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G L Chan

Publications and source records attributed to G L Chan.

At least 19 recordsLinked to original sources
PubMed1992

Routine determination of [18F]-L-6-fluorodopa and its metabolites in blood plasma is essential for accurate positron emission tomography studies.

A batch-contact alumina-extraction method has been used to separate [18F]-L-6-fluorodopa (FD) from its principal metabolite, 3-O-methyl-[18F]-6-fluorodopa (3-OMe-FD), in arterial blood plasma samples collected from subjects pretreated with carbidopa during positron emission tomography (PET) scans. The time course of the metabolite-corrected blood plasma activity is then used as an input function for kinetic analysis of striatal FD uptake. Results obtained from using the batch-contact alumina-extraction method were compared with those from high performance liquid chromatography, and also with those from a chromatographic alumina cartridge technique developed in this laboratory. In 60 human subjects including normal healthy volunteers and patients diagnosed as having a movement disorder, arterial blood plasma samples were collected after FD injection during a two-hour PET scan and analyzed by the batch-contact alumina-extraction method. The activity ratio (metabolites/FD) increased linearly with time for all subjects. However, there was a wide variation in the slope of the plot of the activity ratio (metabolites/FD) versus time among the subjects. No significant linear or curved relationship was observed between the slope and the age of the subject. Separation of FD from its metabolites is therefore necessary for each PET-FD study conducted.

Adsorption↗
PubMed1992

Plasma L-[18F]6-fluorodopa input function: a simplified method.

This article describes a simplified method for the determination of the L-[18F]6-fluorodopa (FDOPA) fraction time course that takes advantage of the strong correlation between the radioactivity ratio (metabolites/FDOPA) and time. Serial arterial blood samples are collected for assay of plasma total radioactivities following an intravenous injection of FDOPA into carbidopapretreated subjects. In addition, a single plasma sample, collected late in the study and analyzed for FDOPA fraction, is sufficient to determine accurately the time course of the FDOPA concentration in plasma. The validated straight-line method greatly simplifies blood analysis for routine positron emission tomography FDOPA studies.

Dihydroxyphenylalanine↗
PubMed1992

Relative performance of specific and nonspecific fluorescence polarization immunoassay for cyclosporine in transplant patients.

The analytical performance of specific and nonspecific fluorescence polarization immunoassays (FPIAs, Abbott Laboratories) for cyclosporine was compared. Both specific and nonspecific FPIAs demonstrated excellent between-run coefficients of variation (5.9% vs. 3.9%) at three levels of control, and a high degree of between-center reproducibility (r2 greater than 0.96). In addition, the correlation between cyclosporine levels measured by specific and nonspecific FPIAs was statistically significant, though imperfect, in both renal (r2 = 0.70) and cardiac transplant patients (r2 = 0.55). In kidney transplant patients, the nonspecific/specific ratio was significantly higher in patients with serum bilirubin concentration exceeding 3 mg/dl (5.9 +/- 2.6 vs. 2.8 +/- 1.1), due to impaired elimination of cyclosporine metabolites in the bile. The nonspecific/specific ratio was also significantly higher in heart transplant patients early (less than 1 month) posttransplant compared with patients in the late posttransplant period (3.4 +/- 0.8 vs. 2.9 +/- 0.8). The Abbott FPIA provides a highly precise method for measuring cyclosporine, with a turnaround time of 15-20 min. The specific monoclonal FPIA has the additional advantage of measuring primarily unchanged cyclosporine and thus has an imperfect correlation with the nonspecific polyclonal FPIA. Together with clinical data, the use of FPIAs may help to improve the efficiency of cyclosporine therapeutic drug monitoring.

Adolescent↗
PubMed1990

Azathioprine metabolism: pharmacokinetics of 6-mercaptopurine, 6-thiouric acid and 6-thioguanine nucleotides in renal transplant patients.

Despite extensive clinical experience with azathioprine (AZA), the disposition of various AZA metabolites remains obscure. We therefore evaluated the pharmacokinetics of three AZA metabolites: 6-mercaptopurine (6-MP), the immediate metabolite; 6-thiouric acid (6-TU), the final end product; and 6-thioguanine nucleotides (TGN), the active moiety; in eight renal transplant patients after oral administration of AZA. The low peak plasma 6-MP level of 73.7 +/- 23.7 ng/mL (mean +/- SD) and the short half-life (t1/2) of 1.9 +/- 0.6 hours suggest rapid conversion of 6-MP to other metabolites. A peak plasma 6-TU concentration of 1210 +/- 785 ng/mL was observed at 3.5 +/- 0.6 hours after the AZA dose. The strong correlation between 6-TU t1/2 and serum creatinine (r = 0.98, P = .0008) supported our previous work showing that 6-TU is primarily excreted by the kidneys. The total TGN levels in red blood cells (RBCs) in each patient remained largely unchanged over 24 hours with the intraindividual coefficient of variation ranging from 4.4% to 29.8%. In comparison, the mean TGN level varied considerably between patients, and ranged from undetectable to 413 pmol per 8 X 10(8) RBCs. However, there was no apparent correlation between white cell counts on day 0 (P greater than .5), day 7 (P greater than .5), or day 14 (P greater than .5) and RBC TGN level. The persistence of TGN in body tissues thus provides a pharmacokinetic rationale for the conventional once or twice daily AZA regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1990

Principles of immunosuppression.

One-year graft survival rates of 80% to 90% can now be achieved routinely for primary cadaveric transplants with a variety of CSA-containing regimens. Further improvement of these excellent results may be difficult because large numbers of patients must be evaluated to provide meaningful conclusions. On the other hand, long-term follow-up of CSA-treated patients has revealed a trend of undaunted allograft attrition with time. Future efforts therefore should be directed at improving long-term allograft results at 5 to 10 years. Further improvement of transplant outcome may be sought through better use of the currently available immunosuppressants or from newer agents. The long-term impact of CSA administration requires further evaluation. Although potent combination protocols provide effective protection against rejection, the potential development of neoplasms must be studied in long-term follow-up. On the other hand, unwarranted fear of progressive nephrotoxicity may result in underdosing of CSA and a high incidence of late rejections. The advent of mAbs has spawned an exciting era of specific immunosuppression. These newer agents may eventually help curtail the complications associated with the current regimens.

Drug Interactions↗
PubMed1990

The pharmacoeconomics of renal transplantation: increased drug costs with decreased hospitalization costs.

We evaluated the economic and clinical effects of two immunosuppressive drug regimens used to treat recipients of human leukocyte antigen (HLA)-identical sibling donor renal transplants during the first posttransplant year. We compared consecutive patients in two groups of 30 who were given either antilymphoblast globulin (ALG), azathioprine, plus prednisone or cyclosporine, azathioprine, and prednisone for immunosuppression. We standardized all dollar values, costs and charges, to the 1986 level using our hospital's health care charge inflation rate. There were no significant differences between the two treatment groups for actual patient (100% vs 93%; p = 0.51) and graft survival rates (100% vs 93%; p = 0.51), average serum creatinine level (1.0 +/- 0.3 vs 1.0 +/- 0.2 mg%; p = 0.46), and most recent creatinine level (1.4 +/- 0.3 vs 1.4 +/- 0.7 mg%; p = 0.45). The average cyclosporine-azathioprine-prednisone costs were $3987/patient more for the first year of therapy than for ALG-azathioprine-prednisone. However, the former regimen produced an average of $9543/patient less in total hospitalization charges. This was due to both a shorter initial hospital stay and a decreased rate of rehospitalization, with a lower frequency of acute rejection episodes (p = 0.001) and infectious complications (p = 0.05). We conclude that, although this cyclosporine-containing protocol was associated with increased drug costs, it is justified by decreased hospitalization charges that resulted from improved efficacy and safety.

Azathioprine↗
PubMed1989

In vitro protein binding of propafenone in normal and uraemic human sera.

The protein binding of propafenone, a Class I antiarrhythmic agent, was studied in vitro using a selective and sensitive electron-capture detection gas-liquid capillary chromatographic assay method developed in our laboratory. The concentration-dependency of the serum protein binding of propafenone was confirmed in vitro by equilibrium dialysis, using serum obtained from healthy human subjects and patients with chronic renal failure. In normal serum the unbound fraction of propafenone was 0.027 at a propafenone concentration of 0.25 microgram.ml-1, 0.041 within the therapeutic concentration range (0.5-2 micrograms.ml-1), 0.138 at a propafenone concentration of 25 micrograms.ml-1, and 0.187 when the propafenone concentration was increased to 100 micrograms.ml-1. There was no evidence of significant concentration-dependent changes in unbound fraction within the propafenone concentration range of 0.5-1.5 micrograms.ml-1. However, concentration-dependent binding was demonstrated at concentrations greater than 1.5 micrograms.ml-1. A high-affinity, low-capacity binding site (K1 = 6.53 x 10(5) l.mol-1; n1P1 = 1.73 x 10(-4) mol.l-1) and a low-affinity, high-capacity binding site (K2 = 8.77 x 10(3) l.mol-1; n2P2 = 8.57 x 10(-3) mol. x l-1) were identified. In pooled uraemic serum the unbound fraction of propafenone was approximately 50% of that of normal serum throughout the concentration range studied (1-5 micrograms.ml-1). In sera from patients with chronic renal failure the increase in propafenone binding ratio or the decrease in unbound fraction was associated with the increase in alpha 1-acid glycoprotein concentrations, and there was a correlation (r = 0.8302) between alpha 1-acid glycoprotein concentration and the propafenone binding ratio.

Adult↗
PubMed1989

Pharmacokinetics of 6-thiouric acid and 6-mercaptopurine in renal allograft recipients after oral administration of azathioprine.

The immunosuppressive activity of azathioprine (AZA) is unpredictable and depends on the formation of intracellular thiopurine ribonucleotides. However, the quantification of these active thiopurines presents difficult analytical problems. It has recently been postulated that plasma concentrations of 6-thiouric acid (6-TU) and 6-mercapto-purine (6-MP), metabolites of AZA, may provide more readily measurable indices of the pharmacologic activity of AZA. In order to evaluate the utility of 6-TU and 6-MP plasma concentrations in monitoring AZA therapy, we studied their pharmacokinetics in 6 renal transplant patients, and their in vitro immunosuppressive potency in a mixed lymphocyte proliferation assay. A peak plasma 6-TU concentration of 710.7 ng/ml was observed at 3.8 h after oral dosing. Good correlation was observed between the elimination t1/2 of 6-TU and serum creatinine, and between AUC over 24 h and serum creatinine. However, we did not observe a second peak in plasma 6-TU concentration that could be attributed to the degradation of active AZA metabolites. 6-MP plasma concentrations in the patients were low (mean peak concentration 36.0 ng/ml) and rapidly disappeared within 8 h. In vitro immunosuppressive activity could not be demonstrated for 6-TU over a concentration range of 1.25 ng/ml to 0.25 mg/ml. We conclude that 6-TU is pharmacologically inert and is primarily eliminated by the kidneys. Our findings currently do not support the use of plasma concentrations of 6-TU or 6-MP to monitor AZA therapy. In order to optimize AZA therapy, analytical techniques that are technically feasible and that can directly quantify the active intracellular thiopurines are being explored.

Adult↗
PubMed1989

Alternative dosing strategy for aminoglycosides: impact on efficacy, nephrotoxicity, and ototoxicity.

Accumulating evidence suggests that the therapeutic margin of aminoglycoside therapy may be improved by manipulation of dosing strategy. Recent understanding of concentration-dependent bactericidal activity and postantibiotic effect argues that the aminoglycosides may be administered in larger doses and at longer dosing intervals than currently recommended without compromising efficacy. Preliminary clinical experience suggests that once-daily regimens are as efficacious as conventional intermittent injections in the treatment of gram-negative infectious including urinary tract infections, cystic fibrosis, and bacteremia in nonneutropenic patients. The transient, high peak serum concentrations achieved in once-daily dosing have not been associated with excessive nephrotoxicity or ototoxicity thus far. Decreased accumulation in renal cortex as a result of saturable renal uptake after the single daily dose may even reduce the incidence or severity of renal damage. Further studies on more patients are required to substantiate these preliminary findings.

Aminoglycosides↗
PubMed1988

Multiple abnormalities in the ultraviolet light response of cultured fibroblasts derived from patients with the basal cell nevus syndrome.

Basal Cell Nevus Syndrome (BCNS) is a rare autosomal-dominant inherited disorder associated with a marked hypersusceptibility to spontaneous and radiation-induced skin cancer. We examined the changes in cell survival, unscheduled DNA synthesis (UDS) and the frequency of sister chromatid exchanges (SCE) induced by ultraviolet light (UVL) in confluent normal and BCNS fibroblasts. BCNS cells appeared slightly hypersensitive to the cytotoxic effects of UVL. The rate of UDS induced by UVL exposure in normal cell strains increased linearly following doses up to 30 J/m2, whereas in BCNS cells UDS became saturated at doses of 10 J/m2 showing no further increase with doses up to 30 J/m2. UDS activity persisted for longer periods after UVL exposure in BCNS as compared with normal cells. The dose-response relationship for UVL-induced SCE was similar in normal and BCNS fibroblasts. However, the frequencies of UVL-induced SCE declined to near background levels in normal cells following 12-24 hr of confluent holding prior to subculture whereas they remained elevated in BCNS cells with holding times up to 24 hr after UVL exposure. Overall, these results suggest that BCNS fibroblasts may have a diminished capacity for the repair of some type of DNA damage as compared with normal fibroblasts.

Adult↗
PubMed1988

Megaloblastic anaemia--a review from University Hospital, Kuala Lumpur.

During a 5 year period, 28 adult patients with megaloblastic anaemia (MA) were treated in University Hospital. 71% of the patients were Indians. Symptoms of anaemia was the main presenting complaint in 18 (64%) of patients while in 2 patients peripheral neuropathy was the main problem. Pancytopenia was a common finding (present in 18 (64%) patients) while 6 (21%) patients had severe thrombocytopenia (less than 20 x 10(9)/L). The peripheral blood morphology provided important diagnostic clues i.e. macrocytes and/or hypersegmented neutrophils seen in most patients. Concurrent iron deficiency 'dampened' the megaloblastic picture. Though most patients suffered from MA of nutritional origin, 3 patients were diagnosed to have pernicious anaemia and 2 patients had myelodysplastic syndrome. Important practice points were detection of concurrent infection and hypokalemia which necessitated appropriate treatment. The controversy of blood transfusion in treatment of MA and the importance of reassessing patients after treatment were highlighted.

Anemia, Macrocytic↗
PubMed1987

Determination of propafenone in biological fluids by fused-silica capillary gas chromatography using electron-capture detection.

A gas-liquid chromatographic method with electron-capture detection using a capillary column with the inlet in the splitless injection mode is reported for the assay of propafenone. A 25 m X 0.31 mm cross-linked, 5% phenylmethylsilicone-coated fused-silica capillary column was employed for all analyses. The present method provides improved selectivity and sensitivity over other existing gas chromatographic and high-performance liquid chromatographic (HPLC) methods. Linearity was observed in the ranges 2.5-50 and 10-100 ng/ml. The coefficient of variation was found to be less than 10% over the concentration ranges studied. Application of the developed method is demonstrated by measuring serum propafenone concentrations over 24 h in a normal healthy volunteer after a single oral dose of propafenone and by measuring trough plasma propafenone concentrations at steady state in patients receiving this new antiarrhythmic drug. Validity of the present method is further demonstrated by comparison of analytical results obtained from measurement of patient samples using a modified published HPLC method.

Acylation↗
PubMed1987

The therapeutic use of azathioprine in renal transplantation.

This review discusses the pharmacokinetics, mechanism of action, clinical use, toxicities, drug interactions, and possible approaches for therapeutic monitoring of azathioprine (AZA). The drug has been used extensively in posttransplant immunosuppressive protocols. Its therapeutic use is hampered by the development of toxicities, however, especially leukopenia, which is a common criterion for dosage adjustment. Azathioprine is rapidly converted in the liver and erythrocytes to 6-mercaptopurine (6MP), which is eventually metabolized to inactive 6-thiouric acid (6TU). The terminal half-lives of AZA and 6MP are 50 and 74 minutes, respectively. While renal dysfunction does not alter the disposition of AZA, hepatic insufficiency attenuates the pharmacologic activity. Immunosuppression depends on the formation of active intracellular thiopurine ribonucleotides, although AZA itself may block antigen recognition. Individualization of AZA regimens by determining tissue concentrations of thioguanine nucleotides, and plasma concentrations of AZA, 6MP, or 6TU may improve the risk:benefit ratio.

Azathioprine↗
PubMed1987

Food increases the bioavailability of propafenone.

The effect of food intake on the bioavailability of propafenone, a new antiarrhythmic agent, was evaluated by comparing its kinetics in 24 healthy volunteers in a fasted state and after a standard breakfast. With food, the maximum plasma drug concentration was reached earlier and was significantly increased. When data from 'slow' metabolizers were excluded, there was an average increase of 147% in the area under the concentration-time curve (AUCo) following the standard breakfast. There was a significant correlation (r = 0.946) between [(AUCo fed - AUCo fasted)/AUCo fasted] and propafenone intrinsic clearance in the fasted state. Food intake, however, does not appear to affect the bioavailability of propafenone in 'slow' metabolizers. Patients should be advised to take propafenone in a constant relationship to food to assure consistent bioavailability.

Adult↗