinical benefit.

Improvement of Renal Dysfunction by Conversion From Calcineurin Inhibitors to Sirolimus After Heart Transplantation

Chronic renal dysfunction is a common occurrence after heart transplantation in patients treated with calcineurin inhibitors (CIs). We evaluated the renal-sparing effects of converting stable heart transplant patients with renal dysfunction from a CI to sirolimus. Beginning in 2000, heart transplant patients with renal dysfunction were converted from a CI to sirolimus. CI was abruptly discontinued and sirolimus added at 5 mg twice a day for 2 days and then 2 mg daily. The treatment goal was a 24-hour level of 6 to 12 ng/ml. All patients were also managed with mycophenolate mofetil (MMF) at 1,000 mg twice daily. Eighty from a total of 235 cardiac transplant patients were converted to sirolimus. The average time post-transplant for conversion was 4.78 years (range 3 days to 16 years). The average age at transplant was 55.43 years (range 15 to 70). At a mean of 304 days post-conversion, the mean serum creatinine (sCr) decreased from 2.04 +/- 0.57 mg/dl pre-conversion to 1.64 +/- 0.48 mg/dl (p < 0.001). In patients whose sCr was <2.5 mg/dl before conversion, the mean SCr level decreased from 1.81 +/- 0.39 to 1.62 +/- 0.5 mg/dl post-conversion (p = 0.01), with no patient developing end-stage renal disease (ESRD). Four patients with sCr > or =2.5 developed ESRD requiring dialysis despite conversion. In the remaining 15 patients with sCr > or =2.5 mg/dl, the sCr decreased from 2.85 +/- 0.29 to 1.73 +/- 0.43 mg/dl (p = 0.001). Conversion to sirolimus from CI is safe and has a renal-sparing effect in the management of heart transplant patients with chronic renal dysfunction. Based on these results, sirolimus has a role as a first-line immunosuppressive agent in heart transplant patients with renal dysfunction.

Randomised controlled trial of C 0 versus C 2 guided therapeutic drug monitoring of cyclosporin-A in stable heart-transplant patients

Objective: to determine if there is benefit in therapeutic drug monitoring (TDM) of Cyclosporin A (CyA) with serum CyA levels 2 hours (C2) rather than 12 hours (C0) after the administration of CyA in stable heart transplant patients.

Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients.

Intestinal cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) both play a vital role in the metabolism of oral cyclosporine (CsA). We investigated the genetic polymorphisms in CYP3A4(promoter region and exons 5, 7 and 9) and MDR1 (exons 12, 21 and 26) genes and the impact of these polymorphisms on the pharmacokinetics of oral CsA in stable heart transplant patients (n = 14). CYP3A4 polymorphisms were rare in the Asian population and transplant patients. Haplotype analysis revealed 12 haplotypes in the Chinese, eight in the Malays and 10 in the Indians. T-T-T was the most common haplotype in all ethnic groups. The frequency of the homozygous mutant genotype at all three loci (TT-TT-TT) was highest in the Indians (31%) compared to 19% and 15% in the Chinese and Malays, respectively. In heart transplant patients, CsA exposure (AUC(0-4 h), AUC(0-12 h) and C(max)) was high in patients with the T-T-T haplotypes compared to those with C-G-C haplotypes. These findings suggest that haplotypes rather than genotypes influence CsA disposition in transplant patients.

C2 Targets and multivariate predictors of C2 levels in stable heart transplant patients immunosuppressed on a C0-based regimen

Neoral dose monitoring in heart transplantation (HT) is based on trough levels (C0), since cyclosporine A (CsA) 2-hr peak (C2) targets have not been established. To identify C2 targets and clinical correlates of C0 and C2, we studied 314 stable HT pts (251 male, aged 50±14 yrs at HT, follow-up 6.8±4 yrs, range 1 mo-15 yrs), on a C0-based regimen. Mean C0 and C2 levels (ng/mL) were 268±80 and 1031±386 respectively for pts (n=19) in the first 3 mo; 230±49 and 955±239 in pts (n=10) between 4 and 12 mo; 157±53 and 745±235 in pts (n=285) after 1 yr. Our target C0 levels (ng/mL) are 150-400 (first 3 mo), 150-300 (4-12 mo), 100-250 (>12mo). For pts within the target C0 the corresponding C2 (ng/mL) were 600-1500 (first 3 mo), 600-1300 (4 to 12 mo), 500-1000 (>12mo). C2 correlated with C0 (Pearson, r=0.61, p=0.0001). C2 correlated better with CsA dose than C0 (r=0.50, p=0.0001 vs r=0.36, p=0.0001). Between pts CsA dose varied by a factor of 9.3; the C/dose ratio varied by a factor of 8.5 for C2 and of 15.6 for C0. Pts with higher C2 (>550) had higher rejection scores at 1 yr (p=0.04) and during whole follow-up (p=0.04) than pts with lower C2 (t-test). This did not apply to higher (>110) C0 vs. lower C0. Both C2 and C0 correlated with blood urea (r=-0.19, p=0.001; r=-0.18, p=0.002) and creatinine (r=-0.16, p=0.004; r=-0.20, p=0.0001 respectively). By logistic regression higher C2 (>550 ng/mL) was associated with higher CsA and steroid load (mg/Kg) at 1 yr (p=0.038; p=0.001 respectively), lower blood urea (p=0.003) and tended to be associated with high total severe rejection score (p=0.07). Regression analysis on higher C0 (>110 ng/mL) did not show associations. Thus, C2 showed better correlation with CsA dose, renal function, rejection profile and less variability between pts than C0. C2 may improve CsA-based immunosuppression in HT.

C2 monitoring of cyclosporine in stable heart transplant patients after two daily and three daily doses

C2 monitoring of cyclosporine in stable heart transplant patients after two daily and three daily doses