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G C Yee

Publications and source records attributed to G C Yee.

At least 55 records · Page 3Linked to original sources
PubMed1986

Age-dependent cyclosporine: pharmacokinetics in marrow transplant recipients.

We evaluated the effect of age on cyclosporine pharmacokinetics in 69 nonobese patients aged 10 months to 56 years (median 22 years) undergoing allogeneic bone marrow transplantation for treatment of aplastic anemia or hematologic malignancy. Cyclosporine pharmacokinetics were studied during the first 2 posttransplant weeks after an intravenous dose of 2.6 to 3.5 mg/kg. Serum cyclosporine concentrations were measured by HPLC. Cyclosporine concentration-time data were fitted to a two-compartment model with a nonlinear regression program. There was a significant inverse linear correlation between age and both total systemic clearance (CL) (r = 0.42; P less than 0.001) and volume of distribution at steady-state (Vss) (r = 0.33; P less than 0.01). Mean (+/- SE) cyclosporine CL was 82 +/- 21, 45 +/- 5, 38 +/- 9, 44 +/- 8, and 20 +/- 3 ml/min/kg and mean cyclosporine Vss was 34 +/- 11, 28 +/- 10, 15 +/- 4, 14 +/- 5, and 4.7 +/- 0.7 L/kg in patients 0 to 10 (n = 12), 11 to 20 (n = 19), 21 to 30 (n = 12), 31 to 40 (n = 17), and greater than 40 (n = 9) years old, respectively. Patients 0 to 10 years old had a significantly higher cyclosporine CL than those 11 to 40 or greater than 40 years old and also had a significantly larger Vss than those greater than 40 yrs old (P less than 0.05). Age-related differences in CL or Vss were also observed when these parameters were normalized by body surface area.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Marrow graft rejection and veno-occlusive disease of the liver in patients with aplastic anemia conditioned with cyclophosphamide and cyclosporine.

Based on studies in multiply transfused dogs showing that cyclosporine (CsA) pregrafting reduced the incidence of rejection, we treated 11 multiply transfused patients with severe aplastic anemia with CsA, 12.5-20 mg/kg/day i.m. on days -6 to -1, and cyclophosphamide, 50 mg/kg/day i.v. on days -5 to -2, followed on day 0 by a marrow graft from an HLA-identical sibling donor. Patients were not given additional infusions of buffy coat cells from their marrow donors. As postgrafting prophylaxis for graft-versus-host disease 10 patients were given CsA, 12.5 mg/kg/day orally, and one patient was given a standard regimen of intermittent methotrexate. Among 10 evaluable patients, 2 rejected their marrow grafts. Eight patients had sustained engraftment. Two of these developed severe veno-occlusive disease of the liver, a complication previously observed only in patients conditioned with total-body irradiation but not in more than 200 patients with aplastic anemia conditioned with cyclophosphamide without the addition of CsA. These data indicate that conditioning of patients with cyclophosphamide and concurrent CsA does not uniformly prevent graft rejection and can result in severe hepatic toxicity.

Adolescent↗
PubMed1986

Cyclosporine monitoring.

Cyclosporine is an important immunosuppressive agent in organ and bone marrow transplantation. The pharmacokinetics of cyclosporine are quite complex and are complicated by the availability of two assay systems that yield differing results. This article summarizes the views from two major solid organ transplant centers and one bone marrow transplant center on important cyclosporine monitoring questions. A general consensus exists in the four areas discussed that: cyclosporine concentrations must be monitored due in part to the extreme variability in kinetics, either blood or plasma can be used in monitoring programs, the radioimmunoassay or high pressure liquid chromatography can be used in routine monitoring, and the interpretation of cyclosporine concentrations must be performed in relation to patient variables that affect drug response and toxicity.

Cyclosporins↗
PubMed1985

Correlation of serum cyclosporine concentration with renal dysfunction in marrow transplant recipients.

We retrospectively analyzed the relationship of serum cyclosporine concentration to renal dysfunction in 63 marrow transplant recipients who received cyclosporine for prophylaxis of acute graft-versus-host disease. Patients were divided into three groups according to their mean trough cyclosporine concentration for the first 28 days of therapy: less than 150, 150-250, and greater than 250 ng/ml. Baseline renal function and exposure to nephrotoxic antibiotics was comparable in the three groups. Renal dysfunction was defined as doubling of baseline serum creatinine. The likelihood of developing renal dysfunction was analyzed with Kaplan-Meier product limit estimates. The log-rank test was used to compare the three groups. Fifty-four (86%) of the patients developed renal dysfunction. The incidence of renal dysfunction was 73%, 95%, and 100%, and it developed at a median of 46, 29, and 20 days in patients with a mean trough concentration of less than 150, 150-250, and greater than 250 ng/ml, respectively (P less than 0.001). Eight of the nine patients who did not develop renal dysfunction had a mean trough concentration of less than 150 ng/ml. These data indicate that the incidence and the rate of development of renal dysfunction are related to serum cyclosporine concentration.

Adolescent↗
PubMed1984

Pharmacokinetics of intravenous cyclosporine in bone marrow transplant patients. Comparison of two assay methods.

The influence of assay method on steady-state cyclosporine (CsA) pharmacokinetics was studied in 18 patients with leukemia or aplastic anemia undergoing allogeneic marrow transplantation who received i.v. CsA for prophylaxis or treatment of graft-versus-host disease. Since CsA is extensively metabolized and subject to biliary elimination, CsA courses were divided according to the presence (serum bilirubin greater than 2.0 mg/dl) or absence (serum bilirubin less than or equal to 1.2 mg/dl) of hepatic dysfunction. All patients had normal renal function. Serum CsA concentrations were measured concurrently by radioimmunoassay (RIA) and high-performance liquid chromatography (HPLC). Serum concentration-time data were analyzed by standard nonlinear regression methods. Systemic clearance (Cls) calculated from HPLC results was higher than that derived from RIA results, regardless of hepatic function (P less than 0.05). These data indicate that results obtained by RIA overestimate CSP concentrations, presumably because of the presence of crossreactive CSP metabolites. These differences can significantly affect derived pharmacokinetic parameters. Therefore, clinicians who make dosage recommendations based on pharmacokinetic parameters should consider the effect of assay method.

Anemia, Aplastic↗
PubMed1984

Effect of hepatic dysfunction on oral cyclosporin pharmacokinetics in marrow transplant patients.

The effect of hepatic dysfunction, defined as abnormal serum bilirubin level, on oral cyclosporin (CSP) pharmacokinetics was examined in 28 marrow transplant patients who received CSP for prophylaxis of graft-v-host disease. Serum CSP concentrations were measured by radioimmunoassay. Forty-one concentration-time courses were studied, divided among patients with no (less than 1.2 mg/dL), mild (1.2 to 2.0 mg/dL), and moderate (2.0 to 5.0 mg/dL) hepatic dysfunction. CSP elimination, as determined by elimination rate constant and clearance, was delayed in patients with moderate hepatic dysfunction compared to those with no hepatic dysfunction (P less than .05). The volume of distribution, lag time for absorption, maximum serum concentration, and time at which the maximum concentration was achieved was not affected by hepatic function. These data indicate that patients with moderate hepatic dysfunction have delayed CSP or CSP metabolite elimination and may be at higher risk for developing CSP-related toxicity.

Administration, Oral↗
PubMed1983

Bleomycin disposition in children with cancer.

Bleomycin kinetics were determined in 14 children after intravenous bolus and prolonged infusion doses. Plasma and urine bleomycin concentrations were determined by radioimmunoassay. After intravenous bolus, bleomycin concentrations were adequately described by a two-compartment open model with a mean t1/2 alpha and t1/2 beta of 0.3 +/- 0.1 and 3.2 +/- 0.7 hr (mean +/- SEM). Volume of the central compartment and volume of distribution at steady-state (Vss) were 4.3 +/- 0.5 and 9.9 +/- 1.1 l/m2. Total plasma (CLT) and renal (CLR) clearance were 51.8 +/- 6.1 and 33.5 +/- 2.4 ml/min/m2. Three intravenous bolus courses were given to two patients who received more than four courses of cisplatin (greater than 300 mg/m2); CLT and CLR for these courses were 18.0 +/- 3.3 and 8.2 ml/min/m2. Conversely, children under 3 yr old eliminated bleomycin more rapidly than older children. Decline in bleomycin concentrations after seven 24- or 48-hr intravenous infusions was described by a one-compartment model. Mean values for plasma t1/2, Vss, CLT, and CLR were 2.1 +/- 0.1 hr, 11.0 +/- 2.6 l/m2, 57.1 +/- 13.5 ml/min/m2, and 33.2 +/- 6.4 ml/min/m2. One patient received his bleomycin infusion when ureteral obstruction was present; CLT and CLR for this course were 4.8 and 4.1 ml/min/m2. These data indicate that young children eliminate bleomycin more rapidly than older children and that children with impaired renal function may have prolonged elevations in plasma concentration due to reduced bleomycin clearance. Bleomycin disposition in older children is as in adults.

Adolescent↗
PubMed1983

Cisplatin-induced changes in bleomycin elimination.

Bleomycin disposition was studied in two children who received at least six courses of vinblastine, bleomycin, and cisplatin. Total plasma clearance of bleomycin decreased from 39 to 18 ml/min/m2, while the terminal-phase half-life increased from 4.4 to 6.0 hrs since the cumulative cisplatin dose was greater than 300 mg/m2. In one patient, renal clearance of bleomycin decreased from 30 to 8.2 ml/min/m2. Changes in serum creatinine or BUN were not predictive of changes in bleomycin elimination.

Adolescent↗
PubMed1982

Clinical pharmacology of bleomycin and cisplatin.

Bleomycin (Blenoxane) and cisplatin (Platinol) are two anticancer drugs, with activity for head and neck tumors, that were introduced into clinical use in the past ten years. Bleomycin is used primarily in the chemotherapy of squamous cell carcinomas, lymphomas, and testicular carcinoma, while cisplatin possesses significant activity against testicular and ovarian carcinoma, head and neck cancer, bladder cancer, and neuroblastoma. Bleomycin is rapidly excreted renally (terminal phase half-life = 2-4 h), although enzymatic inactivation also occurs in many tissues. Cisplatin is nonenzymatically converted to highly protein bound metabolites, which then undergo renal elimination, but total body clearance occurs much more slowly than with bleomycin (terminal phase half-life = 40-50 h). Both agents have acute and chronic toxicities; the acute toxicities are generally reversible but cause a great deal of patient discomfort, while the chronic toxicities are often irreversible and dose-limiting. For bleomycin, the acute toxicities are mucocutaneous are pyretic; severe nausea and vomiting represents the major acute toxicity of cisplatin therapy. Cumulative dose-related pulmonary toxicity is the most serious chronic toxicity of bleomycin. The clinical, radiographic, and pathologic presentations are nonspecific, although identification of high risk patients may be possible with serial pulmonary function tests. Cumulative nephrotoxicity occurs with cisplatin use, and its incidence and severity can be reduced by maintaining adequate hydration and diuresis during and following administration of the drug.

Bleomycin↗
PubMed1982

Disposition of intermediate-dose methotrexate in children with acute lymphocytic leukemia.

Intermediate-dose methotrexate (MTX 200 mg/m2 iv in a bolus dose, followed by 800 mg/m2 iv, infused over 24 hours) is being used as a component of therapy for children with acute lymphocytic leukemia. To define the extent of interpatient variability in MTX disposition, with this dosage and schedule, the systemic clearance of MTX was measured in 69 children (total doses, 717; median, 10 doses per patient). The mean (+/- SD) systemic clearance was 91.6 (+/- 25.2) ml/min/m2 and ranged from 50-161 ml/min/m2. Renal clearance was measured in 16 of these patients and averaged 50.7 (+/- 14) ml/min/m2 during the MTX infusion (0-24 h), at which time mean systemic clearance was 8.7 (+/- 19) and nonrenal clearance was 31.1 (+/- 11.8) ml/min/m2. Measurement of 7-hydroxy-methotrexate in serum and urine was consistent with the substantial amount of nonrenal (metabolic) clearance observed in these patients. Cerebrospinal fluid MTX concentrations, measured at 24 hours, were 0.26 (+/- 0.1) microM when only the intravenous MTX was given and 1.08 (+/- 0.8) microM when an intrathecal dose (12 mg/m2) was also given at the start of the 24-hour infusion. This study establishes that there is substantial interpatient variability in MTX disposition in children and suggests a possible cause of variable patient response to MTX.

Adolescent↗
PubMed1982

Liquid-chromatographic determination of cyclosporine in serum with use of a rapid extraction procedure.

In this procedure, reversed-phase liquid chromatography is used to measure cyclosporine, a fungal metabolite with immunosuppressive activity, in human serum. With a gradient elution, the retention times for cyclosporine and cyclosporin D were 14.1 and 15.7 min, respectively. Ultraviolet absorbance at 215 nm was used to detect cyclosporine; this wavelength improved assay accuracy without decreasing sensitivity, as compared with detection at 205 nm, which is near the absorption maximum. The major advantage of our procedure is the clean-up method, which involves use of disposable extraction columns. This extraction is simple and requires only 10 to 15 min per sample. Results by radioimmunoassay for cyclosporine were unpredictably greater than those measured by the present method. Dosing guidelines for cyclosporine need re-evaluation, based on more specific assay methods.

Chromatography, High Pressure Liquid↗
PubMed1981

Cisplatin disposition in children and adolescents with cancer.

The disposition of cisplatin was evaluated in 28 children and adolescents with cancer, as part of a phase II clinical trial. Patients received either 30 mg/m2 (11) or 90 mg/m2 (17) of cisplatin as a 6-h IV infusion. Serum samples and divided urine collections were obtained over 48 h following completion of the cisplatin infusion, and were assayed in duplicate for total platinum by atomic absorption spectrophotometry. Serum samples obtained up to 4 h after three cisplatin infusions were assayed for parent (free) cisplatin following ultrafiltration. The mean (+/- SE) elimination half-life of free cisplatin in serum was 1.3 (+/- 0.4) h. Serial serum concentrations of total platinum following 90 mg/m2 dosages were adequately described by a biexponential equation. The mean (+/- SE) serum T 1/2 alpha of total platinum was 0.42 (+/- 0.10) h and the mean (+/- SE) T 1/2 beta was 44.43 (+/- 8.24) h. The intercompartment distribution rate constants of a two-compartment kinetic model indicate extensive tissue accumulation of total platinum, with a rate of transport into tissue compartments (K12) that is about six times the rate of transport out of tissues (K21). The mean (+/- SE) renal clearance of total platinum from 0-3 h was 37.36 (+/- 11.96) ml/min/m2 and 35.8 (+/- 13.6) ml/min/m2 for the 30 mg/m2 and 90 mg/m2 groups, respectively. This value decreased to 3.25 (+/- 0.94) and 2.16 (+/- 0.4) ml/min/m2 for the two groups by the 6-12 h interval, and remained between 1 and 3 ml/min/m2 for the duration of the observation period. The ratio of total platinum clearance to creatinine clearance decreased significantly (P less than 0.05) beginning 3 h post-infusion. The change in renal clearance of total platinum is apparently a function of two independent first-order processes for renal clearance of parent drug and cisplatin metabolites.

Adolescent↗
PubMed1980

Phase I clinical and pharmacokinetic study of 4'-(9-acridinylamino)-methanesulfon-m-anisidide in children with cancer.

Forty-one pediatric patients with advanced cancer (24 with acute leukemia and 17 with diverse solid tumors) received 74 courses of therapy with a new chemotherapeutic agent, 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA: NSC 249992). Treatments were given by slow i.v. injection daily for five days every two to three weeks. In patients with leukemia: (a) dosages were escalated from 1.3 to 150 mg/sq m/day; (b) toxicity in the form of stomatitis, vomiting, and phlebitis occurred at dosage levels of 125 to 150 mg/sq m/day; and (c) oncolytic effects were observed in 13 of 24 patients. In patients with solid tumors: (a) dosages were escalated from 5 to 50 mg/sq m/day; (b) toxicity (stomatitis, myelosuppression, and phlebitis) occurred at the dosage level of 50 mg/sq m/day; and (c) no oncolytic responses were noted. Serum concentrations of total and free AMSA were assayed by a fluorescence technique and declined in a biphasic manner with free AMSA declining more rapidly than total AMSA. Dosages of greater than 100 mg/sq m/day were required to maintain serum concentrations of total and free AMSA greater than 0.2 microM for the entire five-day schedule. The results suggest that maximum tolerated dosages of AMSA may differ in children with leukemia and solid tumors; however, hematopoietic toxicity could not be fully evaluated in the patients with leukemia. AMSA has clear antileukemic activity that warrants future Phase II trials.

Adolescent↗