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Biomedical subjects

G C Yee

Publications and source records attributed to G C Yee.

65 records · Page 4Linked to original sources
PubMedDate not supplied

Clinical pharmacology of bleomycin and cisplatin.

Bleomycin (Blenoxane) and cisplatin (Platinol) are two anticancer drugs with activity for head and neck tumors. 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 is effective against testicular and ovarian carcinoma, head and neck cancer, bladder cancer, and neuroblastoma. Bleomycin is rapidly excreted renally (T 1/2 beta = 2-4 hr) 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 (T 1/2 beta = 40-50 hr). 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 and pyretic, while severe nausea and vomiting represent the major acute toxicities 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.

Aged↗
PubMedDate not supplied

Renal cyclosporine clearance in marrow transplant recipients: age-related variation.

Cyclosporine is extensively metabolized in the liver and is subject to biliary elimination. Although only a small amount of the drug is eliminated unchanged in the urine, urine concentrations of the drug are much higher than blood or serum concentrations known to be associated with renal toxicity. Renal clearance (CL) of cyclosporine may be a sensitive correlate of nephrotoxicity, but renal CL studies of cyclosporine have not been reported in transplant patients. Therefore, we studied the renal CL of cyclosporine in 21 patients (median age, 27 yr) with hematologic malignancies undergoing allogeneic bone marrow transplantation. All patients received cyclosporine for prophylaxis or treatment of acute graft vs host disease. At the time of the study, all patients had normal renal function, as determined by serum creatinine concentration. Urine and serum cyclosporine concentrations were measured by high-performance liquid chromatography. Renal cyclosporine CL in different patients ranged from 1.8 to 79.8 mL/min. However, serial renal CL studies performed one week apart in two patients showed minimal intrapatient variability. Patients 25 years old or younger had a higher mean renal cyclosporine CL (39.7 mL/min) than older patients (17.9 mL/min) (P less than .05). These data show that renal cyclosporine CL is related to age and that renal CL in marrow transplant recipients is higher than the reported mean value in non-marrow-transplant patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMedDate not supplied

Reappraisal of guidelines for pharmacokinetic monitoring of aminoglycosides.

The rationale for pharmacokinetic monitoring of aminoglycosides is critically reviewed. Retrospective studies suggest that for optimal antibacterial effect, peak serum gentamicin concentrations should exceed 5 micrograms/ml, despite the fact that these concentrations are indirect measures of the concentration of drug at the site of infection. When quantitative results of antimicrobial susceptibility are known (e.g. MIC or MBC), limited data suggest that for most infections, the peak serum aminoglycoside concentration should exceed the minimum inhibitory concentration by four-fold. However, the optimal duration for which the serum concentration should exceed the MIC or MBC during each dosing interval and the detrimental effect of prolonged subinhibitory drug concentrations have not been evaluated. Furthermore, the immunological competence of the host and the pathogenicity of the infecting organism are important factors in achieving antibacterial response. Using serum creatinine as an indirect and relatively late indicator of nephrotoxicity, nadir gentamicin concentrations greater than 2 micrograms/ml may predispose patients to develop nephrotoxicity. In addition, recent information indicates that patients who accumulate excessive amounts of aminoglycosides in their tissues may be at higher risk for developing nephrotoxicity; these patients may be identified based on the extent of accumulation in their nadir concentrations with continuous dosing. The aminoglycosides diffuse into the inner ear fluids slowly and diffuse out with a half-life of decline in inner ear fluid concentrations slower than that in serum. High transient peak serum concentrations probably do not contribute significantly to the risk of ototoxicity. However, there is evidence from early clinical trials, studies using continuous infusions of aminoglycosides, and animal studies indicating that elevated nadir serum concentrations relate to the development of ototoxicity. There is considerable interpatient variability in the peak serum concentration, even when identical dosages based on body weight or surface area are administered. Similarly, the half-life for decline in serum concentrations is highly variable from patient to patient, even in patients with stable normal renal function. Absorption after intramuscular administration is reliable in most patients, although critically ill patients may experience erratic absorption. The distribution of aminoglycosides is altered in obese patients because of differences in extracellular fluid content between fat and other tissues.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMedDate not supplied

A model for dosing gentamicin in children and adolescents that adjusts for tissue accumulation with continuous dosing.

The pharmacokinetics of gentamicin were evaluated in 50 children and adolescents during a multiple dose course of therapy. Parameters of a 2-compartment pharmacokinetic model were derived from serial serum concentrations and urinary excretion rates measured for up to 11 days following the last dose of gentamicin administered to 10 of these patients. These parameters were used to simulate changes in serum concentrations and half-lives that would occur during a standard 6-hour dosing interval with continuous dosing. The data indicated that the half-life for decline in serum concentrations after the first dose was 76 +/- 8% of the half-life at steady-state, and that the half-life after the fourth dose exceeded 90% of the steady-state half-life. These underestimations of the steady-state serum half-life were incorporated into a 1-compartment model to simulate steady-state peak and nadir serum concentrations by using pharmacokinetic parameters measured after the first dose of gentamicin administered to 40 patients. Steady-state serum concentrations predicted by the true 1-compartment model and by the adjusted model were compared with concentrations measured at steady-state. The concentrations predicted by the former model were significantly different from and consistently less than measured concentrations. Concentrations predicted by the adjusted model were not significantly different from concentrations measured at steady-state. These data indicate that the new model offers a simple and more accurate method of simulating steady-state concentrations from pharmacokinetil for individualising therapy.

Adolescent↗
PubMedDate not supplied

Isolation and identification of a novel human metabolite of cyclosporin A: dihydro-CsA M17.

A novel metabolite of cyclosporin A was observed in human blood and urine. An analytical sample of this metabolite was isolated from human urine and the structure was determined to be (8-hydroxy-6,7-dihydro-MeBMT1) cyclosporin based on the 1H-NMR, 13C-NMR, FAB-MS, and HPLC characteristics of the biological sample as well as by comparison with a synthetically derived authentic sample. The significance of this metabolite in terms of the pathway by which cyclosporin A is metabolized is discussed.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Allogeneic bone marrow transplantation in the treatment of hematologic diseases.

The current use of allogeneic bone marrow transplantation in various hematologic diseases is reviewed. Bone marrow transplantation (BMT) involves infusion of bone marrow from a suitable donor into a properly conditioned recipient. Most BMT is allogeneic, in which the donor is genetically dissimilar but shares some common tissue antigens with the recipient. Almost all patients undergoing allogeneic BMT must be "prepared" with high-dose cyclophosphamide to prevent graft rejection. Most patients with hematologic malignancy also receive total body irradiation to eradicate malignant cells located in areas inaccessible to the systemic circulation. Bone marrow transplantation is the treatment of choice for severe aplastic anemia. In acute myelogenous leukemia, the best results are observed in young patients undergoing BMT in first remission. In acute lymphoblastic leukemia, BMT is usually reserved for patients in second or subsequent remission. Early results are promising in patients with chronic myelogenous leukemia who receive BMT before the accelerated phase or blast crisis of this disease. Allogeneic BMT offers an opportunity for cure in some patients with relapses of Hodgkin's disease or those with certain subtypes of non-Hodgkin's lymphoma. Other diseases for which BMT has been used include severe combined immune deficiency disease, Fanconi's anemia, and multiple myeloma. Complications of BMT include graft failure or rejection, acute and chronic graft-versus-host disease, and infectious complications; late complications, such as restrictive and obstructive pulmonary disease, cataracts, sterility, and secondary malignancies, may also occur. Bone marrow transplantation has become an important treatment for many hematologic diseases, but it will probably remain a treatment reserved for only a few highly specialized centers. If morbidity and mortality caused by transplant-related complications can be reduced, BMT may be offered to older patients and those without HLA-identical sibling donors.

Acute Disease↗
PubMedDate not supplied

The future of cell therapy.

Peripheral blood has replaced bone marrow as a source of hematopoietic stem cells for autologous rescue after high-dose chemotherapy. Patients who receive peripheral blood stem cell (PBSC) transplants experience rapid and sustained hematopoietic reconstitution. As a result, transplant-related mortality is now less than 5% at many centers, and the cost of high-dose chemotherapy has decreased considerably. However, the relapse rate continues to be unacceptably high, and the collection of hematopoietic stem cells from peripheral blood is inconvenient, time consuming, and expensive. This article discusses the current status of novel technologies such as positive selection of hematopoietic stem cells, ex vivo expansion of hematopoietic progenitor cells, allogeneic PBSC transplants, and umbilical cord blood transplants. Several companies are actively developing devices that positively select hematopoietic stem cells. Because positive selection reduces the volume of infused cells, patients experience fewer adverse effects related to dimethylsulfoxide (DMSO) or lysed cells. These devices may also serve as an ex vivo method to remove ("purge") residual tumor cells. Positively selected hematopoietic stem cells may be expanded ex vivo to produce a large number of a specific population of hematopoietic cells. By adding cytokines that stimulate and activate lymphocytes, natural killer cells, and other immune effector cells, investigators could expand the number of immune effector cells with antitumor activity and then infuse them into patients as a form of adoptive immunotherapy. Finally, peripheral blood and umbilical cord blood are promising new sources of hematopoietic stem cells for allogeneic transplants.

Antigens, CD↗
PubMedDate not supplied

Peripheral blood progenitor cell transplantation: economic issues.

High-dose chemotherapy with autologous hematopoietic stem cell rescue is an expensive procedure. It is associated with improved long-term survival in many patients with cancer, but concern is growing about its cost and cost-effectiveness. The cost-effectiveness of high-dose chemotherapy depends largely on the magnitude of the difference in survival between it and standard-dose chemotherapy. Several economic analyses reported that the cost-effectiveness ratio of high-dose chemotherapy in the treatment of breast cancer is in the range of or slightly higher than that reported for other widely accepted medical interventions. Most centers are evaluating new strategies to reduce the overall cost of this therapy, including using peripheral blood progenitor cells rather than bone marrow-derived stem cells, optimizing the collection of peripheral blood progenitor cells, and shifting care from the inpatient to the outpatient setting.

Ambulatory Care↗