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Biomedical subjects

K Lu

Publications and source records attributed to K Lu.

At least 19 recordsLinked to original sources
PubMed1996

Carnitine transport defect in fibroblasts of juvenile visceral steatosis (JVS) mouse.

Juvenile visceral steatosis (JVS) mice are associated with systemic carnitine deficiency (Kuwajima, et al., 1991). In order to investigate the cause of this deficiency, we compared fibroblast carnitine transport activities in normal mice and JVS mice. The kinetic analysis showed that in formal fibroblasts, the Km and Vmax values for saturable uptake was 15.6 microM and 2.56 pmol/min/mg protein, respectively. In JVS fibroblasts, however, saturable uptake was not observed. There was no great difference in the linear component of uptake between normal and JVS fibroblasts. At the physiological concentration (50 microM) of carnitine, the fibroblast carnitine transport activity in JVS mice was decreased to 18% of that in normal mice. Thus there is hardly any carnitine transport activity in the fibroblasts of JVS mice, indicating that the JVS mouse can be regarded as an animal model of primary carnitine deficiency.

Animals↗
PubMed1996

Research on soft-tissue expander permeability to metronidazole and procaine.

This in vitro study was designed to determine if in fact silicone expanders are readily permeable to metronidazole and procaine. The expanders were filled with 0.2% metronidazole or 2% procaine through the filler valves and then immersed wholly in normal saline. At several intervals over 120 hours, a certain amount of the surrounding saline was sampled and the drug levels subsequently determined. In this study, the silicone expanders were indeed readily permeable to the drugs, as measured with an ultraviolet spectrophotometer. A consistent diffusion curve was demonstrated. The rate of diffusion of a drug is inversely proportional to its molecular weight; i.e., the smaller the given drug's molecular weight, the greater is its ability to permeate an expander. In view of this, in the course of expansion, 0.2% metronidazole could be used in clinical expansion instead of normal saline, and a certain amount of antibiotic would diffuse out of the expander to prevent and control the infection.

Humans↗
PubMed1995

Mechanisms of resistance to N-[5-[N-(3,4-dihydro-2-methyl-4- oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl]-L-glutamic acid (ZD1694), a folate-based thymidylate synthase inhibitor, in the HCT-8 human ileocecal adenocarcinoma cell line.

N-[5-[N-(3,4-Dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N- methylamino]-2-thenoyl]-L-glutamic acid (ZD1694) is a folate-based thymidylate synthase (TS; EC 2.1.1.45) inhibitor. Metabolism to higher chain length polyglutamates is essential for its optimal cytotoxic effect. A ZD1694-resistant (300-fold) human ileocecal carcinoma cell line (HCT-8/DW2) was developed, and its mechanism of resistance was evaluated. TS activities in situ and TS protein levels in the HCT-8 parental line and HCT-8/DW2 were similar (168 +/- 47 vs 137 +/- 25 pmol/hr/10(6) cells and 2.05 +/- 0.28 vs 2.07 +/- 0.19 pmol/mg protein, respectively). The IC50 values of ZD1694 for TS inhibition in cell-free extracts were similar in both lines, but the IC50 of ZD1694 for TS inhibition in situ in HCT-8/DW2 cells was 27- and 268-fold higher than that in HCT-8 cells at 0 and 24 hr, respectively, after a 2-hr drug exposure. Folylpolyglutamate synthetase (FPGS; EC6.3.2.17) activity was significantly lower in resistant HCT-8/DW2 cells as compared with parental HCT-8 cells (88 +/- 40 vs 1065 +/- 438 pmol/hr/mg protein when ZD1694 was used as substrate). The combined endogenous pool of methylenetetrahydrofolate and tetrahydrofolate in HCT-8/DW2 cells was also decreased. In addition, HCT-8/DW2 cells accumulated lower levels of methotrexate (MTX) in a 2-hr period, although the initial velocity of MTX transport was similar to that in parental HCT-8 cells. The lower level of FPGS activity and the lower level of (anti)folate accumulation in HCT-8/DW2 correlated with drug resistance and with the higher IC50 of ZD1694 for in situ TS inhibition. In addition, drug resistance was also correlated with the rapid recovery of in situ TS activity after drug treatment. In brief, in this highly ZD1694-resistant HCT-8 cell line, resistance is associated with decreased FPGS activity, which, in turn, affects the metabolism of ZD1694 and consequently the extent and duration of in situ TS inhibition by the drug.

Cell Division↗
PubMed1995

Chemosensitivity to triazene compounds and O6-alkylguanine-DNA alkyltransferase levels: studies with blasts of leukaemic patients.

BACKGROUND: A clinical pilot study performed by our group showed that dacarbazine can induce a marked reduction of blast cells in patients with acute myelogenous leukaemia (AML). Leukaemic blasts (LB) from responsive patients showed low levels of O6-alkylguanine-DNA alkyltransferase (OGAT). DESIGN: An in vitro study was performed to evaluate OGAT levels and sensitivity to temozolomide (a triazene compound that spontaneously decomposes into the active metabolite of dacarbazine) in a relatively large number of LB samples. RESULTS: OGAT levels varied widely among the LB of different patients, with a mean value higher in acute lymphoblastic leukaemias than in AML. About 25% of LB obtained from patients with AML showed low OGAT activity, in the range corresponding to that observed in leukaemic patients responsive to dacarbazine in vivo. A reasonable inverse correlation was found between OGAT levels and LB sensitivity to temozolomide. CONCLUSIONS: Triazenes could have a therapeutic potential in human leukaemias. Moreover, OGAT determination could provide rapid and reliable information about a patient's susceptibility to these antitumor agents.

Adolescent↗
PubMed1995

[Anatomy and clinical application of transcervicothoracic polyphyletic blood supply skin flap].

Transcervicothoracic skin flap was used to repair the faciocervical scars left after burns in 56 cases. Anatomy and clinical application proved that the transverse cervical artery branches out a constant skin artery before it enters the trapezius muscle and this artery, after crossing the clavicle, is divided into two branches, one extending outwards, and the other downwards. The internal thoracic artery branched out an intercostal perforator on the spot 1 cm to the parasternum. The perforator extended along the intercostal plane and belonged to the direct skin artery. The rate for perforation between the second and third ribs was the highest and the diameter of the perforator the greatest. The thoracoacromial skin artery perforated through the medialsemis between the greater pectoral muscle and the deltoid muscle, and extended toward the shoulder, supplying the skin of the infraclavicular, deltoid and upper greater pectoral regions with blood. Anatomy and contrast examination showed that there are extensive anastomoses between the three groups of blood vessels. On the basis of these anastomotic branches, transregional skin flaps can be designed to repair faciocervical damages. These flaps were successfully used in the 56 cases, with 32 cases having the the branch of cervical segment of the trasverse cervical artery as the pedicle, and 24, the second and third perforators of the internal thoracic artery as the pedicle. It was proved that the transregional flaps can be successfully transferred regardless of the sites of the pedicles.

Adolescent↗
PubMed1994

[The causes of necrosis of arteriovenous flap and its modification].

Arteriovenous flaps have been developed for more than ten years, however the cause of necrosis of the flap remains obscure. We observed the changes in the microcirculation of the flap, and it was revealed that most of capillaries were occluded in the early arterialized stage, and the capillary patency was only 10%-20%. The latter was increased to 80%-90% three days later. All these changes were due to the damage of endothelial cells by arterial blood, because of high pressure and oxygen tension, resulting if cell swelling, fissuring, exfoliation and finally thrombosis. As a consequence, the effective microcirculation volume became decreased. As venous endothelial cells required time to adapt arterial blood, and expansion of skin could increase tissue capillaries in number, the arteriovenous flap was modified by skin expansion before arterialization. This method improved the survival rate remarkably.

Animals↗
PubMed1993

Modulation of integrins expression during human osteoblasts "in vitro" differentiation.

We here report the modulation of the adhesion of cultured human osteoblasts on Laminin during the acquisition of differentiated phenotype. We also show that interference with the differentiation program caused by treatment with Retinoic acid of the cultures, causes changes of the capability to adhere to Laminin and type I Collagen. The younger or dedifferentiated cells have lower capability to bind to Laminin or Collagen. The maturation associated changes are specific for the adhesion to the above substrata and do not involve the adhesion to FN or plastic. The alpha subunit(s) of the integrin receptor(s) for these proteins is likely to be responsible for the modulation adhesion to Laminin and Collagen.

Cell Adhesion↗
PubMed1992

Ras proteins are essential and selective for the action of insulin-like growth factor 1 late in the G1 phase of the cell cycle in BALB/c murine fibroblasts.

BALB/c 3T3 cells (A31 cells) require the sequential action of growth factors in order to proliferate from a quiescent growth state. Insulin-like growth factor I (IGF-I) is needed late in the G1 phase of the cell cycle, a time at which expression of the c-Ha-ras protooncogene is near maximal. An anti-ras antibody, introduced by microinjection, specifically blocked the ability of IGF-I to stimulate initiation of DNA synthesis. The antibody was specific for IGF-I; it failed to block serum, platelet-derived growth factor, or epidermal growth factor from inducing c-fos mRNA. By contrast, an anti-G alpha-subunit antibody had no effect on IGF-I-stimulated DNA synthesis but inhibited the induction of c-fos mRNA by platelet-derived growth factor or epidermal growth factor. BPA31 cells are tumorigenic A31-derived cells that progress through G1 in the absence of IGF-I. BPA31 cells produced an autocrine IGF-I that was responsible for the loss of late G1 control; the anti-ras antibody arrested the growth of these cells in late G1. The results suggest that ras proteins are essential for an IGF-I-sensitive, G1 control point.

Animals↗
PubMed1992

Pharmacology of intrathecal VP-16-213 in dogs.

VP-16-213 is an anticancer drug that is active against a number of malignancies including small cell lung cancer, lymphoma, and leukemia which are often complicated by the development of leptomeningeal carcinomatosis. To investigate the potential usefulness of VP-16-213 for intrathecal administration, the pharmacology and toxicity of intrathecal VP-16-213 was determined. VP-16-213 at varying doses (0.01-1.0 mg.kg) was instilled intrathecally in dogs. Plasma, CSF, spinal cord, and brain tissue drug concentrations were determined by radiochemical and high performance liquid chromatography technique. Drug concentrations were strikingly higher in spinal cord tissue near the injection site compared to more distal cord sites. CSF concentration of VP-16-213 is 3-4 logs higher compared to concurrent plasma levels. Severe neurotoxicity occurred at the higher doses used. Due to limited diffusion and extremely low doses which could be used without life-threatening neurotoxicity, VP-16-213 does not appear to be a useful agent for intrathecal administration.

Animals↗
PubMed1991

[Determination of tetramethylpyrazine in traditional Chinese medicines by high performance liquid chromatography].

This paper reports a method for determining tetramethyl pyrazine in pilules, injections and extracts of Ligusticum chuanxiong by high performance liquid chromatography. The results showed the recovery rate to be higher than 97% and the coefficient of variation (CV) to be 1.39% (with in day) and 1.51% (day to day). The lowest detection amount was 0.005 micrograms. The method was easy, fast and accurate.

Chromatography, High Pressure Liquid↗
PubMed1989

Phase I clinical trial and pharmacokinetic evaluation of 4'-0-tetrahydropyranyladriamycin (THP-adriamycin).

Tetrahydropyranyladriamycin (THP-adriamycin) is an anthracycline analogue currently under development in Europe and Japan. Preclinical studies suggest that it may have greater activity and less cardiac toxicity than doxorubicin. We conducted a phase I clinical and pharmacologic study of THP-adriamycin given as a weekly 15-min infusion for 3 weeks, followed by 1 week of observation. Therapy was associated with minimal acute toxicity. The dose-limiting toxicity was neutropenia, usually maximal during the 4th week after treatment; alopecia was rare. The maximum tolerated dose was 25 mg/m2; for phase II studies using this schedule, a dose of 20 mg/m2 weekly for 3 weeks is recommended. Pharmacokinetic studies revealed a triphasic elimination of the parent compound with alpha, beta, and gamma half-lives of 5.6 min, 1.4 h, and 9.3 h, respectively. THP-adriamycin was rapidly taken up by blood cell components, with concentrations in red blood cells (RBCs), lymphocytes, and polymorphonuclear cells exceeding those in plasma. In all, less than 10% of the compound was eliminated in the urine within 24 h.

Chromatography, High Pressure Liquid↗
PubMed1989

Genotoxicity of [1H]benz[de]isoquinoline-1,3[2H]dione,5 amino-2-,[2-dimethylamino) ethyl] (BIDA) in human lymphocytes.

We have investigated the genotoxicity of BIDA in cultured human lymphocytes. Lymphocytes were cultured and stimulated with phytohemagglutinin (PHA) for 72 h. Doses of 0.1, 0.25, 0.5, 0.75, and 1 microgram/ml of BIDA were added to the culture at 1 h (G2 phase), and 6 h (S/G2 phase) before harvesting. Cells were harvested at the end of the 72-h culture period with 1-h colcemid treatment to accumulate mitosis, and further prepared by standard cytogenetic technique. BIDA induced chromatic type breakages and chromatid exchanges at both 1 h and 6 h. The mean number of breakages per cell was 0, 0.1, 1.0, and 1.7 after treatment with 0.1, 0.25, and 0.75 micrograms/ml, respectively. Ai 1 microgram/ml, BIDA severely inhibited cell progression and very few mitoses were observed. At 6 h the mean number of breakages per cell was 0.3 at 0.25 microgram/ml and 1.2 at 0.5 microgram/ml. Very few cells entered mitosis at 0.75 and 1 microgram/ml. To study the effect of BIDA on cells in G0 and G1, BIDA (0.75 microgram/ml) was added for 1 h to the cultures at the beginning of culture (G0), or 24 h after (G1) culture initiation. Afterward, cells were washed and reincubated in the conditioned medium for 71 or 47 h. No chromosomal aberrations were seen in these experiments. The number of chromatid breaks was minimal (0.1 to 0.4/cell). Our study suggests that BIDA induces chromatid type aberrations during G2 and S phases. The absence of chromosome type aberrations in cells treated during G0 and G1 suggests that either BIDA has no effect on these cells or that damaged cells fail to progress through S and G2 to reach mitosis.

Adenine↗
PubMed1988

Pharmacokinetics of Amonafide in dogs.

Amonafide, one of a series of imide derivatives of 1,8-naphthalic acid synthesized by Brana et al. has shown significant antitumor activity against a variety of experimental tumors, including L1210 leukemia and P388 leukemia. Along with the clinical trial at our institute, we have studied the disposition of Amonafide in dogs by HPLC and fluorometry. Six dogs received Amonafide i.v. at 5 mg/kg (100 mg/m2) over 15 min; three were sacrificed at 6 h, and three at 24 h. The initial plasma t1/2 of Amonafide was 2.4 +/- 0.4 min, the intermediate t1/2, 26.8 +/- 3.7 min, and the terminal t1/2, 21.7 +/- 4.0 h. The peak plasma concentration achieved was 6.3 +/- 1.7 micrograms/ml. The average apparent volume of distribution was 12.84 +/- 0.54 1/kg, and the total clearance was 0.56 +/- 0.16 1/kg/h. In 24 h, 9.5% +/- 0.2% of the administered dose was excreted in the urine as the parent drug, and 7.4% +/- 1.4% in the bile in 6 h. Amonafide penetrated the CSF readily and achieved the highest concentration 20-25 min after administration, which was 30% of the concurrent plasma level. Amonafide underwent extensive metabolism to at least three major metabolites and two or more minor metabolites. The alpha and beta plasma t1/2 of the major metabolite, an N-oxide derivative, were 24.8 min and 28.6 h, respectively. The 24-h cumulative urinary excretion was 1.4% of the injected dose, and the cumulative biliary excretion was 16.7% in 6 h. At autopsy 6 h after dosing, the liver contained the highest percentage (0.23% of administered dose) of unchanged Amonafide, followed by the stomach (0.11%), lung (0.04%), kidney (0.04%), and pancreas (0.03%). The rest of the major organs retained less than 0.02% of the Amonafide dose. One day after dosing, no detectable amount of Amonafide was found in any of these tissues, indicating that Amonafide appears to be extensively metabolized and not significantly retained in the dog.

Adenine↗
PubMed1988

Pharmacokinetics of homoharringtonine in dogs.

We studied the pharmacokinetics and distribution of homoharringtonine (HHT), an antitumor alkaloid, in anesthetized dogs using chromatographic and radiochemical techniques. Uniformly tritiated HHT was administered i.v. to five dogs at doses of 0.05 to 0.34 mg/kg, 200 microCi per animal. Unchanged HHT disappeared in a triphasic manner from the plasma with an initial plasma t1/2 of 9.4 +/- 4.2 min, an intermediary t1/2 of 1.4 +/- 0.5 h, and a terminal t1/2 of 40.6 +/- 4.6 h. The plasma clearance was 114.0 +/- 20.1 ml/kg-1 h-1 and the steady-state volume of distribution was 6.2 +/- 0.7 1/kg. In 72 h, 40.1% +/- 4.0% of the administered radioactivity was excreted in the urine, 17.8% +/- 2.7% of which was unchanged HHT. HHT was metabolized extensively to one major and two minor metabolites. Biliary excretion of total radioactivity was 14.4% in 5 h, 2% of which was HHT. HHT concentration in the CSF was highest 4 h after drug administration, about 40% of the concentration in the concurrent plasma. At autopsy 5 h after dosing, the highest percentage of HHT was in the liver (7.4%), followed by the small intestine (2.5%), stomach (1.0%), pancreas (0.8%), kidneys (0.8%), and lungs (0.7%). The heart, spleen, large intestine, and brain each retained less than 0.5%. However, 24 h after dosing, 4% of the HHT still remained in the liver, 1% in the small intestine, and less than 1% in the other organs. HHT seems to be extensively metabolized in dogs and partially retained in the body.

Alkaloids↗
PubMed1987

Central nervous system (CNS) penetration of homoharringtonine (HHT).

Generally tritiated homoharringtonine ([3H]HHT, 150 microCi, 430 micrograms) was administered intravenously to seven patients at varying times before surgical resection of malignant brain tumor. Plasma, urine, cerebrospinal fluid (CSF), and tumor specimens were obtained during surgery, and the concentrations of HHT, its major metabolite, and [3H]HHT equivalent were determined chromatographically and radiochemically. For [3H]HHT equivalent, the concentration in tumor ranged from 0.6 to 4.3 ng/g and the ratio of tumor to plasma concentration from 0.5 to 1.8. In one patient who had CSF available for drug determination, the CSF to plasma ratio of total [3H]HHT was 0.3 at 45 minutes after drug administration and less than 0.2 ng/ml was unchanged HHT. For unchanged HHT, drug concentration in tumor ranged from undetectable (4 patients) to 1.8 ng/g. A major metabolite of HHT was detectable in the tumor specimens of all the patients. These results indicate that homoharringtonine can penetrate into brain tumors; in 3 patients with brain tumors, the ratios of HHT concentration in the tumor to that in the concurrent plasma were greater than one.

Alkaloids↗
PubMed1987

Comparison of CNS penetration, tissue distribution, and pharmacology of VP 16-213 by intracarotid and intravenous administration in dogs.

Eight beagle dogs received [3H]VP 16-213 at 2 mg/kg administered intravenously (IV) or intra-arterially (IC) through a catheter inserted into the internal carotid artery. Blood, urine, bile, and cerebrospinal fluid (CSF) samples were collected at intervals. At 1, 6, 24 hr, and 2 weeks after drug administration the dogs were sacrificed and the major organs analyzed for drug concentration. VP 16-213 concentration was determined by radiochemical assay and high pressure liquid chromatography. The plasma t1/2 in the IC group of dogs was 1.0 hr, the volume of distribution was 1.7 L/kg and the clearance was 1.5 ml/hr/kg. In the IV group the values were 1.7, 3.9, and 1.6, respectively. The CSF concentration peaked at 1 hr by both routes, but was higher at all time points in the IC group. At 24 hr and 2 weeks after IC VP 16-213, drug concentration in brain tissue was at least four times higher in the IC group compared with the IV group. In extracranial organs the reverse was true, with the bone marrow cell concentration 1.6 times higher by IV compared to IC (267.2 ng/g and 164.5 ng/g, respectively). Two major and one minor metabolites were found in plasma, urine, bile, and tissue by both routes, however, not all metabolites were found in all organs and body fluids. No acute neurologic toxicity was noted in the IC group and no histopathologic changes by light microscopy were found in the brain or other organs. IC VP 16-213 produced higher drug concentration in the brain of dogs compared with IV administration and was well tolerated at the dosage used.

Animals↗
PubMed1986

Biochemical pharmacology of N-acetyl-N-(methylcarbamoyloxy)-N'-methylurea (caracemide; NSC-253272).

Preclinical pharmacologic studies of caracemide [N-acetyl-N-(methylcarbamoyloxy)-N'-methylurea; CAR] have demonstrated a marked instability of this compound in the presence of either phosphate buffer (pH 7.4) or human plasma. Using [1-14C-acetyl]CAR and [3H-methylcarbamoyloxy]CAR, three CAR degradation products were identified: product A, N-(methylcarbamoyloxy)acetamide; product B: N-(methylcarbamoyloxy)-N'-methylurea; and product C: N-hydroxy-N'-methylurea. CAR degradation in human plasma was demonstrated by high-performance liquid chromatography (HPLC) to occur in a time- and temperature-dependent manner. A 30-min incubation (37 degrees) of CAR (10(-4) M) with human plasma resulted in degradation of more than 55% of parent compound; at 1 hr, more than 75% of original CAR was degraded. Incubation of [1-14C-acetyl]CAR with rat brain homogenate resulted in the formation of 14CO2. This reaction was partially inhibited by coincubation with physostigmine (10(-3) M). CAR inhibited acetylcholinesterase activity in neuroblastoma cells with an IC50 of 14 microM. In mechanism of action studies, CAR was found to inhibit ribonucleotide reductase activity but only at nine times the IC50 of hydroxyurea. In contrast to hydroxyurea, CAR was found to be non-cell-cycle phase-specific and non-cross-resistant with two CHO cell lines resistant to hydroxyurea. These data demonstrate the instability of CAR; moreover, they suggest that its mechanism of cytotoxicity is distinctly different from that of hydroxyurea and that the neurotoxicity associated with CAR administration may be caused in part by inhibition of acetylcholinesterase activity.

Acetylcholinesterase↗