Blood CsA Concentrations Research Articles

Impact of Cyclosporine a (CsA) Concentration on the Incidence of Severe Acute Graft-Versus-Host Disease (GVHD) after Allogeneic Stem Cell Transplantation (allo-SCT).

CsA is widely used as the backbone immunosuppressive agent for GVHD prevention after allo-SCT. Previous studies have demonstrated that the immunosuppressive effects of CsA (eg. inhibition of calcineurine in lymphocytes) may be correlated with CsA blood concentration, especially in the context of solid organ transplantation. This report aimed to investigate the impact of CsA concentrations in the early post allo- SCT period, on the incidence of severe acute GVHD, in 85 consecutive patients treated in a single centre between Jan. 2006 and Jan. 2008, and for whom CsA concentrations in the blood were monitored weekly after the start of infusion. 85 patients (45 males) received CsA (usually at 3 mg/Kg/d, 2 or 3 days prior to graft infusion) as a 24-h continuous infusion until hematopoietic recovery and switch to oral formulation. Dose modifications of CsA were performed to maintain adequate trough blood levels and to prevent nephrotoxicity. Patients' and donors characteristics were as follow: median age: 51 (range, 18–67), 46 (54%) female donors, 33 (39%) myeloid malignancies, 49 (58%) lymphoid malignancies, and 3 cases of SAA. The stem cell source was PBSC in 66 (78%) patients, while bone marrow was used in 19 (22%) patients. 37 (43.5%) were transplanted from a matched related donor, and 48 (56.5%) from a matched unrelated donor. A myeloablative conditioning regimen was used in 24 (28%) patients, and 61 (72%) received a reduced intensity regimen. The median concentrations of CsA in the blood at 1, 2, 3 and 4 weeks after allo-SCT were 348 (range, 172–733), 284 (range, 137–535), 274 (range, 107–649), and 247 (37–695) ng/mL respectively. All patients engrafted at a median of 17 (range, 0–42) days after allo-SCT. With a median follow-up of 16 (range, 5–29) months, grade 2–4 acute GVHD occurred in 36 patients (42%) at a median of 29 (range, 6–100) days after allo-SCT. The incidence of severe grade 3–4 acute GVHD was 23% (95%CI, 14–32%). In this cohort, all acute GVHD risk factors (age, donor-recipient gender, CMV serostatus, ABO compatibility, diagnosis, disease status, stem cell source, donor type, conditioning regimen type, GVHD prophylaxis regimen, CsA concentrations) were assessed. In multivariate analysis, we found that higher whole-blood CsA concentration in the first week following graft infusion, and before onset of acute GVHD was the strongest parameter significantly associated with a reduced the risk of severe grade 3–4 acute GVHD (P=0.01; RR=0.24; 95%CI, 0.08–0.73). Despite its retrospective nature, these data strongly indicate a close relationship between CsA trough blood concentration during the early post allo-SCT period and the severity of acute GVHD. Inadequate or insufficient early exposures of CsA can be a serious risk for developing severe acute GVHD. Therefore, precise monitoring of CsA concentrations and achievement of a high CsA target concentration may be an effective tool to prevent the onset of severe acute GVHD.

Effect of genetic polymorphisms of CYP3A5 and MDR1 on cyclosporine concentration during the early stage after renal transplantation in Chinese patients co-treated with diltiazem

The aim of this study was to assess the influence of the cytochrome (CYP450)3A5 and multidrug resistance (MDR1) gene polymorphisms on cyclosporine A (CsA) trough concentration during the early stage after renal transplantation in Chinese patients co-treated with diltiazem. CYP3A5*3 (A6986G) and MDR1 C1236T, G2677T/A and C3435T polymorphisms were determined by PCR followed by restriction fragment length polymorphism (RFLP) analysis. A total of 112 Chinese renal transplant patients were enrolled in the study. The whole blood trough concentration was measured at 7 days after transplantation, and the dose-adjusted trough levels were compared among the different genotypes. The dose-adjusted trough levels of CsA were significantly higher in MDR1 2677TT carriers than in GG plus GT carriers (59.5 +/- 15.9 vs. 34.5 +/- 9.4 vs. 43.2 +/- 13.6 ng/mL per mg per kg; P < 0.0001). In patients who were co-treated with diltiazem, compared with carriers of haplotype T-T-C, the carriers of haplotype C-G-C and haplotype T-G-T had significantly lower dose-adjusted trough blood concentrations of CsA than the non-carrier group (P = 0.002, P = 0.000 and P = 0.000, respectively). However, no evidence was found that there was a relationship between the CYP3A5*3, MDR1 C1236T and MDR1 C3435T polymorphisms and CsA dose-adjusted trough concentrations. This study demonstrated that the G2677T/A single nucleotide polymorphisms in MDR1 and MDR1 haplotypes C-G-C, T-G-T and T-T-C are associated with the CsA concentration during the very early post-transplant period in Chinese renal transplant patients co-treated with diltiazem. These polymorphisms may be useful for determining the appropriate initial dose of CsA after renal transplantation.

ABCB1 G2677 Allele Is Associated with High Dose Requirement of Cyclosporin A to Prevent Renal Allograft Rejection in North India

Interindividual heterogeneity in expression of ABCB1 gene has been suspected to be one of the factors resulting in cyclosporin (CsA) pharmacokinetic variation. The present study explored the association of ABCB1 SNPs on CsA dose requirements and dose-adjusted C2 levels (CsA level/daily dose requirement) in renal allograft recipients. Daily doses (mg/kg/day) and dose-adjusted C2 levels (microg/mL per mg/kg/day) at 1 and 3 months for 155 recipients on CsA therapy were compared according to allelic status of ABCB1 c.1236C>T, c. 2064-76T>A, c.2677G>T and c.3435C>T. Dose-adjusted C2 levels were lower in ABCB1 c.2677G>T GG genotype as compared to GT/TT genotypes at 1 and 3 months, suggesting that for a given dose their CsA blood concentration is lower (p=0.009 and p=0.043). GG genotype was further associated with lower allograft survival as revealed by Kaplan-Meier analysis (p=0.021). Identification of ABCB12677GG patients may have a clinically significant impact on allograft outcome and may be helpful in providing pre-transplant pharmacogenetic information to individualize CsA dosing.

ABCB1 polymorphisms may have a minor effect on ciclosporin blood concentrations in myasthenia gravis patients

Ciclosporin (CsA), which is widely used in autoimmune disease and transplantation, has a narrow therapeutic index. It also shows considerable interindividual variability in its pharmacokinetics, which may be attributable to polymorphisms of the multidrug efflux pump P-glycoprotein, encoded by MDR-1. The aim was to determine the role of genetic polymorphisms in MDR-1 with respect to interindividual variability of CsA blood concentrations in myasthenia gravis (MG) patients. MG patients (n = 129) receiving CsA were genotyped for MDR-1 1236C-->T (exon 12), 2677G-->T (exon 21) and 3435C-->T (exon 26). Trough blood and peak blood concentrations were determined to see if there was correlation with the corresponding genotype. We observed a trend for CsA blood concentrations, especially peak blood concentrations, to be higher with the wild-type allele compared with minor alleles in genotype and haplotype. Furthermore, under the same CsA regimen, it was found that the trough concentrations of variant genotype (ABCB1 1236TT or ABCB1 2677TT) were significant greater than those of wild-type (ABCB1 1236CC or ABCB1 2677GG, respectively) (P = 0.0222 and 0.0081). The trough concentrations of wild-type haplotype pair group were significantly lower those that of the mutant type pair group (TT-TT-TT) (P = 0.007). ABCB1 polymorphisms in both genotype and haplotype may have a minor effect on the CsA blood concentrations.

Monitoring treatment with cyclosporine microemulsion in myasthenia gravis

To examine whether the monitoring of cyclosporine (CsA) blood concentrations is of benefit in CsA microemulsion pre-concentrate (MEPC) therapy for myasthenia gravis (MG). We measured CsA blood concentrations both 2 h after administration (C2) and immediately before administration (C0) and examined associations with changes to clinical parameters in 20 MG patients treated with CsA MEPC in an unblinded, 6-month prospective open trial. Initial dose of CsA MEPC (4.7 +/- 0.5 mg/kg/day) provided both high C2 levels and safe C0 levels. Disease severity, daily dose of prednisolone, acetylcholine receptor-antibody titre levels and levels of interleukin-2 production by peripheral blood mononuclear cells were significantly reduced following treatment with CsA MEPC. A significant correlation existed between C2 levels following the initial dose and clinical improvement in responder MG patients. C0 levels were significantly higher in patients who exhibited increased serum creatinine or hypertension compared with patients free from side effects. Body mass index of individual patients was significantly correlated with C0 level, and may thus offer a useful marker to predict C0 levels. CsA MEPC was effective at suppressing symptoms and T-cell-dependent pathogenesis of MG, and monitoring of C2 and C0 levels can be useful to estimate efficacy and safety of the drug.

Variation in Leukocyte Subset Concentrations Affects Calcineurin Activity Measurement: Implications for Pharmacodynamic Monitoring Strategies

In renal transplantation patients, therapeutic drug monitoring of the calcineurin (CN) inhibitor cyclosporin A (CsA) is mandatory because of the drug's narrow therapeutic index. Pharmacodynamic monitoring of CN inhibition therapy could provide a tool to define and maintain the therapeutic efficacy of CsA therapy. We investigated the effect of variation in cell counts of leukocyte subsets on leukocyte CN activity measurement in renal transplant recipients. We measured leukocyte CN activity, whole blood CsA concentrations, and leukocyte subset cell counts in 25 renal transplant recipients. Blood was collected before graft implantation and CsA therapy, 1 day before transplantation when CsA therapy was already started, and 5 days after transplantation. Monocyte, granulocyte, CD4+ T-cell, CD8+ T-cell, B-cell, and natural killer-cell CN activities and CsA inhibition sensitivities were determined in vitro by a spectrophotometric CN assay. Leukocyte CN activity was inhibited after drug intake. Inter- and intrapatient variation in leukocyte subset cell counts resulted in variation of sample composition. The mean (SD) CN activity varied among leukocyte cell subsets, ranging from 650 (230) to 166 (26) pmol/min/10(6) cells for monocytes and CD4+ T cells, respectively. CsA half maximal inhibitory concentration (IC(50)) values ranged from 15 to 78 microg/L for monocytes and B cells, respectively. Inter- and intraindividual leukocyte subset cell count variation can affect measured CN activity independent of CsA concentration. Cell-specific activity and drug sensitivity should be considered for sample validation to optimize method specificity when pharmacodynamic monitoring strategies are applied in a clinical setting.

Mechanism of decrease of oral bioavailability of cyclosporin A during immunotherapy upon coadministration of amphotericin B

The trough level of blood concentration of cyclosporin A (CyA) in a patient receiving immunotherapy was observed to decrease following coadministration of amphotericin B (AMB). This clinical observation was confirmed experimentally in Wistar rats intravenously given AMB (1.5 or 3.0 mg/kg) or saline (control) for 4 days, followed by CyA (10 mg/kg). The blood concentration of CyA after i.v. or p.o. administration in both AMB groups was significantly decreased compared with the control. The oral bioavailability of CyA after 1.5 or 3.0 mg/kg AMB treatment was decreased to 67% or 46%, respectively, of that of the control group. AMB treatment increased the expression levels of mdr1a and mdr1b mRNAs in the duodenum to about three times the control, and expression of CYP3A2 mRNA in the liver was increased to about twice the control. The P-gp and CYP3A2 proteins were increased significantly. These findings suggest that the oral bioavailability of CyA is reduced as a result of both increased efflux transport via P-glycoprotein in the duodenum and an increased first-pass effect of CYP3A2-mediated hepatic metabolic activity, induced by AMB. It is suggested that careful monitoring of CyA levels is necessary in the event of AMB administration to patients receiving immunotherapy with CyA.

Effect of Multiple Oral Dosing of Fluconazole on the Pharmacokinetics of Cyclosporine in Healthy Beagles

Fluconazole (Fcz) is successfully used in human organ transplant patients as an antifungal therapy. However, Fcz can increase the cyclosporine (CsA) trough level and lead to CsA nephrotoxicity. In canine renal transplantation, CsA has been used as a major immunosuppressant, and it is important to control its trough level. However, the interaction of Fcz with CsA has not yet been reported in dogs. In this study, the effect of Fcz treatment on the pharmacokinetics of CsA in four healthy beagles was investigated using a four-period crossover design. The treatments included CsA alone (A), CsA + multiple-dose Fcz 50 mg (B), CsA + multiple-dose Fcz 25 mg (C) and CsA + single-dose Fcz 50 mg (D). Blood CsA concentrations were measured at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hr after CsA administration. The AUC(0-12) and C(max) values for treatment B were significantly higher than those for the other treatments. In particular, the AUC(0-12) of treatment B was about two times higher than that of treatment A. Fcz administration did not significantly prolong the half-life or mean residence time of CsA. The results of our study show that administration of multiple therapeutic doses of Fcz can significantly increase the CsA blood concentration, which might partially depend upon the Fcz blood concentration. When Fcz is used in CsA-based canine renal transplantation, it may be necessary to adjust the CsA trough level by decreasing the dose.

Treatment of Severe Alopecia Areata: Combination Therapy Using Systemic Cyclosporine A with Low Dose Corticosteroids.

Combination therapy using cyclosporine A (CsA) together with low-dose corticosteroids has adequate efficacy with little toxicity for the treatment of severe alopecia areata (AA). We wanted to evaluate the clinical efficacy of combination therapy using CsA with low-dose corticosteroid for the treatment of severe AA and we also wanted to determine the safe therapeutic concentration of CsA in the peripheral blood. We treated 34 cases of severe AA with combination therapy for 24 weeks and we evaluated the efficacy at 12 and 24 weeks. We monitored the peripheral blood concentration of CsA to determine the therapeutic range of CsA that has the fewest side effects. Of the patients, 77.4% (n=24) and 22.6% (n=10) were classified in the responder and poor-responder groups, respectively. The mean trough concentration of CsA was 95.1 and 101.2 ng/ml in the responder and poor-responder groups, respectively. For the patients with side effects associated with CsA, the mean CsA concentration was 195.8 ng/ml. We found that combination therapy with systemic CsA and low-dose corticosteroids effectively treats severe AA and this therapy results in a safe, therapeutic concentration of CsA in the peripheral blood.

면역억제제의 약물속도론적/약력학적 파라미터에 기초한 표현형과 유전형의 상관성

Cyclosporine (CsA) and tacrolimus (FK506) have a narrow therapeutic range, and their pharmacokinetic (PK) characteristic varies among individual. They are also substrates for cytochrome P450 (CYP) 3A4, 3A5 genes, and P-glycoprotein, the product of the multidrug resistance 1 (MDR1). The aims were to investigate the relationship between CYP3A and MDR1 genotypes and their PK parameters among healthy subjects. We investigated the genotype for CYP3A and MDR1 gene in human using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. After oral administration of CsA and FK506 (100 mg and 1 mg, respectively), whole blood samples were taken up to 24 hours. Blood CsA and FK506 concentrations were measured by LC/MS/MS. Each PK parameters were compared using Kruskal-Wallis test according to the CYP3A and MDR1 genotype. We found that the values of AVC for CsA were significantly different among CYP3A5 and MDR1 exon 26 (C3435T) genotypes (P=0.037 and P=0.049). On the other hand, the AUC for FK506 was significantly different only among CYP3A5 genotypes (P=0.013). The results clearly demonstrate the effects of CYP3A5 and MDR1 exon 26 on Cys and FK506 disposition.

Achievement of Target Cyclosporine Concentrations as a Predictor of Severe Acute Graft Versus Host Disease in Children Undergoing Hematopoietic Stem Cell Transplantation and Receiving Cyclosporine and Methotrexate Prophylaxis

This study evaluates our institution's target trough cyclosporine (CSA) concentrations as predictors of severe acute graft versus host disease (aGvHD) in children receiving either matched related or unrelated hematopoietic stem cell transplantation (HSCT). The outcomes of 87 consecutive children who underwent allogeneic HSCT and received CSA and methotrexate as prophylaxis against aGvHD between October 1, 1999 and September 30, 2002 were retrospectively evaluated. The proportion of time that each patient maintained a whole blood CSA concentration within or above the initial target range (105-155 ng/mL or 155-210 ng/mL) was calculated for each of the following time periods: in each week after HSCT from day 0 to +28; in the week preceding engraftment; and in the week preceding the onset of aGvHD. Patients were prospectively evaluated twice weekly for the presence and severity of aGvHD by senior attending physicians. The relationship between potential predictors and the development of severe aGvHD was examined using univariate logistic regression. The main variables of interest were the proportion of time that therapeutic or supratherapeutic CSA concentrations were maintained; median CSA concentrations; the number of methotrexate doses received; and the use of folinic acid rescue. Mean follow-up time was 3.0+/-1.9 years among children who survived beyond day +100. Three variables were significantly associated with the development of severe aGvHD on univariate analysis: initial CSA target concentration [odds ratio (OR), 0.24; P=0.03], proportion of time the target CSA concentration was achieved during the second week after transplant (OR, 0.16; P=0.02), and proportion of time the target CSA concentration was achieved during the week before engraftment (OR, 0.22; P=0.0489). Multivariable analysis demonstrated an inverse relationship between the median CSA concentration during the week before engraftment and the development of severe aGvHD (OR, 0.99; P=0.045). These results suggest that achievement of our CSA target concentrations is important to aGvHD outcomes.

Comparison of Three Methods for Cyclosporine Therapeutic Monitoring

Cyclosporine (CsA) is an immunosuppressive drug used extensively in human transplants of solid organs or bone marrow as well as in the treatment of autoimmune diseases. To optimize immunosuppressive efficacy and minimize adverse reactions, blood CsA concentrations are monitored to allow appropriate dosage adjustments. To establish objective criteria to compare various techniques of CsA monitoring, we performed a detailed study over 5 months to compare and evaluate three immunoassays methods in comparison to the reference method of high-performance liquid chromatography (HPLC). Our study included 976 samples that were evaluated by: the COBAS INTEGRA 800 (Roche Laboratories); the V-Twin ® (Dade Behring Laboratories); and the AxSYM ® FPIA (Abbott Laboratories). Our results showed that all of the immunoassays yielded slightly higher concentrations than HPLC. However CsA concentrations obtained by AxSYM were most close to those of HPLC, so that this method seemed to be more specific than the other two.

Therapeutic Drug Monitoring of Kidney Transplant Recipients Using Profiled Support Vector Machines

This paper proposes a twofold approach for therapeutic drug monitoring (TDM) of kidney recipients using support vector machines (SVMs), for both predicting and detecting Cyclosporine A (CyA) blood concentrations. The final goal is to build useful, robust, and ultimately understandable models for individualizing the dosage of CyA. We compare SVMs with several neural network models, such as the multilayer perceptron (MLP), the Elman recurrent network, finite/infinite impulse response networks, and neural network ARMAX approaches. In addition, we present a profile-dependent SVM (PD-SVM), which incorporates a priori knowledge in both tasks. Models are compared numerically, statistically, and in the presence of additive noise. Data from 57 renal allograft recipients were used to develop the models. Patients followed a standard triple therapy, and CyA trough concentration was the dependent variable. The best results for the CyA blood concentration prediction were obtained using the PD-SVM (mean error of 0.36 ng/mL and root-mean-square error of 52.01 ng/mL in the validation set) and appeared to be more robust in the presence of additive noise. The proposed PD-SVM improved results from the standard SVM and MLP, specially significant (both numerical and statistically) in the one-against-all scheme. Finally, some clinical conclusions were obtained from sensitivity rankings of the models and distribution of support vectors. We conclude that the PD-SVM approach produces more accurate and robust models than do neural networks. Finally, a software tool for aiding medical decision-making including the prediction models is presented

Blood Concentration Curve of Cyclosporine: Impact of Itraconazole in Lung Transplant Recipients

Although the influence of cytochrome P450 inhibitory drugs on the area under the curve (AUC) of cyclosporine (CsA) has been described, data concerning the impact of these substances on the shape of the blood concentration curve are scarce. By assessment of CsA blood levels before and 1, 2, and 4 hr after oral intake (C0, C1, C2, and C4, respectively) CsA profiling examinations were performed in 20 lung transplant recipients taking 400 mg, 200 mg, and no itraconazole, respectively. The three groups showed comparable results for C0, C2, and AUC(0-12). Greater values were found for Cmax, Cmax-C0, peak-trough fluctuation and rise to Cmax in favor of the non-itraconazole group. Additionally, tmax was shorter in the non-itraconazole group. Comedication with the metabolic inhibitor itraconazole is associated with a flattening of the CsA blood concentration profile in lung transplant recipients. These changes cannot be assessed by isolated C0, C2, or AUC(0-12) values alone.

Comparative in vivo bioequivalence and in vitro dissolution of two cyclosporin A soft gelatin capsule formulations

A study was conducted to establish the bioequivalence between a newly developed cyclosporin A (CsA) oral formulation, Deximune soft-gelatin capsules (Dexcel Ltd.) and Sandimmune Neoral (Novartis Inc.). The clinical investigation was designed as a randomized, open-labeled, two-period, two-treatment crossover study, in 24 healthy fasted male volunteers. The subjects were administered a single 200 mg CsA dose of either formulation. Serial venous blood samples were obtained over 24 hours after each administration to measure CsA in whole blood by a specific TDx-immunoassay. In addition, the comparative drug release rate was assessed using a dissolution apparatus test according to the USP-24 method. For both treatments, a mean maximum blood concentration (Cmax) of approximately 1,200 ng/ml was obtained at about 1.6 hours (tmax) after administration and the geometric mean of the area under the blood concentration-time curve (AUC) both for test and reference was approximately 4,900 ng x h/ml. Bioequivalence was conclusively demonstrated for both rate (Cmax and tmax) and extent (AUC) of CsA absorption, between the two treatments. Moreover, the CsA blood concentration measurement at 2 hours after administration (C2), demonstrated equivalent results between the two products. The point estimates and their 90% confidence intervals were within the respective equivalence ranges for the pharmacokinetic parameters and were included in the range for drugs with a narrow therapeutic index. The comparative dissolution test for both formulations showed an in vitro release rate of more than 90% within 15 minutes. Based on the results, the two oral CsA formulations compared are bioequivalent and can be interchanged without need for dosage adjustment.

Treatment of Myelodysplastic Syndrome with Cyclosporin A

A multicenter prospective study was carried out to evaluate the efficacy of cyclosporin A (CsA) in 32 patients with myelodysplastic syndromes. The FAB subtypes of the patients included refractory anemia, refractory anemia with ringed sideroblasts, and refractory anemia with excess blasts. The dosage of CsA was 3 to 6 mg/kg per day and was adjusted according to the blood concentration of CsA and the responses of patients. The drug was administered twice a day for more than 3 months. After 3 months of treatment, hematological improvement was observed in 18 of 32 patients (56.3%) by the criteria of the International Working Group. At the end of the follow-up (median time, 14 months), 4 patients showed alteration of disease progression, including 1 complete remission and 3 partial remissions, and 16 patients showed hematological improvement. There were a total of 20 responders. The response rate was 62.5% (20/32). It was shown that the CsA therapy was effective in patients with refractory anemia or refractory anemia with excess blasts and both hypo- and hyperplastic bone marrows might respond to the therapy. The survival time was significantly longer in responders than in nonresponders. The study shows that CsA therapy is potentially the most effective therapy for myelodysplastic syndromes.

Pharmacodynamic Monitoring of Cyclosporine A in Renal Allograft Recipients Shows a Quantitative Relationship Between Immunosuppression and the Occurrence of Recurrent Infections and Malignancies

At present it is unclear which dose and consecutive blood levels of cyclosporine A (CsA) are optimal with respect to immunosuppressive efficacy and drug specific side effects at the level of individual patients. Several pharmacodynamic measures of CsA effects have been proposed, but have not become clinical routine yet. Besides the lack of practicability, the biological relevance of these assays has not been determined so far. Residual expression of nuclear factor of activated T-cells (NFAT)-regulated genes two hours after drug intake was used as molecular pharmacodynamic marker to assess CsA effects on lymphocytes and correlated with the frequency of recurrent infections and malignancies in patients with five or more years of follow-up posttransplantation. Recurrent infectious complications were observed in 44% and malignancies in 20% of the 133 patients studied. Patients with a strong suppression of NFAT-regulated genes by CsA--as judged by a residual level of transcription of less than 15% after drug intake--develop more frequent infections (53% vs. 29%; P = 0.005) and malignancies (22% vs. 4%; P = 0.002). The lack of correlation between the incidence of these complications and CsA blood concentration might point to the interindividual differences in the sensitivity towards calcineurin inhibition. The data presented here reveal a clear relation between the frequency of infectious and malignant complications and the degree of suppression of NFAT-regulated genes by CsA in transplanted patients. Therefore, pharmacodynamic monitoring of CsA efficacy in transplanted patients might be a useful tool to adjust immunosuppressive therapy in individual patients.

Insights into the effects of hyperlipoproteinemia on cyclosporine A biodistribution and relationship to renal function

The purpose of this study was to assess the effect of hyperlipoproteinemia on the biodistribution of cyclosporine A (CyA), an extensively lipoprotein bound immunosuppressant, in a rat model and to determine the potential toxicological significance of this effect. Normolipidemic and hyperlipoproteinemic rats were given a single 5 mg/kg dose of CyA as intravenous bolus and at selected times postdose, tissues, blood, and plasma were harvested and assayed for CyA content. Hyperlipoproteinemia was induced by intraperitoneal injection of 1 g/kg poloxamer 407. Compared with normolipidemic animals, hyperlipoproteinemic rats had higher plasma, blood, kidney, and liver CyA concentrations. In contrast, in heart and spleen the concentrations were decreased in hyperlipoproteinemia. The nephrotoxic effect of CyA was also evaluated in normolipidemic and hyperlipoproteinemic rats after 7 days of dosing with 20 mg/kg/day. In both groups of animals, repeated doses of CyA were associated with equivalent decreases in creatinine and urea clearances compared with matching control and predose baseline measures. The concentrations of drug in kidney were equivalent at the conclusion of the study. However, despite these similarities there was microscopic evidence of more severe changes in the kidneys in the hyperlipoproteinemic rats, which also experienced a significant decrease in body weight compared with the normolipedemic animals. In conclusion, the distribution of CyA to kidneys was enhanced in poloxamer 407-induced hyperlipoproteinemic rats after single doses, and with repeated doses there was an apparent greater adverse effect on these animals compared with normolipidemic animals.

Curative effects of cyclosporin A therapy upon myelodysplastic syndrome

To evaluate the efficacy of cyclosporin A (CsA) in treatment of myelodysplastic syndromes (MDS). Thirty-three patients with MDS, including refractory anemia (RA, n = 24), refractory anemia with ringed sideroblasts (RAS, n = 2), and refractory anemia with excess blasts (RAEB, n = 7), 23 males and 10 females, aged 46 (6 approximately 71), hospitalized in 4 CsA, grade 3 hospitals in Beijing who failed to respond to folic acid and vitamin B12, received CsA 3 approximately 5 mg x kg(-1)x d(-1), 2 times per days, taken orally in 2 separate doses for at least 3 months (2 approximately 27 months). During the course of treatment the dosage was adjusted according to the CsA blood concentration and curative effect. Follow-up was conducted for 14 months on average. The curative effect of those who took CSA for more than 2 months underwent statistical analysis, and for those who took CSA for less than 2 months only the side effects underwent statistical analysis. After 3 months of the treatment, the hematological improvement (HI) was observed in 18 of the 32 evaluative patients (56.3%) by the criteria of the International Working Group (IWG). At the end of the follow-up 4 patients showed alteration of disease progression, including 1 case of complete remission (CR) and 3 cases of partial remission (PR), and 16 patients showed homological improvement, responders numbering 20 totally, with a response rate of 62.5% (20/32). One of the 20 patients respondent to CsA died and 7 of the 12 patients who failed to respond to CsA died. Improving the clinical manifestations and lengthening the survival time, CsA therapy is effective in the patients with RA or RAEB, and both hypoplastic bone marrow and hyperplastic bone marrows respond to the therapy. CsA therapy is potentially the most effective therapy for MDS.

Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood–brain barrier can be studied with PET

Active efflux transporters in the blood–brain barrier lower the brain concentrations of many drug molecules and endogenous substances and thus affect their central action. The objective of this investigation was to study the dynamics of the entire inhibition process of the efflux transporter P-glycoprotein (P-gp), using positron emission tomography (PET). The P-gp marker [ 11C]verapamil was administered to anesthetized rats as an i.v. bolus dose followed by graded infusions via a computerized pump system to obtain a steady-state concentration of [ 11C]verapamil in brain. The P-gp modulator cyclosporin A (CsA) (3, 10 and 25 mg/kg) was administered as a short bolus injection 30 min after the start of the [ 11C]verapamil infusion. The CsA pharmacokinetics was studied in whole blood in a parallel group of rats. The CsA blood concentrations were used as input to model P-gp inhibition. The inhibition of P-gp was observed as a rapid increase in brain concentrations of [ 11C]verapamil, with a maximum after 5, 7.5 and 17.5 min for the respective doses. The respective increases in maximal [ 11C]verapamil concentrations were 1.5, 2.5 and 4 times the baseline concentration. A model in which CsA inhibited P-gp by decreasing the transport of [ 11C]verapamil out from the brain resulted in the best fit. Our data suggest that it is not the CsA concentration in blood, but rather the CsA concentration in an effect compartment, probably the endothelial cells of the blood–brain barrier that is responsible for the inhibition of P-gp.