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M L Chen

Publications and source records attributed to M L Chen.

At least 91 records · Page 5Linked to original sources
PubMed1998

Metrics comparing simulated early concentration profiles for the determination of bioequivalence.

PURPOSE: To compare the effectiveness of various metrics which evaluate bioequivalence in the early phase of concentration-time profiles. METHODS: Two-period crossover trials were simulated with increasing assumed ratio of the true absorption rate constants of the two formulations, and with various kinetic models. Kinetic sensitivities (KS) and standard errors (SE) of the various metrics were recorded and the percentage of trials accepting bioequivalence (the statistical power) was evaluated. The principal metrics included the partial AUC(AUCP), the intercept obtained by linear extrapolation of the ratios of the lower over higher concentrations (C) measured for the two formulations (I L/H), and the ratios of intercepts extrapolated from logarithmic C/ time values of the two products (MLOG). For comparison, also properties of CMAX and an ideally evaluated measure (Id) were determined. RESULTS: MLOG showed generally the highest statistical power and KS, and also the largest SE, closely followed by I L/H. Partial AUC exhibited lower power and KS, but also smaller SE than the intercept procedures. The three methods had much higher power, KS and SE than CMAX. These comparisons were maintained over various kinetic conditions and experimental designs. The effective evaluation of bioequivalence in the early phase of studies is assured with 3 (or more) measurements until the population average peak of the reference formulation. CONCLUSIONS: The three principal methods assess bioequivalence very effectively in the early phase of a concentration-time profile. MLOG had the highest statistical power, closely followed by I L/H and then by partial AUC.

Area Under Curve↗
PubMed1998

The duration of measuring partial AUCs for the assessment of bioequivalence.

PURPOSE: To determine favourable sampling conditions for assessing bioequivalence by the comparison of partial AUCs in the early phase of concentration-time profiles. METHODS: Two-period crossover trials were simulated. They assumed a wide range of the ratios of absorption rate constants of the test (T) and reference (R) formulations (kaT/kaR). Averages and standard deviations of the corresponding ratios of simulated partial AUCs (AUCpT/AUCpR) were determined together with the statistical power of assessing bioequivalence, i.e., the percentage of simulated trials in which bioequivalence was declared. RESULTS: The power for stating bioequivalence was high when AUCp was recorded until the earlier rather than the later of two peaks in each subject. Similarly, power was comparatively high when AUCp was measured until the time of the reference peak instead of multiples of this time. Power was high also when AUCp was determined until the fixed true, population mean time of the reference formulation instead of multiples of this time. The pattern for the kinetic sensitivity parallelled that found for the power, while the standard deviations changed generally in the opposite direction. CONCLUSIONS: The effectiveness (power) of evaluating bioequivalence in the early phase of concentration-time profiles by partial AUCs generally decreases when the duration for measuring the metric is extended. Among the investigated designs, determination of partial AUCs until the earlier of two peaks in each subject is the most powerful.

Area Under Curve↗
PubMed1998

Induction of apoptosis in human leukemic U937 cells by tetrandrine.

Tetrandrine, a calcium channel antagonist, is a plant alkaloid possessing various pharmacological activities including anti-tumor activity. We studied tetrandrine to determine whether or not this anti-tumor effect occurs through induction of apoptosis. Tetrandrine inhibited both proliferation and clonogenicity of human leukemic U937 cells at an optimal concentration of 2.5 microg/ml. This growth inhibition was dose and time dependent, and accompanied with evidence of apoptotic changes. The characteristic morphological changes of apoptosis were observed in U937 cells under light microscopy and DNA fragmentation was noted by gel electrophoresis. Moreover, flow cytometric detection of surface phosphatidyl serine expression of U937 cells after treatment with tetrandrine confirmed the induction of apoptosis in these cells. The induction of apoptosis by tetrandrine would appear to proceed via non-Ca2+-dependent pathways.

Alkaloids↗
PubMed1998

Urinary 1-hydroxypyrene concentrations in coke oven workers.

OBJECTIVES: To investigate the relation of individual occupational exposure to total particulates benzene soluble fraction (BSF) of ambient air with urinary 1-hydroxypyrene (1-OHP) concentrations among coke oven workers in Taiwan. METHODS: 80 coke oven workers and 50 referents were monitored individually for the BSF of breathing zone air over three consecutive days. Exposures were categorised as high, medium, or low among coke oven workers based on exposure situations. The high exposure group (n = 18) worked over the oven. The medium and low exposure groups (n = 41 and n = 21) worked at the side of the oven for > 4 hours and < 4 hours a day, respectively. Urine was collected before the shift on the morning of day 1 and after the shift on the afternoon of day 3 to find the change of 1-OHP concentrations across the shift. RESULTS: The median (range) changes of urinary 1-OHP concentrations across the shift for various exposure situations (microgram/g creatinine) were as follows: high 182 (7 to 3168); medium 9 (-8 to 511); low 7 (-6 to 28); and referents 0.2 (-2 to 72). This change of urinary 1-OHP was highly associated with individual occupational exposure to the BSF in air (r = 0.74 and 0.64, p < 0.001). The regression model showed significant effects of individual exposures to the BSF and alcohol consumption on urinary postshift 1-OHP after adjusting for preshift 1-OHP in the total population (n = 130). More exposure to the BSF led to higher postshift 1-OHP (p < 0.001); current drinkers of > 120 g/week had lower urinary postshift 1-OHP than never and former drinkers (p = 0.01). A 10-fold increase in the average BSF in air resulted in about a 2.5-fold increase in postshift 1-OHP among the 80 coke oven workers. CONCLUSION: Urinary 1-OHP concentrations can be used as a good biomarker to assess individual exposure to the BSF in air. Alcohol drinking may modify the toxicokinetic pathway of the BSF; the effects of alcohol should be investigated further in occupational studies.

Adult↗
PubMed1998

Transcriptional activation of functional endogenous estrogen receptor gene expression in MCF10AT cells: a model for early breast cancer.

Utilizing the MCF10AT xenograft model for progression of human proliferative breast disease, we detected expression of the endogenous estrogen receptor (ER) gene only in MCF10AneoT and cells of the MCF10AT system, all of which stably express a transfected mutated T24 Ha-ras gene. ER transcripts were undetectable in the parental MCF10A cells and in MCF10A cells transfected with normal c-Ha-ras or vector. ER transcripts expressed in MCF10AT cells contain a normal full-length ER coding region and direct synthesis of a normally sized ER protein. The protein is functional based on its ability to mediate estradiol (E2)-induced increases of transcription from both endogenous and exogenous E2-regulated genes. Transcriptional activation of the endogenous ER gene does not appear to be related to a change in methylation status of the gene since a diagnostic CpG site in exon 1 that is methylated in ER-negative breast tumors and completely unmethylated in ER-positive breast tumors is hypomethylated to the same extent in ER-negative MCF10A cells and ER-positive MCF10AT cells. E2 increased both the number and size of soft-agar colonies formed by MCF10AT3c cells, a line from a third generation MCF10AT xenograft lesion. This suggests that xenograft passage has selected for growth regulatory pathways that are E2-responsive and that identification of these pathways and their role in progression will aid in determining how E2 acts to increase risk of breast cancer.

Animals↗
PubMed1998

Temporal changes in urinary 1-hydroxypyrene concentrations in coke-oven workers.

Coke-oven workers are exposed to high concentrations of coke-oven emissions, which are comprised mainly of polycyclic aromatic hydrocarbons. We conducted a pilot study to determine the time changes in urinary 1-hydroxypyrene (1-OHP) concentrations, as a metabolite of pyrene, in coke-oven workers after exposure to a benzene-soluble fraction (BSF) of total particulates. Thirteen subjects, including 2 men (referents) from an administrative area, 6 workers who work at the sideoven, and 5 who work on the top of the oven in one coke-oven plant were studied. After 1.5 to 2 days off, subjects were monitored individually for breathing zone air BSF over 3 consecutive days in August 1995. Seven spot urine samples, including preshift and postshift urine over 3 days and preshift urine on a fourth-day morning, were collected to determine 1-OHP concentrations by fluorescent spectrophotometry. The mean ambient BSF concentrations in the sideoven and topside oven workers ranged from 18 to 159 microg/m3 and from 251 to 1362 microg/ m3, respectively, whereas the BSF concentrations in the referents were low but detectable (11 and 29 microg/m3). Urinary 1-OHP concentrations increased during the work period, from 10+/-3 and 41+/-9 microg/g creatinine (mean+/-SE) on the preshift first day to 57+/-26 and 334+/-63 microg/g creatinine on the postshift third day in the sideoven and topside oven workers, respectively. However, the urinary 1-OHP concentrations were relatively flat in the two referents. The across-shift change in urinary 1-OHP defined as postshift 1-OHP on the third day minus preshift 1-OHP on the first day was highly associated with individual mean occupational exposure to air BSF (r = 0.80, P = 0.001). Repeated-measures regression analyses revealed that daily postshift 1-OHP concentrations were marginally associated with daily air BSF. A 10-fold increase of daily air BSF resulted in a 1.67-fold increase of daily postshift 1-OHP levels (95% confidence interval = 0.99-2.83; P = 0.07). After adjusting for daily preshift 1-OHP concentrations, we found that a 10-fold increase of daily air BSF resulted in a 1.90-fold increase of daily postshift 1-OHP levels (95% confidence interval = 1.10-3.28; P = 0.03). Although the sample size is small in this study, these results indicate that daily postshift 1-OHP levels in urine are determined mainly by current occupational exposure to coke-oven emissions.

Air Pollutants, Occupational↗
PubMed1998

False-positive 2-[F-18]-fluoro-2-deoxy-D-glucose positron emission tomography studies for evaluation of focal pulmonary abnormalities.

Positron emission tomography (PET) with 2-[F-18]-fluoro-2-deoxy-D-glucose (FDG) can demonstrate the glucose metabolism characteristics of a lesion, which may be helpful in differentiating between benign and malignant focal pulmonary lesions. Malignant cells demonstrate higher glucose metabolic activity than benign lesions. However, some inflammatory processes also show significant FDG uptake. We present two cases where high FDG uptake was found in inflammatory lesions in the lungs. The first case was that of a 38-year-old woman with chronic cough for more than 20 years. FDG PET revealed a hypermetabolic lesion with a lesion-to-background ratio of 8.0 at the posterior aspect of the right middle lung. She underwent thoracotomy and tumor resection, and was diagnosed with cryptococcosis. The second case was that of a 72-year-old woman who had pulmonary tuberculosis previously with cavitation in the left lower lobe. She suffered from fever, chills and severe hemoptysis for several days before this admission. FDG PET revealed a hypermetabolic ring at the periphery of the cavity. The lesion-to-background ratio was 7.8. Echo-guided biopsy showed no evidence of malignancy. She was treated with antibiotics and the symptoms subsided gradually. Lung abscess complicating a pre-existing cavity was diagnosed. These two cases substantiate that positive FDG PET results should be interpreted with caution in differentiating benign from malignant pulmonary abnormalities, especially in regions with a high prevalence of granulomatous lesions.

Adult↗
PubMed1997

Vaporizing characteristics of mixed-solvents in indoor environment.

Vapor pressure is usually used for predicting the phase-transfer of solvent. Combining it with molar ratio of component in liquid phase, airborne concentration of solvent is theoretically calculated. It's worthwhile to clarify if it is true in real environment. This study examines the vaporizing profile of xylol (commercial xylene) manipulation in a paint-manufacturing plant. Twelve workers equipped with 3M 3500 passive organic vapor monitors were sampled for 3 days. Solvents were analyzed by a gas chromatograph with flame ionization detector. According to the results, concentration ratio of airborne ethylbenzene and xylene is 0.384, though the ratio is 1.0 in the liquid phase and both solvents have similar vapor pressures. This finding suggests that predicting solvent's airborne concentration by liquid composition and vapor pressure may distort the air pollution profile. Moreover, high temperature increased airborne concentration significantly.

Air Pollution, Indoor↗
PubMed1997

Clinical and perinatal sonographic features of congenital adrenal cystic neuroblastoma: a case report with review of the literature.

Cystic formation in association with adrenal neuroblastoma may be related to hemorrhage and necrosis of the tumor. We present an unusual case of congenital cystic fetal neuroblastoma of the right adrenal gland detected at 37 weeks' gestation which evolved into a complex echogenic mass 6 weeks after birth. Surgical exploration revealed a 3.5 x 3 x 3 cm right complex adrenal tumor which was resected. The infant did well 10 weeks after tumor resection. Typically adrenal hemorrhage may appear sonographically to be entirely echogenic, of mixed echogenicity, or anechoic when first imaged. Gradually, the texture of the hematoma will evolve and become more cystic and echolucent on follow-up ultrasound examinations. In contrast, our case of congenital adrenal cystic neuroblastoma became more complex after resolution of the hemorrhagic cyst. This case suggests that adrenal hemorrhagic and adrenal cystic neuroblastoma with a hemorrhagic cyst have different sonographic appearances. We suggest that additional imaging and surgical intervention should be considered whenever a cystic suprarenal mass becomes more complex after resolution and demonstrates no significant decrease in size in postnatal examinations.

Adrenal Gland Neoplasms↗
PubMed1997

Protective effect of tetrandrine on normal human mononuclear cells against ionizing irradiation.

Tetrandrine, an alkaloid isolated from the plant Stephania tetrandra, at low concentration (2 micrograms/ml) was shown to protect normal human mononuclear cells in vitro against damage due to a single high-dose of ionizing irradiation (10 Gy). The cell survival rate increased from 58.3 +/- 2.2% in the irradiated group to 78.0 +/- 2.6% in the tetrandrine-pretreated group, and similarly, the percentage of necrotic cells declined from 20.7 +/- 2.5% to 10.7 +/- 1.9%, respectively. This protective effect of tetrandrine for cell surviving fraction increased in a dose-dependent manner. Tetrandrine was also found to inhibit inflammatory responses induced by irradiation including the release of superoxide (NBT [nitroblue tetrazolium] reduction decreased from 21.3 +/- 2.3% to 10.2 +/- 2.5%) and phagocytic activity (decreased from 80.7 +/- 3.8% to 50.7 +/- 2.3%, the same range level as that of the control group). However, the alkaloid demonstrated no effect on the production of nitric oxide. In terms of cell morphology, only two types were observed-normal or necrotic cells, and there were no characteristics of programmed cell death. These results indicate that tetrandrine possesses radioprotective activity against 10 Gy of ionizing irradiation and could suppress irradiation-induced inflammatory processes.

Alkaloids↗
PubMed1997

Induction of 24-hydroxylase cytochrome P450 mRNA by 1,25-dihydroxyvitamin D and phorbol esters in normal rat kidney (NRK-52E) cells.

The biologically active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D), acts on intestinal, renal, and bone cells to regulate skeletal and mineral metabolism. 1,25(OH)2D also induces 24-hydroxylase activity in these target cells. The 24-hydroxylase hydroxylates 1,25(OH)2D to 1,24,25-trihydroxyvitamin D and 25(OH)D to 24,25-dihydroxyvitamin D. The production of 1,24,25-trihydroxyvitamin D is thought to be the first step in the inactivation of 1,25(OH)2D by its target tissues. Previous studies have characterized the induction of the 24-hydroxylase by 1,25(OH)2D in clonal cell lines from intestine and bone. The purpose of these studies was to characterize the induction of the 24-hydroxylase by 1,25(OH)2D in the kidney, using the clonal rat renal cell line NRK-52E. 1,25(OH)2D (10(-7)M) increased the mRNA levels for the cytochrome P450 component of the 24-hydroxylase (P450cc24) by sevenfold after 36 h in NRK-52E cells. 1,25(OH)2D increased P450cc24 mRNA levels in a dose-dependent manner with an EC50 of 10(-8) M. In parallel experiments, 1,25(OH)2D significantly increased 24-hydroxylase enzyme activity after 48-72 h. The increase in P450cc24 mRNA induced by 1,25(OH)2D required ongoing transcription and translation and was inhibited by H-7, a protein kinase C inhibitor. Tetradecanoyl phorbol acetate markedly increased the magnitude of the tissue responsiveness to 1,25(OH)2D by a protein kinase C-dependent pathway. These studies demonstrate that 1,25(OH)2D increases P450cc24 mRNA levels in NRK-52E cells by a mechanism requiring new protein synthesis and involving protein kinase C. This is in contrast to the action of 1,25(OH)2D in intestinal cells, which does not require new protein synthesis, and in osteoblastic cells, which does not involve protein kinase C.

Animals↗
PubMed1996

Heteromultimeric interactions among K+ channel subunits from Shaker and eag families in Xenopus oocytes.

Heteromultimeric interactions of K+ channel subunits across different families have been thought to contribute to the functional diversity of ionic currents, as suggested by previous genetic evidence. We present here direct demonstration in Xenopus oocytes that subunits from distinct eag and Shaker families functionally interact, most likely as heteromultimeric channels. Coexpression with eag accelerates the inactivation and slows the recovery from inactivation of the transient Shaker current. Site-directed mutagenesis indicates that the eag carboxyl terminus is crucial for this interaction, exerting effects preferentially on N-type inactivation. Many members of the eag and Shaker families have now been identified and their human homologs implicated in cardiac and neurological disorders. Studies on channel subunit interactions may prove important in understanding the disease pattern and the complex functions of the brain.

Alternative Splicing↗
PubMed1996

Absorption rate vs. exposure: which is more useful for bioequivalence testing?

PURPOSE: The goals were to evaluate the usefulness of Cmax/AUClqc, ratio of the maximum plasma drug concentration to the area under the plasma concentration-time curve to the time of the last quantifiable concentration, in bioequivalence testing and to explore the use of exposure as a replacement for the concepts of rate and extent of drug absorption. METHODS: The bioequivalence of products differing in both rate (ka) and extent (F) of absorption was assessed under conditions similar to those encountered in a typical trial. A one-compartment model drug with first-order absorption (rate constant = ka) and eliminations was used. Variability was introduced in all model parameters using Monte Carlo techniques. The results were expressed in terms of the probability of declaring bioequivalence in a cross-over trial with 24 subjects using Cmax/AUClqc, AUClqc, and Cmax as bioequivalence measures. RESULTS: The outcome of a bioequivalence trial was shown to depend on the measure. Cmax/AUClqc reflected changes in ka, but not in F. AUClqc showed dependence on F, but virtually no dependence on ka. For Cmax, a 3- to 4-fold increase in ka and a concomittant 20% decrease in F, as well as corresponding changes in the opposite directions, resulted in bioequivalent outcomes. CONCLUSIONS: It was concluded that use of Cmax/AUClqc should be discouraged and that defining bioequivalence in terms of rate and extent of absorption has major problems. The goal of bioequivalence trials should be to assure that the shape of the concentration-time curve of the test product is sufficiently similar to that of the reference product. To this end, the use of "exposure" rather than "rate and extent of absorption" concepts is encouraged.

Absorption↗
PubMed1996

The relationship of aging to endotoxin shock and to production of TNF-alpha.

BACKGROUND: Aged people are considered prone to gram-negative bacteremia and septic shock. This relationship was tested in murine endotoxin shock. METHODS: Balb/c mice of various ages (1.4-13.4 months) were intraperitoneally injected with lipopolysaccharide (LPS), and rates of survival were observed. The production of TNF-alpha in vivo induced by LPS was measured. RESULTS: The survival rates were the smallest in the oldest and youngest groups. Production of TNF-alpha attained a maximum at 2 h after LPS injection and was smaller in the oldest group; it had a reciprocal relationship to survival rates in each group except the youngest group. CONCLUSION: Old and young mice had smaller rates of survival and greater production of TNF-alpha following endotoxin shock induced by LPS.

Aging↗
PubMed1996

Induction of vitamin D receptor mRNA expression in psoriatic plaques correlates with clinical response to 1,25-dihydroxyvitamin D3.

Psoriasis is a skin disorder characterized by hyperproliferation of epidermal keratinocytes. 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3) and its analogs have been shown to inhibit keratinocyte proliferation in vitro and to be therapeutically effective for the treatment of psoriasis. Some patients with psoriasis, however, do not have a favorable response to 1 alpha,25 (OH)2D3 therapy. To evaluate the differential responsiveness to 1 alpha (OH)2D3 treatment, we examined the expression of vitamin D receptor mRNA in psoriatic lesions by reverse transcription-polymerase chain reaction using glyceraldehyde-3-phosphate dehydrogenase as an internal control. In this double-blind clinical trial, we recruited 18 patients who received topical treatment of 1 alpha,25(OH)2D3 (15 microgram/g Vaseline) or placebo on separated psoriatic lesions for 8 weeks. In patients who showed >90% clinical improvements of their psoriatic lesions with 1 alpha,25(OH)2D3 (n=9), an increase of 130+/-37% in vitamin D receptor mRNA level was observed in 1 alpha,25(OH)2D3-treated lesions when compared with the corresponding placebo controls. There was no increase in vitamin D receptor mRNA level in the lesions treated with this drug in patients who did not respond to the treatment. These data suggest that the antiproliferative activity of 1 alpha,25(OH)2D3 is closely associated with the expression of its cognate receptor.

Base Sequence↗
PubMed1996

High-efficiency gene transfer into CD34+ cells with a human immunodeficiency virus type 1-based retroviral vector pseudotyped with vesicular stomatitis virus envelope glycoprotein G.

Currently, amphotropic retroviral vectors are widely used for gene transfer into CD34+ hematopoietic progenitor cells. The relatively low levels of transduction efficiency associated with these vectors in human cells is due to low viral titers and limitations in concentrating the virus because of the inherent fragility of retroviral envelopes. Here we show that a human immunodeficiency virus type 1 (HIV-1)-based retroviral vector containing the firefly luciferase reporter gene can be pseudotyped with a broad-host-range vesicular stomatitis virus envelope glycoprotein G (VSV-G). Higher-efficiency gene transfer into CD34+ cells was achieved with a VSV-G-pseudotyped HIV-1 vector than with a vector packaged in an amphotropic envelope. Concentration of virus without loss of viral infectivity permitted a higher multiplicity of infection, with a consequent higher efficiency of gene transfer, reaching 2.8 copies per cell. These vectors also showed remarkable stability during storage at 4 degrees C for a week. In addition, there was no significant loss of titer after freezing and thawing of the stock virus. The ability of VSV-G-pseudotyped retroviral vectors to achieve a severalfold increase in levels of transduction into CD34+ cells will allow high-efficiency gene transfer into hematopoietic progenitor cells for gene therapy purposes. Furthermore, since it has now become possible to infect CD34+ cells with pseudotyped HIV-1 with a high level of efficiency in vitro, many important questions regarding the effect of HIV-1 on lineage-specific differentiation of hematopoietic progenitors can now be addressed.

Animals↗