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Biomedical subjects

B D Kahan

Publications and source records attributed to B D Kahan.

At least 19 recordsLinked to original sources
PubMed1998

Impact of early cyclosporin average blood concentration on early kidney transplant failure.

This retrospective study served to examine the correlation between the degree of cyclosporin (CyA) exposure, as estimated by a single pharmacokinetic (PK) profile performed at 1 week post-transplant, and the outcome of 290 consecutive renal transplants performed over a 6-year period. For this retrospective analysis patients were stratified into four historical groups based on 12-versus 24-h PK studies and on the use of radioimmunoassay versus fluorescence polarization immunoassay methods for estimates of CyA concentrations. Four PK measures-trough concentration (C0), average concentration values (Cav; i.e., the dosing interval-corrected area under the concentration-time curve), maximum concentration (Cmax), and time to maximum concentration (tmax)-were examined as predictors of patient, graft, and rejection-free survival rates for each of the four groups individually and for all groups combined. Patients with an initial Cav > or = 550 ng/ml had higher 1-year (88%) and 6-year (66%) graft survival rates than patients with Cav < 550 ng/ml, who had 1- and 6-year graft survival rates of 80% and 59%, respectively (P = NS). Statistically significant differences were observed in graft survival rates between patients with Cav < 550 versus Cav > or = 550 ng/ml at 30 (88% vs 96%; P < 0.02), 60 (85% vs 94%; P < 0.007), 90 (85% vs 94%; P < 0.02), and 180 (83% vs 92%; P < 0.05) days. Moreover, patients with Cav < 550 ng/ml displayed more severe rejection episodes, as judged by Banff classification, than patients who displayed Cav > or = 550 ng/ml (grades II and III; 71% vs 50%; P = 0.036). In contrast, the C0, Cmax and tmax values did not correlate with patient, graft, or rejection-free survival rates. The pharmacokinetic parameter of Cav correlated strongly with early graft survival and may therefore, be a useful predictor of those renal transplant patients who may require more intensive post-transplant monitoring of CyA concentrations by serial PK studies to improve graft survival.

Adult↗
PubMed1998

The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent.

INTRODUCTION: Sirolimus and cyclosporine (INN, ciclosporin) share the same cytochrome P4503A metabolic pathways, and both drugs are substrates for p-glycoprotein countertransport. These factors most likely affect the bioavailability of both drugs. This study served to examine whether the timing of the administration of cyclosporine and sirolimus might significantly affect the relative bioavailability of one or both of these drugs. METHODS: In this randomized crossover trial, 24 stable kidney transplant recipients who were treated after transplant with a combination of sirolimus, cyclosporine, and prednisone for at least 3 months before study initiation, received individualized doses of sirolimus once daily and cyclosporine in the microemulsion formulation twice a day. A total of 20 patients completed the full crossover design. Patients were randomized to one of two dosing schedules: 10 of the patients who completed the study received the morning doses of sirolimus and cyclosporine concomitantly for the first 7 days (schedule I), and from days 8 to 14 the sirolimus dose was administered 4 hours after the morning cyclosporine dose. Ten of the patients received the sirolimus dose 4 hours after the morning cyclosporine dose for the first 7 days (schedule II), and from days 8 to 14 they received concomitant morning doses of cyclosporine and sirolimus. Pharmacokinetic profiles of sirolimus and cyclosporine performed on all patients on days 7, 14, and 15 yielded the area under the concentration-time curve (AUC), peak concentration (Cmax), time to Cmax (tmax), trough cyclosporine concentration (Co), and trough sirolimus concentration (Co) values. RESULTS: Sirolimus AUC and sirolimus trough levels were consistently and significantly higher when both cyclosporine and sirolimus were administered concomitantly than when they were administered 4 hours apart. No effect attributable to timing of drug administration could be found on cyclosporine pharmacokinetic parameters. CONCLUSION: This study shows that the relative timing of administration of cyclosporine and sirolimus significantly affects the blood concentrations of sirolimus.

Adult↗
PubMed1997

Induction of tolerance toward rat cardiac allografts by treatment with allochimeric class I MHC antigen and FTY720.

BACKGROUND: The combination of FTY 720, a novel immunosuppressant, and allochimeric class I MHC proteins bearing donor-type amino acid (aa) epitope substitutions for host-type sequences induces tolerance of Wistar Furth (WF; RT1.Au) heart allografts in ACI (RT1.Aa) recipients. METHODS: Allochimeric alpha(1h)l58-80-RT1.Aa proteins were produced by substituting the allogeneic nucleotide sequence encoding 10 aa residues unique to the alpha1 helical (alpha1h) region of RT1.Al Lewis (Asp58, Arg62, Glu63, Gln65, Lys66, Gly69, Asn70, Asn73, Ser77, and Asn80) for native RT1.Aa residues. The RT1.Au and the RT1.Al haplotypes share four of these aa (Arg62, Glu63, Gln65, and Gly69). A baculovirus/Spodoptera frugiperda insect cell system was used to express the alpha(1h)l58-80-RT1.Aa proteins. RESULTS: The addition of a 3-day oral gavage of 0.05 mg/kg/day FTY720 to a single portal vein injection of 10 microg alpha(1h)l58-80-RT1.Aa protein induced permanent acceptance of WF heart allografts in 16 of 26 ACI recipients (>100 days); the alpha(1h)l58-80-RT1.Aa protein alone only modestly prolonged WF heart survival (13.8+/-0.8 days). The same tolerogenic protocol did not prolong the survival of third-party Brown Norway (RT1.An) heart allografts (14.3+/-2.5 days) compared with FTY720 alone (14.0+/-2.3 days; NS). Tolerant ACI recipients bearing primary WF heart allografts for more than 100 days accepted second WF hearts, but promptly rejected third-party Brown Norway heart grafts (9.3+/-1.5 days). The tolerant state was transferred to irradiated ACI rats (400 rad) with either purified T cells (4-10 x 10[7]) or serum (1-2 ml) from tolerant hosts, and was not broken by daily intraperitoneal injections of interleukin-2 (1000 U/day; 7 days). CONCLUSIONS: The combination of allochimeric protein with FTY720 induces transplantation tolerance, a state that may be associated with the appearance of donor-specific regulatory factors.

Animals↗
PubMed1997

Localization of cryptic tolerogenic epitopes in the alpha1-helical region of the RT1.Au alloantigen.

BACKGROUND: Transplantation tolerance is induced by perioperative administration of host class I major histocompatibility complex proteins bearing donor-type amino acid (a.a.) epitopes substituted for native residues. Herein we demonstrate that two cryptic tolerogenic a.a. epitopes are localized in the alpha1-helical region of the rat RT1.Au class I major histocompatibility complex alloantigen. METHODS: Three allochimeric proteins were produced by superimposing the nucleotides encoding donor-type RT1.Au a.a. onto the host RT1.Aa backbone using the polymerase chain reaction-based method of gene splicing with overlap extension. We substituted nucleotide sequences encoding all nine (Arg62, Glu63, Gln65, Gly66, Gly69, His70, Val73, Asn74, and Asn77; alpha1h u62-77-RT1.Aa), the first four (Arg62, Glu63, Gln65, and Gly69; alpha1h u62-69-RT1.Aa), or the last four (His70, Val73, Asn74, and Asn77; alpha1h u70-77-RT1.Aa) alpha1-helical RT1.Au polymorphic a.a. in RT1.Aa cDNA. A baculovirus/Spodoptera frugiperda (Sf9) expression system was harnessed for production of the proteins. RESULTS: Untreated ACI (RT1a) rats reject Wistar-Furth (WF; RT1u) heart allografts at a mean survival time of 8.9+/-1.0 days. A single portal vein injection of 10 microg of alpha1h u62-77-RT1.Aa protein had no effect on the survival of WF heart allografts (10.5+/-0.6 days) in ACI hosts. Interestingly, portal vein administration of 10 microg of alpha1h u70-77-RT1.Aa induced transplantation tolerance toward WF grafts in four of six untreated ACI recipients (>100 days; P<0.01). In contrast, 10 microg of alpha1h u62-69-RT1.Aa only prolonged the survival of WF heart allografts in ACI hosts (14.0+/-0.8 days; P<0.01). However, when combined with a 7-day course of cyclosporine (4.0 mg/kg; oral gavage), alpha1h u62-69-RT1.Aa induced tolerance toward WF allografts in five of seven ACI recipients (>170 days; P<0.01). Long-term survival of WF grafts was not achieved when a 7-day course of cyclosporine was administered alone (14.3+/-3.0 days) or with 10 microg of alpha1h u62-77-RT1.Aa (14.6+/-0.6 days; NS). CONCLUSIONS: These findings suggest that the use of allochimeric proteins may provide a novel approach to the induction of tolerance.

Animals↗
PubMed1997

Phase I safety and pharmacokinetic studies of brequinar sodium after single ascending oral doses in stable renal, hepatic, and cardiac allograft recipients.

Brequinar sodium (BQR), a substituted 4-quinoline carboxylic acid, was in clinical development in combination with cyclosporine (CsA) as a potentially effective therapy for the treatment and prophylaxis of rejection in organ transplant patients. This phase I study was performed in stable renal, hepatic, and cardiac transplant patients receiving CsA and prednisone maintenance therapy for immunosuppression. The pharmacokinetic objectives of this study were to characterize the pharmacokinetics of (a) single oral 0.5- to 4-mg/kg doses of BQR when given in combination with CsA and prednisone to stable renal, hepatic, and cardiac transplant patients and (b) steady-state oral doses of CsA, with and without single oral doses of BQR. In all three patient populations, the pharmacokinetics of BQR were characterized by a lower oral clearance (12-19 mL/min) than that seen in previous studies in patients with cancer (approximately 30 mL/min at similar doses) and a long terminal half life (13-18 hrs). This slower oral clearance for BQR could be due either to a drug interaction between BQR and CsA or to altered clearance or metabolic processes in patients with transplants. Steady-state CsA trough levels and the oral clearance of CsA were not affected by BQR coadministration. Among the three transplant populations, the cardiac transplant patients had lower oral clearance values of BQR and of CsA. The cause of this lower clearance is not known. Safety results indicate that BQR was well tolerated by this patient population.

Administration, Oral↗
PubMed1997

Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration.

In this 2-week, ascending dose study, the pharmacokinetic activity of sirolimus was examined in 40 stable renal transplant patients treated with cyclosporine and prednisone. Nine dose levels (range, 0.5-6.5 mg/m2/12 hr) of sirolimus were studied in a parallel design. Mean values for the pharmacokinetic parameters of sirolimus calculated in all dose groups were as follows: time to peak blood concentration, 1.4 +/- 1.2 hours; terminal half-life, 62 +/- 16 hours; oral dose clearance, 208 +/- 95 mL/h/kg; apparent oral steady-state volume of distribution, 12 +/- 5 L/kg; and blood/plasma ratio, 38 +/- 13. The intersubject variabilities in dose clearance, steady-state volume of distribution, and blood/plasma ratio were 4.5-fold. Preliminary assessments suggests linear dose proportionality. An excellent correlation existed between area under the concentration-time curve and trough blood concentration at steady state. Sirolimus did not produce any significant changes in area under the concentration-time curve of cyclosporine. Preliminary analysis suggested that values for the pharmacokinetic parameters of sirolimus vary among races (black versus nonblack) but not among genders.

Administration, Oral↗
PubMed1997

A pharmacokinetic comparison of the corn oil versus microemulsion gelcap formulation of cyclosporin used de novo after renal transplantation.

The initial poor absorption of the corn oil-based, gel capsule oral formulation of cyclosporin (CyA) greatly limits its use for inception of immunosuppressive therapy. Insufficient drug concentrations during the early post-transplant period predispose to renal allograft rejection. The present study served to compare the time required to achieve the therapeutic CyA concentrations after de novo administration of the corn oil-based gel capsule (CyA-GC; n = 11) versus the microemulsion (CyA-ME; n = 11) formulation of CyA. During the 1st month after renal transplantation, patients underwent serial pharmacokinetic profiling from which we obtained observed and dose-corrected values of several parameters. Although patients in neither the CyA-GC nor the CyA-ME group adequately absorbed the drug during days 0-2, from day 3 to 4 patients in the CyA-ME group showed significantly greater absorption than those in the CyA-GC group (P = 0.041). Patients in the CyA-ME group reached the 1st month target average concentration (Cav) values (> or = 550 ng/ml) earlier than those in the CyA-GC group and required significantly lower daily CyA doses (P = 0.018). We conclude that therapeutic CyA levels can be achieved more rapidly and with lower doses of the drug after de novo administration of CyA-ME than with CyA-GC.

Administration, Oral↗
PubMed1997

Distribution of sirolimus in rat tissue.

OBJECTIVES: To examine the distribution of sirolimus (SRL, rapamycin), an immunosuppressive macrolide antibiotic, in the tissues of adult male Wistar-Furth rats following continuous intravenous infusion (CIVI) and repeated daily peroral gavage (PO). DESIGN AND METHODS: Animals received 14-day courses of SRL by either CIVI (0.04-0.4 mg/kg/day) or PO (0.4-1.6 mg/kg/day) administration. Samples of whole blood and homogenates of five solid organs (heart, kidney, liver, lung and spleen), and portions of intestinal, muscle and testicular tissues were prepared on day 13 of CIVI treatment or 24 hours after administration of the 14th PO dose. SRL concentrations were determined by high performance liquid chromatography with reference to calibration curves produced from SRL-spiked whole blood or tissue homogenates prepared from drug-free animals. RESULTS: Following PO but not CIVI administration, SRL concentrations in whole blood and all tissues increased linearly in relation to dose. SRL was extensively distributed among most tissues tested (tissue partitions coefficients of > 40 were observed in some cases). Comparatively, SRL whole blood concentrations were low. The ratio between the SRL whole blood concentrations after PO versus after CIVI administration (at like doses of 0.4 mg/kg/day) was 0.04. Therefore, we inferred that the oral bioavailability of SRL was low. CONCLUSIONS: The linear relationships between PO dose and SRL concentrations in whole blood and tissues may be attributed to the low oral bioavailability of SRL, which is indicated by the low levels of SRL observed in whole blood and tissues after PO administration. The nonlinear relationships between CIVI dose and SRL concentrations in whole blood and tissues may result because although whole blood depots may be saturated with SRL, the tissues continue to absorb SRL as the dose of SRL increases. Thus, because a high percentage of SRL is widely distributed into tissues stores, caution must be used when administering this drug in humans.

Animals↗
PubMed1997

Radioreceptor assay for sirolimus in patients with decreased platelet counts.

OBJECTIVE: Sirolimus (RAPA) is a new immunosuppressive drug currently in Phase III clinical trials in combination with cyclosporine A (CsA). The toxicity profiles for CsA and RAPA are only partially overlapping, with RAPA toxicity consisting primarily of hyperlipidemia and myelodepression but without the nephrotoxicity, neurotoxicity, and hepatotoxicity, which are seen with CsA. Patients in the clinical trial are being monitored using HPLC or LC/MS/MS assays; there is no immunoassay for RAPA reported to date. We have previously reported a radioreceptor assay (RRA) for RAPA, which has an excellent correlation with the HPLC assay (r = 0.997). The RRA has several advantages including excellent precision, sensitivity, rapid turnaround time, and a one-step extraction procedure. We report the evaluation of blood samples from patients who were exhibiting RAPA toxicity and comparison of the RRA results with the HPLC results. METHODS: EDTA whole blood specimens (n = 42) were obtained from six renal transplant recipients taking RAPA and CsA and exhibiting decreased platelet counts. Thirty-two samples from patients without decreased platelet counts were also received. The samples were analyzed with the RRA and the results were compared to those obtained with the HPLC assay. RESULTS: By HPLC, the results ranged from 3.2-72.6 micrograms/L RAPA with 43% of the results > or = 30 micrograms/L. With the RRA, the range was 7.7-83.0 micrograms/L RAPA equivalents, with 60% of the results > or = 30 micrograms/L. The RRA results are distinctly higher than the HPLC results all along the range. The correlation between the two assays was 0.861, with a slope of 0.966 and a Y-intercept of 11.1. CONCLUSION: Since the RRA is consistently higher than HPLC concentration in patients with decreased platelet counts, but correlates well in patients with no signs of toxicity, the RRA may be useful for monitoring patients for toxicity, by giving a better indication of increasing degree of immunosuppression than the HPLC assay.

Chromatography, High Pressure Liquid↗
PubMed1997

Cytokine mRNA expression in tolerant heart allografts after immunosuppression with cyclosporine, sirolimus or brequinar.

We sought to examine the impact of the preferential activation of Th2 cells on the induction and maintenance of a tolerant state in heart allograft rat recipients treated with a short course of cyclosporine (CsA), sirolimus (SRL) or brequinar (BQR). A quantitative polymerase chain reaction (PCR) method was used to measure the levels of cytokine mRNAs, namely interferon (IFN)-gamma and interleukin (IL)-2 in T helper 1 (Th1) cells and IL-4, IL-5 and IL-10 in Th2 cells. Our main findings were that on day 5 postgrafting allografts from untreated recipients had increased levels of IFN-gamma (216 +/- 119 fg), IL-2 (449 +/- 75 fg), IL-4 (6.2 +/- 1.3 fg), IL-5 (34.8 +/- 9.3 fg) and IL-10 (1554 +/- 184 fg) mRNAs compared with normal hearts. CsA reduced the levels of IFN-gamma, IL-2, IL-5 and IL-10, but not IL-4, mRNAs. SRL did not affect the expression of cytokine mRNAs. BQR decreased the levels of IFN-gamma, IL-2 and IL-10, but not IL-5 or IL-4 mRNAs. Compared with grafts from untreated recipients, those from CsA- or BQR-treated tolerant hosts (day 100) displayed undetectable IL-2 mRNA levels, and reduced levels of IFN-gamma, IL-4 and IL-10 mRNAs. In fact, the patterns of cytokine mRNA expression in grafts from CsA- and BQR-treated tolerant hosts were similar to those of normal hearts. Grafts from SRL-treated tolerant hosts merely showed slightly increased Th2 cell activity. In conclusion the selective activation of Th2 cells is not absolutely required for induction or maintenance of tolerance.

Animals↗
PubMed1997

Synergistic mechanisms by which sirolimus and cyclosporin inhibit rat heart and kidney allograft rejection.

The studies presented herein examined the mechanism(s) whereby sirolimus (SRL) and cyclosporin (CsA) act synergistically to block allograft rejection. Combination index (CI = 1 reflects additive, CI > 1 antagonistic, and CI < 1 synergistic, effects) analysis documented potent synergism between SRL and CsA to block allograft rejection. Combinations of the two drugs produced synergistic prolongation of heart (CI = 0.001-0.2) or kidney (CI = 0.03-0.5) allograft survival at SRL/CsA ratios ranging from 1:12.5 to 1:200. Pharmacokinetic analysis of the individual drugs showed that CsA does not affect the blood levels of SRL, and SRL mildly increases the levels of CsA in SRL/CsA-treated rats. Quantitative polymerase chain reaction analysis was used to document that both subtherapeutic (1.0 mg/kg) and therapeutic (2.0 or 4.0 mg/kg) CsA doses inhibited the expression of interferon-gamma (IFN-gamma) (P < 0.03) and IL-2 (P < 0.003) mRNA produced by T helper (Th) 1 cells, as well as IL-10 (P < 0.001), but not IL-4 (NS) mRNA produced by Th2 cells. Contrariwise, all tested SRL doses (0.02, 0.04 or 0.08 mg/kg) did not affect cytokine mRNA expression. However, heart allografts from rat recipients treated with synergistic SRL/CsA doses displayed reduced levels of IFN-gamma (P < 0.01), IL-2 (P < 0.001) and IL-10 (P < 0.001) mRNA. Thus, because subtherapeutic doses of CsA reduce Th1/Th2 activity, thereby facilitating the inhibition of signal transduction by low does of SRL, the two agents act synergistically to inhibit allograft rejection.

Animals↗
PubMed1997

Sirolimus in transplantation.

Although sirolimus (SRL) alone was very effective in rodents and pigs, it produced toxic side effects in dogs. Low doses of SRL combined with cyclosporine/brequinar (CsA/BQR) combinations achieved potent immunosuppression in the CsA-resistant mouse model. Similarly, SRL/CsA/BQR therapy protected kidney allografts from rejection in dogs without producing toxic side effects. In the CsA-sensitive rat model SRL/CsA combinations produced a potent synergistic interaction. In addition, recent clinical trials document the beneficial effects of low SRL doses in human kidney transplant recipients. Sirolimus, when combined with standard immunosuppressive therapy, remarkably reduces the incidence of acute rejection and permits individual drug dose reduction.

Animals↗