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PubMed1988

Comparison of three immunosuppressive regimens in cadaver renal transplantation: long-term cyclosporine, short-term cyclosporine followed by azathioprine and prednisolone, and azathioprine and prednisolone without cyclosporine.

We conducted a randomized trial in seven Australian hospitals of the efficacy and safety of three immunosuppressive regimens after first transplantation of a cadaver kidney: long-term cyclosporine, short-term (three months) cyclosporine followed by azathioprine and prednisolone, and azathioprine and prednisolone without cyclosporine. Patients assigned to long-term cyclosporine (n = 138) or short-term cyclosporine followed by azathioprine and prednisolone (n = 141) had similar actuarial 12-month survival (98.4 vs. 96.4 percent) and graft survival (83.9 vs. 82.1 percent). Patients assigned to receive only azathioprine and prednisolone (n = 138), with optional use of antithymocyte globulin, had a significantly poorer survival rate (91.3 percent, P = 0.015) because of deaths from cardiac causes and infection, but their graft survival of 76.0 percent (P = 0.31) did not differ significantly from that of either group receiving cyclosporine. After the switch from cyclosporine to azathioprine and prednisolone, 15 percent of patients had reversible rejection episodes, but the frequency of rejection and graft loss did not differ from that in the long-term cyclosporine group. After the change to azathioprine and prednisolone, serum creatinine levels declined in nearly all patients, so that after three months they were comparable to those in the group receiving azathioprine and prednisolone only, and significantly lower than those in the group receiving long-term cyclosporine therapy (P less than 0.003). We conclude that the two cyclosporine regimens result in comparable patient and graft survival, but that changing to azathioprine and prednisolone at three months improves graft function.

Adult↗
PubMed1991

Investigations on the metabolic pathways of cyclosporine: I. Excretion of cyclosporine and its metabolites in human bile--isolation of 12 new cyclosporine metabolites.

1. Cyclosporine metabolites of known and unknown structures were isolated, by semi-preparative h.p.l.c., from human bile from the T-tube of liver-grafted patients, who received cyclosporine treatment. Their structures were elucidated by FAB mass spectrometry and 1H-n.m.r. spectroscopy. 2. Twelve of the cyclosporine metabolites, with known chemical structures, were isolated and identified using authentic standard material. 3. Four isolated fractions contained tri-hydroxylated metabolites; two fractions contained di-hydroxylated, demethylated metabolites; one fraction contained a tri-hydroxylated, demethylated metabolite; and one fraction a mono-hydroxylated, demethylated metabolite. The exact metabolism sites were partially defined. 4. Two carboxylated cyclosporine metabolites, of which one was hydroxylated in an unknown position, were isolated. 5. One new metabolite proved to be a glucuronylated phase II metabolite. Deglucuronylation of this metabolite by beta-glururonidase yielded metabolite AM1c. The proposed structure was AM1c-Glc; is a proposed extension of the Hawk's Cay nomenclature of the cyclosporine metabolites for glucuronylated metabolites. 6. One of the unknown metabolites was hydroxylated in two positions of amino acid 1. The proposed nomenclature was 'AM11d', where '1d' indicates hydroxylation at the delta C of amino acid 1. 7. A metabolite with an aldehyde functional group at amino acid 1, which had two isomeric forms, was isolated. I.r.-spectroscopy indicated that isomerism may be caused by conjugation of the aldehyde group with the double bond between C6 and C7 of amino acid 1.

Aldehydes↗
PubMed1998

Comparative study of cyclosporin A, cyclosporin G, and the novel cyclosporin derivative IMM 125 in isolated glomeruli and cultured rat mesangial cells: a morphometric analysis.

BACKGROUND: One adverse side-effect of the immunosuppressive drug cyclosporin A (CsA) is a decrease in glomerular filtration rate (GFR). This effect might be the result of increased glomerular contractions. The present study compared the contractile effects of CsA, cyclosporin G (CsG) and the novel cyclosporin derivative IMM 125 in isolated rat glomeruli and primary cultures of rat mesangial cells. METHODS: Interactive image analysis was used to measure glomerular and mesangial cell contraction. RESULTS: CsA, CsG, and IMM 125 at concentrations of 0, 10(-9), 10(-8), 10(-7), 10(-6) and 10(-5) M caused a time-dependent and a concentration-dependent contraction of isolated glomeruli and mesangial cells 30 min after incubation. In glomeruli, CsA was more potent than CsG and IMM 125. In mesangial cells, IMM 125 also exhibited the lowest contractile activity, while CsA and CsG were almost equally myoreactive. The absolute degree of the glomerular contraction was proportional to the number of contracting mesangial cells in one glomeruli. The number of responding cells after incubation with IMM 125 and CsG were lower compared to CsA, which might explain the different response with CsG and CsA in both models. CONCLUSIONS: Since the concentrations used in these experiments were close to that reached in rat serum after treatment with CsA, the present results suggest that the contractile effects of IMM 125 and CsG in isolated glomeruli were clearly smaller compared to CsA, which might reflect the cyclosporins induced GFR changes in vivo.

Animals↗
PubMed1988

Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs.

The rate of formation of the three initial metabolites of cyclosporine metabolism has been determined in liver microsomes of 15 kidney transplant donors. Interindividual variation in metabolite formation was considerable but all three metabolites varied in parallel. An antiserum raised against a steroid-inducible rat cytochrome P-450 (P-450 PCN) strongly inhibited the formation of these metabolites. Immunoquantitation of the protein recognized by a monoclonal antibody reacting with human cytochromes P-450 of the P-450III gene family, homologues of rat P-450 PCN and rabbit P-4503C, revealed a high degree of correlation with microsomal cyclosporine metabolism. The data suggest that this cytochrome P-450 is the major cyclosporine-metabolizing enzyme in human liver. The substrate specificity and the known inducers and inhibitors of this cytochrome P-450 explain several clinically observed drug interactions with cyclosporine.

Cyclosporins↗
PubMed1992

Comparison of the properties of the CsA analogs monoacetyl CyC (o-acetyl-threonine2 cyclosporin) and methyl-alanyl CsA (N-methyl-L-alanyl6 cyclosporin); monoacetyl cyclosporin is immunosuppressive without binding to cyclophilin.

Cyclosporin (CsA) is an immunosuppressant which binds to cyclophilin (Cyp). The relationship between Cyp binding and immunosuppression has been questioned since one of the analogs of CsA, N-methyl-L-alanyl6 cyclosporin (methyl-alanyl CsA) binds to Cyp but is not immunosuppressive. We compared the immunosuppressive properties of CsA, methyl-alanyl CsA and o-acetyl-threonine2 cyclosporin (monoacetyl CyC), since monoacetyl CyC does not bind to Cyp when tested in cell-free assays and its immunosuppressive properties had not been tested. Cyp is a peptidyl-prolyl isomerase which is abundant in all human tissues, yet the activities of CsA are mostly confined to inhibition of T cell and thymocyte activation, and to neuro- and nephro-toxicity and are independent of inhibition of the isomerase. Activation of thymocytes and of T cells is regulated by the binding of a nuclear factor(s) (NFs) to the NF-AT region (-285 to -255) of the IL-2 promoter. We studied inhibition of binding to the NF-AT region of NFs derived from primary cultures of thymocytes treated with CsA or its analogs. In addition, we compared the effect of CsA and its analogs on the expression of the IL-2 gene in a stably transfected Jurkat-cell line (Fgl 5) which contains three copies of NF-AT and the reporter enzyme beta-galactosidase; and on inhibition of proliferation induced by concanavalin A (Con A) or IL-2. We found that monoacetyl CyC which does not bind to Cyp is immunosuppressive by our criteria when tested in cultured cells due to either a different mechanism of action or to metabolic activation.

Amino Acid Isomerases↗
PubMed2003

Two new cyclosporin folds observed in the structures of the immunosuppressant cyclosporin G and the formyl peptide receptor antagonist cyclosporin H at ultra-high resolution.

Cyclosporins are cyclic undecapeptides of fungal origin the best known of which, CsA, is a lead clinical immunosuppressant; CsG is a potential clinical immunosuppressant differing from CsA in residue 2 (L-alpha-amino-butyric acid in CsA, L-norvaline in CsG); and CsH is an inverse formyl peptide receptor agonist, differing from CsA in the chiral inversion of MeVal-11 from L to D. Crystal structure determinations of CsG and CsH were undertaken to identify structural and surface features important for biological activity and the future design of new cyclosporin derivatives. Ultra-high resolution X-ray structures (0.80 to 0.87 A resolution) determined for two crystal forms of both CsH and CsG in the presence and absence of Mg2+ are described. A major outcome of this study is the observation that the local change in chirality between CsA and CsH is associated with a major structural transformation from open beta-sheet in CsA to a highly convoluted conformation in CsH. CsG also possesses a completely novel cloverleaf motif with no H-bonded secondary structure features in spite of the minimal chemical difference with CsA. Unlike CsA, the structures of both CsH and CsG are heavily solvated. This study therefore shows that the chemical differences between the three cyclosporins, CsA, CsG and CsH can invoke unpredictably major differences in their 3D structures. The 9-11 cis-peptide bond in CsA moves to 11-1 in CsG, influencing the overall molecular conformation, while the peptide bonds in the highly convoluted loop conformation of CsH are all trans.

Crystallography, X-Ray↗
PubMed1985

Comparison of the pharmacological profiles of cyclosporine, (Nva2)-cyclosporine and (Val2)dihydro-cyclosporine.

The pharmacological profiles of two new derivatives of the immunosuppressive drug, cyclosporine, is presented here. (Nva2)-CS has very similar properties to CS, but lacks the nephrotoxic side-effects. This derivative appears to be a potential successor to cyclosporine. (Val2)DH-CS seems to have a different spectrum of activities. It does not suppress humoral immunity and allograft rejection, but suppresses some types of cell-mediated immune responses. This derivative may prove useful in autoimmune situations where T cells are involved in the disease process.

Animals↗
PubMed1993

Cross-reactivities of cyclosporin G (NVa2 cyclosporin) and metabolites in cyclosporin A immunoassays.

Immunoassays of cyclosporin A (CsA) have been routinely used to measure CsG. We investigated the cross-reactivities of CsG and its metabolites, as well as the proportion CsG constitutes in relation to total drug measured, for six CsG metabolites (GM1, GM9, GM4N, GM1c, GM1c9, GM19) in the following CsA assays: Sandimmune selective RIA (SS), Sandimmune nonselective RIA (NS), Cyclotrac SP-RIA (CT), fluorescence polarization immunoassay (FPIA), and enzyme immunoassay (EMIT). The cross-reactivity of CsG in these assays was as follows: SS, FPIA, CT, approximately 100%; NS, approximately 40%; EMIT, < 2%. The cross-reactivities of CsG metabolites were investigated in all assays except EMIT and varied among metabolites and assays. The most significant variance was found with the NS assay, where most of the metabolites exhibited cross-reactivities of > 40%. In contrast, in the SS, FPIA, and CT assays, cross-reactivities of < 5% were observed for most of the metabolites. The ranking of cross-reactivities of CsG metabolites in the assays is SS = CT < FPIA < NS. The degree of cross-reactivity did not change significantly when the SS, CT, and FPIA assays were calibrated with CsG instead of CsA--whether parent CsG was present or not. The data suggest that the SS, CT, and FPIA methods would be suitable for the routine monitoring of CsG.

Cross Reactions↗
PubMed2003

An open, randomized comparison study of cyclosporine A, cyclosporine A + methotrexate and cyclosporine A + hydroxychloroquine in the treatment of early severe rheumatoid arthritis.

PURPOSE: To determine whether a regimen of cyclosporine (CSA) and methotrexate (MTX), or CSA and hydroxychloroquine (HCQ) introduced in early rheumatoid arthritis (RA) can produce a significant improvement in clinical outcome and/or retard radiographic damage in comparison with standard monotherapy with CSA alone. METHODS: One hundred five patients with active RA of less than 36 months duration, who had never previously been treated with immunosuppressive agents, were included in a 12-month, multi-center, open, randomized trial. Patients who fulfilled the criteria for early severe RA were randomized to receive either combination therapy (CSA + MTX n = 34, CSA + HCQ n = 35) or CSA alone (n = 36). RESULTS: CSA + MTX was more effective than the other two treatment groups in controlling RA symptoms. CSA+MTX did not show a significant radiographic progression according to Larsen-Dale (0.90 +/- 3.89 compared to baseline values, P > 0.05); moreover, patients treated with CSA alone or CSA+HCQ showed a significant worsening of Larsen-Dale score (2.91 +/- 5.99 and 2.97 +/- 4.28 respectively vs baseline values, P < 0.05), although not significant when compared with the CSA + HCQ group (P = 0.56 and 0.39, respectively). CONCLUSIONS: This trial indicated that CSA+MTX was more effective than the other two treatments in improving clinical data and inhibiting radiographic progression, although the differences were not significant in this relatively small study. However, the difference was significant in favor of CSA + MTX regarding ACR 50% response.

Antirheumatic Agents↗
PubMed1987

Effect of cyclosporine, cyclosporine metabolite 17, and other cyclosporine-related compounds on T lymphocyte clones derived from rejected human kidney grafts. I. Inhibition of proliferation.

The effect of cyclosporine and metabolite 17 (M17) as well as other CsA-related compounds (CsG, dihydro-CsC, dihydro-CsD, CsH, B5.49, and H7.94) was tested on T lymphocyte clone proliferation. In these experiments, antigen and interleukin 2 (IL-2) dependent long-term T lymphocyte clones derived from a rejected human kidney graft infiltrate were used. They were specifically committed (proliferation and cytotoxicity) for the donor Epstein-Barr virus (EBV)-transformed cells. CsA strongly inhibited clone T cell proliferation induced by the antigen. Inhibition of antigen-driven proliferation was reversed by pure recombinant IL-2 (rec-IL-2) only when low amounts of CsA (less than 25 ng/ml) were used, whereas this lymphokine was ineffective at higher but still pharmacological CsA concentrations (50-500 ng/ml). Increasing rec-IL-2 concentrations did not modify this finding. In addition, CsA, did not inhibit the growth signal(s) induced by rec-IL-2/IL-2 receptor interactions when R-IL-2 is pre-expressed on clone cells. M17 was far less effective in inhibiting antigen-induced clone cell proliferation (50% inhibition at 16 ng/ml versus 500 ng/ml with, respectively, CsA and M17) but was nevertheless inhibitory. This observation, if extended to other metabolites, could be important for interpretation of the relevance of "CsA" concentration through radio-immunoassay monitoring of recipients' blood. Although CsA appeared to display the major inhibitory effect, dihydro-CsC and CsG, as well as B5.49 and H7.94 CsA-related compounds, also exhibited strong activity. Dihydro-CsD was less inhibitory, and CsH had no effect.

Clone Cells↗
PubMed1997

Equivalence of cyclosporine blood level assays in patients receiving cyclosporine microemulsion or cyclosporine. The Sandoz Neoral Study Group N103.

The more rapid absorption of the cyclosporin A (CyA) microemulsion formulation (Neoral, NEO) compared to Sandimmune (SIM) might bypass intestinal metabolism resulting in differing amounts of CyA metabolites in blood as compared to SIM. If true, then CyA levels obtained with a CyA monoclonal antibody assay (TDx) that has metabolite cross-reactivity might differ depending on the CyA formulation received by the patient, thereby affecting safety and efficacy. Fifty-one NEO vs. 50 SIM treated de novo renal transplant recipients from a multicenter double-blind randomized trial had morning, whole-blood, trough-samples obtained at the ends of weeks 1, 4, 8, and 12 post-transplant assayed for CyA by HPLC and TDx. The slopes (ratio of TDx value to HPLC value) for the regression lines between TDx and HPLC levels as a function of time post-transplant and CyA formulation were determined using a general linear model. For NEO, the slopes at each week (1.21-1.41 x HPLC) did not differ significantly (p = 0.82). For SIM, the week 1 slope (1.2) was significantly (p = 0.006) less than the other weeks (1.4-1.44). The slopes (NEO vs. SIM) were not different at either week 1 (1.21 vs. 1.22, p = 0.82) or at pooled weeks 4, 8, and 12 (1.33 vs. 1.4, p = 0.1). These results indicate that despite the improved absorption, TDx values obtained on NEO are qualitatively similar to those obtained on SIM.

Absorption↗
PubMed1998

Cyclosporin microemulsion (Neoral). A pharmacoeconomic review of its use compared with standard cyclosporin in renal and hepatic transplantation.

UNLABELLED: Cyclosporin microemulsion (Neoral) is a self-emulsifying preconcentrate of cyclosporin which is more rapidly and consistently absorbed than the original oil-based formulation of cyclosporin (standard formulation; Sandimmun, Sandimmune). This superior pharmacokinetic profile suggests that cyclosporin microemulsion may be associated with improved therapeutic and economic outcomes compared with the standard formulation. Clinical studies comparing the 2 formulations of cyclosporin (using the recommended 1:1 dosage conversion factor) in de novo or stable renal and de novo liver transplant patients have demonstrated that cyclosporin microemulsion is as efficacious as the standard formulation. Rates of acute and chronic graft rejection are generally unaffected by the formulation of cyclosporin, although a trend toward fewer rejection episodes in cyclosporin microemulsion recipients was noted in several randomised studies (reaching statistical significance in 4 studies). Most transplant recipients experience adverse events during cyclosporin therapy, and with higher and more reliable maximum blood concentrations achieved by cyclosporin microemulsion, there is a potential risk of more drug-related adverse events. However, most studies have suggested that the frequency of drug-related adverse events (including nephrotoxicity) is not affected by the formulation of cyclosporin. Analyses of healthcare resource utilisation and associated costs in renal and liver transplant patients in Canadian and European studies have suggested that the cost of using cyclosporin microemulsion may be lower than the cost of using the standard formulation. Lower resource consumption among cyclosporin microemulsion recipients in several studies led to slightly (but not statistically significantly) lower overall healthcare costs in this group. The cost of cyclosporin itself was not included in most of these analyses; however, because the 2 formulations of cyclosporin are used in similar dosages and have similar acquisition costs, this was probably not an important factor in determining relative costs. A single cost analysis comparing cyclosporin microemulsion and tacrolimus suggested that the 2 drugs were associated with similar overall costs. The available economic data on the use of cyclosporin microemulsion are subject to a number of important limitations. In particular, only partial results and study methodology have been reported for most analyses. Several studies were based on small patient groups (< 25) and short periods of follow-up (3 months), although some economic studies included larger patient groups receiving treatment for up to 1 year. Moreover, all of the analyses published to date were 'protocol driven' studies, and hence may not reflect resource use in usual clinical practice. CONCLUSION: In de novo and stable renal and de novo liver transplant recipients, cyclosporin microemulsion is as effective and well tolerated as the standard formulation of cyclosporin. Economic analyses comparing the 2 formulations indicate a consistent, although small and not statistically significant, reduction in overall healthcare costs associated with use of cyclosporin microemulsion.

Chemistry, Pharmaceutical↗
PubMed1987

Pharmacodynamics of cyclosporine-ketoconazole interaction in mice. Combined therapy potentiates cyclosporine immunosuppression and toxicity.

We have previously studied the pharmacokinetics of the cyclosporine-ketoconazole interaction and shown that ketoconazole inhibits the metabolism of cyclosporine in mice. In the present study we investigated the pharmacodynamics of the interaction and found that ketoconazole increased the immunosuppressive activity and toxicity of cyclosporine in vivo. Mice were treated orally with cyclosporine (25-200 mg/kg/day), ketoconazole (100 mg/kg/day), drug vehicle, or drug combination for 14 days. Immunosuppression was studied by assaying radiometrically the delayed hypersensitivity response in mice that were sensitized and challenged to keyhole limpet hemocyanin. The dose-response curve for cyclosporine was shifted to the left when cyclosporine and ketoconazole were coadministered compared with treatment with cyclosporine alone. The dose that produced 50% of the maximal immunosuppression (ED50) for cyclosporine alone was 89 mg/kg/day, whereas the ED50 for cyclosporine, when combined with ketoconazole, was 33 mg/kg/day. Ketoconazole alone was not immunosuppressive. Toxicity was measured by the length of survival during a ten-day period of treatment. Animals receiving both drugs had a significantly lower survival: the ten-day survival of animals treated with 200 mg/kg/day of cyclosporine was 100% in the absence of ketoconazole treatment and 62.5% with 100 mg/kg/day of ketoconazole. The results of our study have two important implications. First, the effect of ketoconazole on cyclosporine immunosuppression is quantitatively similar to its effect on cyclosporine kinetics. Because of this two- to three-fold increase in both unchanged cyclosporine blood levels and immunosuppression, our results suggest that unchanged cyclosporine--not its metabolites--is the primary pharmacological agent of cyclosporine in vivo immunosuppression. Second, to avoid cyclosporine-induced nephrotoxicity, it has been recommended that the dosage of cyclosporine be decreased when this drug combination is used clinically. The results of this study suggest that a decrease in cyclosporine dosage will not lower the level of immunosuppression in these patients.

Animals↗
PubMed2006

Role of P-glycoprotein in cyclosporine cytotoxicity in the cyclosporine-sirolimus interaction.

Cyclosporine nephrotoxicity remains a major side effect in solid organ transplantation, and can be exacerbated by concomitant administration of sirolimus. Cyclosporine and sirolimus are P-glycoprotein (Pgp) substrates. We hypothesized that the Pgp activity level may affect cyclosporine cytotoxicity by interfering with the ability of Pgp to remove cyclosporine from within tubular cells, and that an interaction between cyclosporine and sirolimus on Pgp function may explain the enhancement of cyclosporine nephrotoxicity by sirolimus. Cyclosporine cytotoxicity was evaluated in primary cultures of normal human renal epithelial cells (HRECs) by cell viability and cytotoxicity assays. Verapamil, quinine, PSC833, and PGP-4008 were used as Pgp inhibitors. Rhodamine-123 (R-123), a fluorescent substrate of Pgp, was used to assess Pgp-mediated transport. Cellular cyclosporine concentration was measured by high-performance liquid chromatography coupled to tandem mass spectrometry. Pgp expression and function were confirmed in HRECs and cyclosporine and sirolimus were shown to be Pgp inhibitors in this model. Verapamil-induced inhibition of Pgp led to a significant increase in cellular concentration of cyclosporine (P<0.05). Cyclosporine exerted a concentration-dependent cytotoxic effect on HRECs that was significantly increased by inhibition of Pgp activity. Sirolimus exerted an inhibitory effect on R-123 efflux in HRECs and increased cellular cyclosporine concentrations in a dose-dependent manner. These data demonstrate that Pgp plays a critical role in protecting renal epithelial cells from cyclosporine toxicity. The inhibitory effect of sirolimus on Pgp-mediated efflux and the cellular concentration of cyclosporine could explain the exacerbation of cyclosporine nephrotoxicity observed clinically.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

A new proposal for the mechanism of cyclosporine A nephrotoxicity. Inhibition of renal microsomal protein chain elongation following in vivo cyclosporine A.

In this paper, we report experiments examining the effect of cyclosporine A on "run-off" translation in microsomes isolated from tissues of Sprague-Dawley rats. In microsomes isolated from rat brain, kidney and thymus, cyclosporine A added in vitro in concentrations of up to 100 micrograms/ml did not reduce [3H]L-leucine incorporation relative to controls. A small dose-dependent reduction in [3H]leucine incorporation was observed in microsomes isolated from rat liver when cyclosporine A was added in high concentrations (5 and 6% at 25 and 100 micrograms/ml). However, when cyclosporine A was injected at 50 mg/kg/day for 10 days, [3H]L-leucine incorporation was inhibited 99.9% in microsomes isolated from kidney. The oral administration of cyclosporine A at 50 mg/kg/day for 6-10 days produced a 75% inhibition of incorporation by isolated renal microsomes. These changes were observed in the absence of measurable reductions in "run-off" transcription measured as [3H]UTP incorporation by renal nuclei exposed to cyclosporine A in concentrations of up to 100 micrograms/ml in vitro or isolated from animals given oral cyclosporine A at 50 mg/kg/day for 6 days. Cross-over experiments were performed using microsomes and microsomal supernatant fractions (cell saps) from tissues of animals treated with cyclosporine A and control vehicle. Renal cell sap from cyclosporine A treated animals inhibited [3H]L-leucine incorporation by microsomes isolated from the kidneys or other tissues of animals treated with control vehicle. These experiments demonstrated that a translation inhibitor was present in the cell sap of cyclosporine A treated animals which could directly block translation elongation in microsomes from control animals. When renal cell sap from both control and cyclosporine A treated animals was added to control microsomes, inhibition was still prominent, suggesting the presence of an inhibitor rather than the absence of an elongation factor. Oral administration of cyclosporine A at 50 mg/kg/day for 6 days depressed renal microsomal [3H]L-leucine incorporation equally in male and female rats to 25% of control. The dose-response relationship for microsomal protein synthesis inhibition after 6 days of oral cyclosporine A administration was: 5 mg/kg, 73.7% of control; 10 mg/kg, 64.1% of control; 25 mg/kg, 54.9% of control and 50 mg/kg, 24.1% of control. Renal microsomal protein synthesis following oral cyclosporine A at 50 mg/kg/day was reduced to 54% of control by day 2 and was maximally inhibited at 25-30% of control by day 4.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Clinical response does not correlate with intestinal or blood cyclosporine concentrations in patients with Crohn's disease treated with high-dose oral cyclosporine.

OBJECTIVE: High-dose ( >5 mg/kg/d) oral cyclosporine may be effective treatment for Crohn's disease, whereas low-dose oral cyclosporine ( < or = 5 mg/kg/d) is not. This study determined the correlation between blood and intestinal tissue cyclosporine concentrations and clinical response in patients with Crohn's disease treated with cyclosporine 8 mg/kg/day. METHODS: Twelve patients with inflammatory Crohn's disease were treated for 6 wk with oral cyclosporine 8 mg/kg/day, adjusted to a whole blood cyclosporine concentration (chromatography) of 200-300 ng/ml. Response was determined by the Crohn's disease activity index. Cyclosporine was measured in intestinal tissue biopsies obtained by colonoscopy at week 6 (chromatography). RESULTS: Eight patients responded and four did not respond. There were no significant differences between the responders and nonresponders in the mean whole blood or intestinal tissue cyclosporine concentrations. Similarly, there were no significant correlations between change in the Crohn's disease activity index score (baseline to week 6) and whole blood or intestinal tissue cyclosporine concentrations. Cyclosporine side effects, including nephrotoxicity and peroneal nerve palsy, were common. CONCLUSIONS: Clinical response did not correlate with whole blood or intestinal tissue cyclosporine concentrations in patients treated with high-dose cyclosporine for Crohn's disease. Cyclosporine side effects, including a significant decrease in renal function, were common.

Administration, Oral↗
PubMed1996

A comparison of cyclosporine A and cyclosporine G in a rabbit heterotopic cardiac transplant model: graft outcome and histological findings.

Cervical heterotopic heart transplants were performed on 20 male New Zealand white rabbits comprising 4 treatment groups. Animals in each group were injected daily via the marginal ear vein and received one of the following regimes: Cyclosporine A, 10 mg/kg/day; Cyclosporine G, 15 mg/kg/day; cremophor-El, 3ml/day; or normal saline. Measurement of 24 hour trough blood concentrations revealed no significant differences between the average concentrations of Cyclosporine A and Cyclosporine G. Animals were examined daily and the cervical allografts assessed by palpation for viability/rejection. The duration of the study ended for each animal when the graft stopped beating at which time the animals were euthanized and the transplanted heart and native kidneys harvested and processed for light microscopy evaluation of rejection and drug toxicity, respectively. Graft survival in the Cyclosporine A group significantly surpassed that seen in the Cyclosporine G group as well as the control groups, whereas in animals treated with Cyclosporine G, graft survival was not different from controls. In the native kidney, there were no differences in glomerular tuft area or volume density amongst drug-treated or control animals. In contrast, tubule atrophy and interstitial fibrosis were markedly greater in Cyclosporine A-treated vs Cyclosporine G-treated animals. The results of this study indicate that, whereas Cyclosporine G is less nephrotoxic than Cyclosporine A, given equivalent blood concentrations Cyclosporine A delays rejection of a cardiac allograft significantly longer than Cyclosporine G in this animal species.

Animals↗
PubMed1987

A comparison of cyclosporine A and Nva2-cyclosporine (cyclosporine G) in a rat renal allograft model.

We compared CsG and CsA in the DA-to-Lewis rat renal allograft model. At equivalent oral doses, plasma radioimmunoassay (RIA) CsG levels were higher than CsA (P less than 0.02). Neither drug prevented rejection at doses of 5 mg/kg/day. CsG-treated rats had a higher rejection rate at doses of 7.5 mg/kg/day (P less than 0.05). Both drugs were equally effective in preventing rejection at doses of 10 mg/kg/day. Neither drug was nephrotoxic at the doses used in this study. CsG is a potent immunosuppressant, and thus a potential clinical successor to CsA. Since CsG and CsA provide equivalent immunosuppression at therapeutic doses, CsG's clinical significance will ultimately depend on its nephrotoxicity in man.

Animals↗