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Biomedical subjects

T L Loo

Publications and source records attributed to T L Loo.

At least 55 records · Page 3Linked to original sources
PubMed1982

Comparison of the reversed-phase high-performance liquid chromatographic separations of fluoropyrimides, pyrimidines, and purines.

The reversed-phase, high-performance liquid chromatographic separation of fluoropyrimidines, pyrimidines, and purines was investigated under isocratic conditions at ambient temperature. The performance of nine analytical, commercially available columns with five mobile phases is compared, and capacity and resolution factors are reported. The variables determining resolution are discussed, and the systems accomplishing the desired separation of fluoropyrimidine and pyrimidine bases and nucleosides are described. The best chromatographic results are achieved by using Spherisorb ODS-2 as stationary phase and 0.05 M monobasic ammonium phosphate (pH 3.5) as mobile phase.

Chromatography, High Pressure Liquid↗
PubMed1982

Human tissue distribution of platinum after cis-diamminedichloroplatinum.

Using X-ray fluorescence spectrometry, platinum concentrations were determined in autopsy tissue samples from 12 patients who had received cis-diamminedichloroplatinum (DDP) 20-120 mg/m2 up to 6 months antemortem. Tissue platinum concentrations were highest in liver (0.5-3.7 micrograms/g wet weight), prostate (1.6-3.6 micrograms/g), and kidney (0.4-2.9 micrograms/g), somewhat lower in bladder, muscle, testicle, pancreas, and spleen, and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum, Platinum concentrations in tumors were generally somewhat lower than the concentration in the organ in which the tumor was located, with the exception of intracerebral tumors. Different metastatic sites in the same patient had substantially different platinum concentrations and hepatic metastases had the highest concentrations. Intra-arterial administration of drug may augment tissue concentrations of platinum. In a patient undergoing therapeutic abortion 4 days after treatment, the platinum concentration was 0.5 micrograms/g in the placenta and 0.3 micrograms/g in the fetus. The data suggest that for in vitro sensitivity testing, DDP concentrations of less than or equal to 7 micrograms/ml should be used.

Autopsy↗
PubMed1982

Pharmacology of mitoxantrone in cancer patients.

Radioactive mitoxantrone was administered at doses of 1-12 mg/m2 by rapid IV infusion to 11 patients. Of the 11 patients, six had normal liver and kidney function tests while the remaining five had abnormal third space and/or hepatic dysfunction. In the former group, the initial t1/2 was 13.7 min and terminal t1/2 was 37.4 h. The apparent volume of distribution was 13.8 l/kg. The total clearance rate was 230.7 ml/kg/h. The recovery of unchanged mitoxantrone from urine was 6.8% at 24 h and 7.3% at 72 h, while the corresponding recovery of total radioactivity was 9.4% at 24 h and 11.3% at 72 h. In the five patients with abnormal liver function or third space the initial t1/2 was variable and ranged from 11.5-63.6 min, and the terminal t1/2 ranged from 53.3-173.2 h, whereas the total clearance rate varied from 52.7-170.2 ml/kg/h. However, the cumulative urinary excretion of unchanged mitoxantrone was similar to that of patients with normal hepatic function: 3.9 at 24 h and 5 at 72 h. Biliary excretion was studied in one of these patients, who had jaundice and hepatic impairment; only 2.3% of 14C was excreted in 24 h and 2.7% in 96 h, of which 39% and 41%, respectively, were unchanged mitoxantrone. Our results suggest that mitoxantrone is taken up rapidly by tissue from which it is released slowly. Reduction of mitoxantrone dose is therefore advisable in patients with liver dysfunction or abnormal third space.

Aged↗
PubMed1982

Pharmacokinetics and metabolism of beta-2'-deoxythioguanosine and 6-thioguanine in man.

Resistance to the antileukemic agent 6-thioguanine (TG) inevitably develops in animal tumors. However, a new agent, beta-2'-deoxythioguanosine (beta-TGdR) can overcome TG resistance in animal tumor models and is therefore of potential clinical use. The pharmacokinetics of radiolabeled TG were compared with those of beta-TGdR in patients with cancer after intravenous administration. [35S]-beta-TGdR (5.4 mg/kg, 200 mg/m2, 200 microCi total) was administered to five patients; the radiolabel in the plasma declined with an initial half-life (t1/2) of 14 min and a terminal t1/2 of 19.3 h. Within 24 h, 65% of the radiolabel was excreted in the urine. In contrast, after administration of [35S]-6-TG (3.4 mg/kg, 125 mg/m2, 200 microCi total) the average initial t1/2 was 40 min while the terminal phase t1/2 was 28.9 h. Urinary excretion of the radiolabel was 75% of the dose 24 h after administration. Both thiopurines were rapidly and extensively degraded and excreted as 6-thioxanthine, inorganic sulfate, S-methyl-6-thioxanthine, and 6-thiouric acid in addition to other products. Small amounts of unchanged drug were also excreted. These studies suggest that beta-TGdR is merely a latent form of TG.

Allopurinol↗
PubMed1982

Clinical kinetics of 1, 4-dihydroxy-5,8-bis [(2-[(2-hydroxyethyl) amino] ethyl] amino ]-9, 10-anthracenedione.

The clinical kinetics of 1, 4-dihydroxy-5,8-bis[[ 2-[(2-hydroxyethyl) amino] ethyl] amino]-9,10-anthracenedione dihydrochloride (DHAQ) are reported. DHAQ, 1 to 3 mg/m2, was administered as an intravenous bolus to six patients with metastatic cancer. Plasma clearance of the drug followed a biphasic pattern with a harmonic mean initial half-life (t 1/2) of 13.7 min and a terminal t 1/2 of 37.4 hr. Recovery of unchanged drug in the urine was 6.8% at 24 hr and 7.3% at 72 hr, while the corresponding recovery of total radioactivity was 9.4% and 11.3%. Apparent volume of distribution of DHAQ was about 13.8 +/- 2.9 l/kg. Total clearance was 238.7 ml/kg/hr, twice the creatinine clearance.

Adult↗
PubMed1982

Combination chemotherapy with cyclophosphamide and ftorafur against advanced L1210 murine leukemia.

The antitumor activity of cyclophosphamide (CP) in combination with ftorafur (FT) against advanced L1210 murine leukemia was investigated and compared with the activity of the combination of CP and 5-FU. CP at doses of 200--350 mg/kg was highly active, the most effective dose (% treated/control = 327) being 300 mg/kg. The activity of FT up to the LD10 dose and of 5-FU at 50 mg/kg was minimal (% treated/control less than or equal to 142). Coadministration of 200 mg/kg of FT with 100 mg/kg of CP resulted in an increase in activity as compared with the respective dose of CP alone as did the coadministration of 400 mg/kg of FT with 200 mg/kg of CP; the activities, however, were no better than that resulting from treatment with 300 mg/kg of CP alone. The coadministration of CP and 600 mg/kg of FT resulted in an increase in host toxic reactions and loss of antitumor activity, as did the coadministration of 400 mg/kg of FT with 300 mg/kg of CP. Treatment with FT at 400 or 600 mg/kg 24 hours before or after administration of CP at 200 or 300 mg/kg did not increase the activity over that occurring when the respective combinations of the drugs were coadministered. The activity of the combination of CP with 5-FU at doses previously reported to be synergistic was equal to that observed when mice were treated with 300 mg/kg of CP alone. These data suggest that FT increases the cytotoxicity of CP but that the combination is not synergistic.

Animals↗
PubMed1982

Effect of malnutrition on methotrexate toxicity and tissue levels of dihydrofolate reductase in the rat.

The effect of malnutrition on the toxicity of methotrexate (MTX) and the dihydrofolate reductase (DHFR) content of the liver, small intestinal mucosa, kidney, and bone marrow of male Sprague-Dawley rats was studied. Malnutrition was induced by reducing the daily intake of chow to one third for 14 days. A single ip treatment with MTX was lethal to three of nine rats at a dose of 37.5 mg/kg and to three of five rats at a dose of 50.0 mg/kg but caused only transient weight loss to similarly treated full-fed, age-matched controls. Although the body weights and absolute tissue weights were reduced in malnourished rats, only the liver and small intestinal mucosa were smaller relative to their respective body weights. The cellular DHFR content of liver and bone marrow from malnourished rats was lower than that from the controls, although in terms of the content per gram of tissue, there was no significant change. While the total DHFR in malnourished rat tissues was significantly lower than that for the controls, only the total-liver DHFR was lower relative to the body weight. The increased toxicity of MTX to malnourished rats may be related to the DHFR levels in the liver and bone marrow.

Animals↗
PubMed1981

Mass spectrometry of permethylated folic acid analogs.

Folic acid and several analogs have been characterized as their permethylated derivatives. These derivatives are readily evaporated from the solid probe and provide spectra with abundant molecular ions and characteristic fragment ions. This method has been used to confirm the identities of the two methotrexate metabolites, 7-hydroxymethotrexate and 4-amino-4-deoxy-N(10)-methylpteroic acid, which have been isolated from human urine. The permethylation products of the folate cofactors, dihydrofolic acid, tetrahydrofolic acid and leucovorin, are also characterized.

Chromatography, High Pressure Liquid↗
PubMed1981

Disposition of methylglyoxal bis(guanylhydrazone) (MGBG, NSC-32946) in man.

A high-pressure liquid chromatographic method was utilized to determine the concentration of the antileukemic agent methylgloxal bis(guanylhydrazone) (MGBG, NSC-32946) in tissue samples obtained at autopsy from patients who received MGBG. In a patient with cholangiocarcinoma who received one course of MGBG (500 mg/m2), the highest drug concentration was found in normal liver tissue. However, the drug concentration in intrahepatic tumor tissue was only 10% of that found in uninvolved liver. In a patient with acute myelogenous leukemia (AML) who received 12 courses of MGBG therapy, highly infiltrated lymph node tissue was found to contain the highest concentration of MGBG. High concentrations of the drug were also found in liver, spleen, kidney, adrenal, and thyroid. The drug penetrated well into normal brain tissue. After repeated administration, high drug concentrations were found in cerebral and cerebellar gray matter. These studies suggest that there is no selective uptake of MGBG into solid tumors early after drug administration and provide a pharmacologic rationale for testing this agent against endocrine and intracerebral tumors in man.

Absorption↗
PubMed1981

Disposition and metabolism of thiopurines III. beta-2'-Deoxythioguanosine and 6-thioguanine in the dog.

The anticancer agent beta-2' deoxythioguanosine (beta-TGdR, NSC-71261) has potential utility for the treatment of hematologic tumors resistant to 6-thioguanine (TG). We have studied the pharmacology and metabolism of these two agents in the beagle dog. [35S] beta-TGdR was administered as an IV bolus to five dogs at a dose of 10 mg/kg. Plasma radioactivity declined biphasically with an average terminal t 1/2 of 3.7 h. Cumulative urinary excretion of the radiolabel 5 h after administration was 19% of the total dose. In another four dogs that received 100 mg/kg (2.71 g), the average terminal plasma t 1/2 was 7.7 h and the 5-h cumulative urinary excretion was 28% of the total dose. [35S]Thioguanine, 5 mg/kg was similarly administered IV to three beagle dogs. The average terminal t 1/2 of [35S]TG and metabolites was 4.6 h, and the 5-h cumulative urinary excretion of the [35S] label was 47%. Similar studies were conducted in three beagle dogs that received the same dose of [8(14)C]TG. In these studies, however, the terminal phase t 1/2 of 14C in plasma was 1.9 h. Cumulative urinary excretion of the 14C was 40% in 5 h. Both TG and beta-TGdR were rapidly and extensively degraded. Neither of these agents and none of their metabolites was found in the cerebrospinal fluid in significant concentrations. In the dog, beta-TGdR was rapidly metabolized to TG and may serve as a slow release form of TG.

Allopurinol↗
PubMed1981

Effects of endotoxin on the pharmacology of antineoplastic agents.

Patients with cancer often develop serious gram-negative bacterial infections. Since bacterial endotoxins have been shown to affect the in vitro hepatic metabolism of antineoplastic agents, significant infection may adversely affect drug pharmacokinetics and metabolism in these patients. To evaluate the clinical significance of these effects, bacterial endotoxin (0.5 mg/kg, IV) was administered to male beagle dogs 1 or 24 h prior to the administration of radiolabeled 5-fluorouracil (5-FU), methotrexate (MTX), arabinosylcytosine (Ara-C), or vinblastine (VLB) as an IV bolus. Drug levels in plasma and urine were measured at various times after administration and standard pharmacokinetic parameters were calculated. The pharmacokinetics of all four agents were found to be significantly altered by the administration of bacterial endotoxin. However, there were no detectable patterns to these changes so that no predictions could be made. In studies on rats, chronic, nonlethal endotoxin administration (0.8 mg . kg-1 . day-1 for 10 days) resulted in a dramatic decrease in the distribution of [14C]methylglyoxal bis(guanylhydrazone) (MGBG) in liver, kidney, intestine, heart and lung tissue. This suggests that bacterial endotoxin may also effect drug pharmacokinetics by altering drug penetration into various organs. In studies on hepatic microsomes isolated from rats, bacterial endotoxin incubation affected aniline hydroxylase activity only at concentrations greater than 0.4 mg/ml, at least tenfold higher than the LD 50 of endotoxin in rats. It therefore seems likely that the endotoxin may require in vivo metabolism to affect changes in drug metabolism and disposition.

Animals↗
PubMed1981

Pharmacology of pentamethylmelamine in humans.

A rapid, specific high-pressure liquid chromatographic assay was used to study the pharmacology of pentamethylmelamine in 21 patients (28 infusions) receiving 80 to 1500 mg/sq m. In patients with normal liver function, pentamethylmelamine was rapidly cleared from the plasma with a terminal half-life of 2.2 hr. Abnormal liver function tended to correlate with increased half-life and reduced total clearance. In addition, increased neurological toxicity was associated with hepatic abnormalities. The N2,N2,N4,N6-tetramethylmelamine, N2,N4,N6-trimethylmelamine, dimethylmelamine, and monomethylmelamine metabolites were detected in plasma. The terminal plasma half-lives of these metabolites increased with decreasing number of methyl group. With liver dysfunction, the plasma clearance of these metabolites also decreased and central nervous system toxicity increased. Although the antitumor activity of pentamethylmelamine is thought to be mediated by the intermediate hydroxymethyl metabolites produced by hepatic microsomal oxidation or by the formaldehyde generated, the neurological toxicity appears to depend upon the pharmacokinetics of the drug and its demethylated metabolites.

Altretamine↗
PubMed1981

Pharmacokinetics of [14C]methylglyoxal-bis-guanylhydrazone) in patients with leukemia.

Methylglyoxal-bis(guanylhydrazone) (MGBG; NSC 32946), a competitive inhibitor of S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50), currently being reevaluated for its clinical antileukemic activity. MGBG labeled with 14C in the guanylhydrazone moiety was administered i.v. (150 microCi; specific activity, 1.9 microCi/mumol; 20 mg total) to six patients with leukemia. All patients in the study had normal renal and hepatic function. [14C]MGBG underwent no in vivo metabolism; it disappeared from the plasma with an average terminal t 1/2 of 4.1 hr. The 72-hr cumulative urinary excretion was only 14.5 +/- 2.2% (S.E.M.) of the total radioactive dose. The apparent volume of distribution was 661 ml/kg and the total clearance rate was 21.2 ml/kg/min. The low urinary excretion rate and the relatively rapid plasma clearance suggest that MGBG may be sequestered in the body. Therefore, if MGBG is administered by a frequent treatment schedule, the prolonged biological half-life in humans may significantly contribute to its clinical toxicity.

Drug Evaluation↗