Search PubMed⌕ Search

Biomedical subjects

K Lu

Publications and source records attributed to K Lu.

At least 145 records · Page 8Linked to original sources
PubMed1983

Clinical pharmacokinetics of vinblastine by continuous intravenous infusion.

Vinblastine (VLB) is moderately active clinically against advanced breast cancer. Since VLB is extensively taken up by platelets and thus only partially available to tumor cells, to enhance the therapeutic index of VLB we have therefore administered this agent by continuous i.v. infusion to patients with advanced breast cancer. In conjunction with the clinical trial, we conducted pharmacokinetic studies of generally tritiated VLB, using radiochemical and chromatographic techniques. The elimination of VLB from the plasma of patients who received it by 5-day i.v. infusion at 1 to 2 mg/sq m daily was biphasic. In four patients who achieved partial remission, the average plasma half-life of VLB during the terminal phase was 29.4 +/- 14.6 days, with a total clearance of 36 +/- 8 ml/kg/hr, and a steady-state apparent volume of distribution of 28.1 +/- 8.5 liters/kg. However, in three patients whose disease merely stabilized, the plasma half-life was 6.4 +/- 1.6 days, the total clearance was 137 +/- 2.9 ml/kg/hr, and the volume of distribution was 33.0 +/- 11.6 liters/kg. In contrast, in five patients with refractory disease, these parameters were 2.3 +/- 0.3 days, 541 +/- 124 ml/kg/hr, and 37.6 +/- 8.6 liters/kg. Since the apparent volumes of distributions at steady state did not differ significantly among these three groups, whereas the values of the total clearance were markedly dissimilar, the plasma half-lives of VLB were significantly shorter in patients not responsive to continuous infusion therapy with this drug. Although the number of patients studied was small, it nevertheless appears that favorable clinical response of patients with advanced breast cancer is associated with slow total clearance of the drug.

Breast Neoplasms↗
PubMed1983

Clinical pharmacokinetics of 5-methyltetrahydrohomofolate.

DL-N5-Methyltetrahydrohomofolate (MTHHF; NSC-139490; N- [(4-[(2-(2-amino-3,4,5,6,7,8-hexahydro-4-oxo-5-methyl-6- pteridinyl)ethyl) amino) benzoyl)] -L-glutamate), a new folate antagonist of relatively low toxicity, is active against experimental tumor systems resistant to methotrexate and consequently now in clinical trial. We investigated its clinical pharmacokinetics in six patients; four of them received by rapid i.v. infusion tracer doses of [N5-methyl-14C]MTHHF ranging from 13 to 16 mg/sq m, and 2 received 150 mg/sq m; the total radioactivity dose was 100 to 200 mu Ci/patient. MTHHF was assayed by radiochemical and chromatographic techniques. The elimination of MTHHF from the plasma followed a triexponential pattern, with a harmonic mean initial half-life of 20.1 min, an intermediary half-life of 4.5 hr, and a terminal half-life of 74.6 hr. The apparent volume of distribution was 1.6 liters/kg, suggesting rapid and extensive tissue binding. This, together with the low total clearance of 0.2 ml/kg/min, contributed to the long half-life of this agent. Although 68% of the administered dose was excreted in the urine on the first day, only an additional 1% was excreted on the ensuing 3 days. In the two patients who received the higher dose, very little MTHHF was found in the cerebrospinal fluid. In concentrations ranging from 25 to 500 micrograms/ml, the drug was about 50% bound to plasma protein. MTHHF was not metabolized in humans as also reported in animals. These results suggest that MTHHF is excreted in the bile to certain extent. Moreover, since it tends to localize and persist in the body, to forestall cumulative toxicity, frequent administration of this agent should be undertaken only with caution.

Breast Neoplasms↗
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↗
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

Atherosclerosis and dissipative structures.

The theory of dissipative structure is applied to the study of atherosclerosis. An autocatalytic theoretical model is suggested. The behaviors of the model are in agreement with the facts of experimental atherosclerosis. We predict the high effectiveness of combinative therapy for atherosclerosis with drugs affecting protein metabolism and lipid metabolism. It was verified by animal experimentation. Further possible developments are briefly discussed. This work is the theoretical foundation of the Multi-Risk Factor Intervention trial (MRFIT) which is popularized clinically in its beginning all over the world.

Animals↗
PubMed1980

The pharmacologic fate of the antitumor agent 2-amino-1,3,4-thiadiazole in the dog.

Anticipating the renewed clinical trial of the antitumor agent 2-amino-1,3,4-thiadiazole (AT, NSC-4728), we have studied the pharmacologic fate of AT-5-14C in beagle dogs. The drug was only minimally metabolized in 5 h; the radioactivities in the urine, and particularly in the plasma, resided almost entirely in unchanged AT. In four dogs, after IV administration of AT-5-14C at 10 mg/kg (200 mg/m2), 150-200 muCi per animal, the terminal plasma t1/2 of AT was 13 h, and less than 10% of the administered dose appeared in the urine in 5 h. When the dose was raised to 25 mg/kg (500 mg/m2) in four dogs, the average plasma t1/2 of AT was 10 h; the 5-h cumulative excretion of the agent was 9% of the dose in the urine, 0.3% in the bile, and 0.1% as 14CO2 in the expired air. The average total clearance of AT was 0.70 ml/kg/min. Drug concentrations in the cerebrospinal fluid were 95% of those in the plasma at semi-steady state. At autopsy 5 h after dosing, more than 75% of the administered radioactivity was retained in the body, the highest amounts in terms of micrograms per gram of wet tissue being in the liver, kidney, lung and stomach. No appreciable changes in AT pharmacokinetics were evident upon simultaneous IV administration of allopurinol at 30 or 60 mg/kg. AT was less than 7% bound to dog plasma protein at 25 degrees C in concentrations of 12-100 microgram/ml.

Animals↗
PubMed1980

Pharmacological disposition of 1,4-bis (2-[(2-hydroxyethyl)amino]-ethylamino)-9,10-anthracenedione diacetate in the dog.

1,4-Bis (2-[(2-hydroxyethyl)amino]ethylamino)-9,10-anthracenedione (NSC 287513) (HAQ) may be selected for clinical trial based on its activity against a number of transplantable rodent tumors. Using a high-pressure liquid chromatograph assay, we have studied the pharmacological fate of HAQ in beagles. After i.v. administration of HAQ at 15 mg/kg (300 mg/sq m), the initial plasma t1/2 of the agent was 9.4 min, and the terminal t1/2 was 115.2 min. A maximal plasma concentration of 24.9 mg of HAQ per liter was attained. A high plasma clearance of 23.5 ml/kg/min was observed in these animals. The extrapolated apparent volume of distribution was 693.7 ml/kg, comparable to that of antipyrine in the dog. In 5 hr, 24.0% of the administered HAQ has been excreted in the urine unchanged, and a trace of a metabolite was detected, amounting to less than 2% of the UV-absorbing (254 nm) materials. However, hepatobiliary excretion constituted the primary route of drug elimination since 39.5% of the dose was found in the bile during the same period. An extraction procedure has been developed to quantify HAQ in tissue homogenates with 75 to 80% recovery. At autopsy, 5 hr after dosing, drug distribution in terms of percentage of the dose administered is as follows: liver, 7%; kidneys, 3.5%; pancreas, 3.1%; small intestine, 1.5%; stomach, 1.3%; spleen, 0.7%; lungs, 0.5%; heart, 0.4%; large intestine, 0.4%; and brain, 0.2%.

Animals↗
PubMed1979

Dichloroallyl lawsone.

Dichloroallyl lawsone (DCL, NSC-126771), a synthetic analogue of the antimalarial lapachol, is potentially useful in cancer chemotherapy. Unlike most anticancer agents, DCL is not significantly myelosuppressive in animals but it induces acute cardiac toxicity in the rhesus monkey. This cardiac toxicity seems to be correlated with the maximal plasma DCL concentration, about 130 mg/L in the monkey. We have studied DCL pharmacokinetics in patients in an attempt to define safe dose limits for the Phase I clinical trial. After the rapid intravenous infusion of 10 mg/m2 of radioactive [1- or 4-14C]DCL, 250 muCi per patient, the mean peak plasma concentration of unchanged DCL in four patients was 2.9 +/- 0.3 mg/L. The drug had a mean initial plasma half-life of 48.9 +/- 19 min and a terminal half-life of 20.3 +/- 1.8 hr, with a C X t of 50.1 +/- 12 mg/L/hr, and a clearance rate of 0.08 ml/kg/min. These data suggest that in clinical trials the DCL dose given by rapid intravenous infusion should not exceed 450 mg/m2 so that the maximal plasma drug concentration remains below 130 mg/L.

Antineoplastic Agents↗
PubMed1978

Disposition and metabolism of 1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) in humans.

The pharmacology of high-dose 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) has been studied by radiochemical and chromatographic techniques in eight patients. Plasma disappearance of FT was exponential, with a half-life of 8.8 hr. Plasma concentrations of 5-fluorouracil (FUra) were sustained at 12.8 nmol/ml (1.7 microgram/ml) for at least 48 hr after FT administration. The concentrations of FUra derived from the administration of FT were considerably greater than were those achieved by constant infusion of FUra at the maximal tolerated dose of 1.1 g/sq m without causing unacceptable mucositis. The cumulative urinary excretion was 20% of the administered dose in 24 hr. FT underwent in vivo biotransformation to 2 hydroxytetrahydrofuranyl-5-fluorouracil derivatives in addition to anabolites and catabolites of FUra. High concentrations of FT and FUra were present in the cerebrospinal fluid, which could account for the severe central nervous system toxicity of FT at high doses. We conclude that the antitumor activity of FT is partially attributable to its slow release of FUra.

Animals↗
PubMedDate not supplied

New tumor markers: CA125 and beyond.

A variety of biomarkers have been developed to monitor growth of ovarian cancer and to detect disease at an early interval. CA125 (MUC16) has provided a useful serum tumor marker for monitoring response to chemotherapy, detecting disease recurrence, distinguishing malignant from benign pelvic masses, and potentially improving clinical trial design. A rapid fall in CA125 during chemotherapy predicts a favorable prognosis and could be used to redistribute patients on multiarmed randomized clinical trials. Several studies now document that CA125 can serve as a surrogate marker for response in phase II trials. Serial measurement of CA125 might also provide a useful marker for monitoring stabilization of disease with cytostatic targeted therapeutic agents. The greatest potential for serum markers may be in detecting ovarian cancer at an early stage. A rising CA125 can be used to trigger transvaginal sonography (TVS) in a small fraction of patients. An algorithm has been developed that calculates risk of ovarian cancer based on serial CA125 values and refers patients at highest risk for TVS. Use of the algorithm is currently being evaluated in a trial with 200,000 women in the UK that will test critically the ability of a two-stage screening strategy to improve survival in ovarian cancer. Whatever the outcome, as 20% of ovarian cancers have little or no expression of CA125, additional serum markers will be required to detect all patients in an initial phase of screening. More than 30 serum markers have been evaluated alone and in combination with CA125 by different investigators. Some of the most promising include: HE4, mesothelin, M-CSF, osteopontin, kallikrein(s), and soluble EGF receptor. Two proteomic approaches have been used: one examines the pattern of peaks on mass spectroscopy and the other uses proteomic analysis to identify a limited number of critical markers that can be assayed by more conventional methods. Both approaches are promising and require further development. Several groups are placing markers on multiplex platforms to permit simultaneous assay of multiple markers with very small volumes of serum. Mathematical techniques are being developed to analyze combinations of marker levels to improve sensitivity and specificity. In the future, serum markers should improve the sensitivity of detecting recurrent disease as well as facilitate earlier detection of ovarian cancer.

Biomarkers, Tumor↗
PubMedDate not supplied

Effects of gamma-interferon on keratocyte-induced collagen gel contraction and keratocyte proliferation.

PURPOSE: Gamma-interferon has been shown to be an effective immunoregulatory polypeptide that can modulate fibroblastic response. We investigated the effects of gamma-interferon on keratocyte proliferation and keratocyte-induced collagen gel contraction. METHODS: Gamma-interferon in concentrations of 0.01, 1, 100, and 1000 U/ml of media was added to keratocytes embedded in polymerized type I collagen and the gel area was measured after 5 days with an image analysis system. The rate of keratocyte proliferation within and outside the collagen gel under the influence of gamma-interferon was also investigated. RESULTS: Keratocyte-induced collagen gel contraction was significantly inhibited at all concentrations above 0.01 U/ml. The keratocyte proliferation was not affected by low and moderate concentrations and was significantly stimulated at concentration of 1000 U/ml. CONCLUSION: Keratocyte-induced collagen gel contraction is inhibited by gamma-interferon and the mechanism of this effect is not inhibition of keratocyte proliferation by gamma-interferon.

Cell Division↗
PubMedDate not supplied

[Production of early cytokines after infection with A/Leningrad/134/57 (H2N2) wide-type virus and cold-adapted attenuated vaccine viruses].

The production of proinflammatory cytokines was studied following experimental infection of BALB/c mice with influenza viruses that differed in virulence. The generation of TNF-alpha, IL-6, IL-12, and IFN-gamma was investigated in the lung homogenates in the early periods after intranasal infection of mice with A/Leningrad/134/57 (H2N2) wild-type virus and cold-adapted attenuated vaccine viruses: A/Leningrad/134/17157 (H2N2) and A/Leningrad/134/47/57 (H2N2). Wild-type virus induced substantially higher levels of proinflammatory cytokines: TNF-alpha, IL-6, IL-12, and IFN-gamma. After infection with the cold-adapted viruses, the levels of the cytokines were reduced as compared to those induced by the wild-type virus. The A/Leningrad/134/47/57 virus was marked by a noticeable production of IL-6 and IFN-gamma in the murine lung, but it was less than with wild-type virus infection. At the same time, the more attenuated strain A/Leningrad/134/47/57 induced TNF-alpha and IFN-gamma in the quantities similar to those in the control animals. Thus, a response of proinflammatory cytokines in early infection in the murine lung depended on the level of viral replication in the lower respiratory tract and on the attenuation of influenza virus strains.

Administration, Intranasal↗