Biomedical subjects

T J Liu

Publications and source records attributed to T J Liu.

At least 19 recordsLinked to original sources

PubMed2005

PAX6 suppresses growth of human glioblastoma cells.

PURPOSE: Glioblastomas (GBMs) are the most common primary malignant brain tumors. Majority of GBMs has loss of heterozygosity of chromosome 10. The PAX6 encodes a transcription factor that involves in development of the brain, where its expression persists. We have reported that the expression of PAX6 was significantly reduced in GBMs and that a low level of PAX6 expression is a harbinger of an unfavorable prognosis for patients with malignant astrocytic glioma. Interestingly, PAX6 expression was increased in suppressed somatic cell hybrids derived from introducing a normal human chromosome 10 into U251 GBM cells. Thus it is interesting to determine if repression of PAX6 expression is involved in anti-tumor suppression function in GBM. EXPERIMENTAL DESIGN: We overexpressed PAX6 in a GBM cell line U251HF via either stable transfection or infection with recombinant adenovirus, and examined cell growth in vitro and in vivo. RESULT: Although we did not observe changes in the cell doubling time for PAX6-stable transfectants, significantly fewer numbers of PAX6-positive colonies grew in soft agar. Transient overexpression of PAX6 via adenovirus, however, suppressed cell growth by increasing the number of cells in G1 and by decreasing the number of cells in S-phase, and later on caused a dramatic level of cell death. Repeated subcutaneous and intracranial implantation experiments in nude mice using PAX6-stable transfectants provided solid evidence that PAX6 suppressed tumor growth in vivo and significantly extended mouse survival. CONCLUSION: Our data demonstrate that PAX6exerts a tumor suppressor function that limits the growth of GBM cells.

Animals↗

PubMed2001

Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN.

Human gliomas are highly invasive, and remain to be a major obstacle for any effective therapeutic remedy. Among many other factors, gliomas express elevated levels of matrix metalloproteinases (MMPs), which have been implicated to play an important role in tumor invasion as well as neovascularization. The tumor suppressor gene mutated in multiple advanced cancers/phosphatase and tensin homologue (MMAC/PTEN) has been shown to inhibit cell migration, spreading, and focal adhesion. In this study, we determined whether MMAC/PTEN inhibits tumor invasion by modulating MMP-2 activity. Our results showed that reintroduction of the MMAC/PTEN gene into human glioma U251 and U87 cells modified their phenotype and growth characteristics. The ability of MMAC/PTEN to induce anoikis in U251 cells was accompanied by a significant inhibition of in vitro invasion (70%). Expression of MMAC/PTEN in U251 and U87 cells inhibited MMP-2 enzymatic activity as determined by zymography. Furthermore, MMAC/PTEN expression strongly decreased MMP-2 mRNA levels, which correlated well with the inhibition of invasion capacity in these cells. Concomitant with MMP-2 expression and activity, MMP-2 promoter activity was also reduced in MMAC/PTEN expressing cells. Our observations suggest that MMAC/PTEN inhibits tumor cell invasion in part by regulating MMP-2 gene transcription and thereby its enzymatic activity. Further characterization of this regulation will facilitate the development of MMAC/PTEN based gene therapy for gliomas.

Anoikis↗

PubMed2001

Restoration of endogenous wild-type p53 activity in a glioblastoma cell line with intrinsic temperature-sensitive p53 induces growth arrest but not apoptosis.

p53 protein is a transcription factor involved in multiple tumor-suppressor activities including cell cycle control and apoptosis. TP53 gene is frequently mutated in glioblastoma, suggesting the importance of inactivation of this gene product in gliomagenesis. Restoration of p53 function in glioblastoma cell lines deficient for p53 has shown that p53 induces growth arrest or apoptosis depending on the cell line and vector used to transduce wild-type TP53 alleles. Considering that astrocytes grow and express p53, it is not clear whether these results reflect physiologic responses or the result of p53 overexpression in combination with cellular responses to viral vector infection. Here, we reassessed this issue using a glioblastoma cell line (LN382) that expresses an endogenous temperature-sensitive mutant p53. This cell line expresses TP53 alleles (100% as determined by a p53 transcriptional assay in yeast) mutated at codon 197 GTG (Val) > CTG (Leu). We found that the p53 protein in these cells acted as an inactive mutant at 37 degrees C and as a functional wild-type p53 below 34 degrees C as demonstrated by several lines of evidence, including (i) restoration of transactivating ability in yeast, (ii) induction of p53-modulated genes such as CDKN1(p21) and transforming growth factor-alpha, (iii) disappearance of accumulated p53 protein in the nucleus and (iv) decrease in steady state p53 protein levels. This temperature switch allowed p53 levels, which were close to physiological levels to dramatically reduce LN382 cell proliferation by inducing a G(1)/S cell cycle block, but not to induce apoptosis. The lack of apoptosis was considered to be a result of the low level p53 expression, because increasing wild-type p53 levels by adenoviral-mediated gene transfer caused apoptosis in these cells. The LN382 cell line will be extremely useful for investigations into the roles of p53 in cellular responses to a variety of stimuli or damages.

Apoptosis↗

PubMed2001

Transfer of E2F-1 to human glioma cells results in transcriptional up-regulation of Bcl-2.

Strong evidence exists to support the tenet that activation of E2F transcription factors, via alterations in the p16-cyclin D-Rb pathway, is a key event in the malignant progression of most human malignant gliomas. The oncogenic ability of E2F has been related to the E2F-mediated up-regulation of several proteins that positively regulate cell proliferation. However, E2F may indirectly enhance proliferation by activating antiapoptotic molecules. In this work, we sought to ascertain whether E2F-1-mediated events involve the up-regulation of the antiapoptotic molecule Bcl-2. Western blot analyses showed up-regulation of Bcl-2 but not of Bcl-x(L) by 24 h after the transfer of E2F-1. Northern blot studies showed that transfer of E2F-1 also up-regulated Bcl-2 RNA. In support of these findings and the concept that E2F-1 has a direct effect in the induction of Bcl-2, we found a putative E2F binding site within the Bcl-2 sequence. Subsequent gel-mobility shift and supershift experiments involving the CTCCGCGC site in the bcl-2 promoter showed that E2F-1 bound Bcl-2. Transactivation experiments consistently showed that ectopic E2F-1 activated responsive elements located in the -1448/-1441 region in the P1 promoter region of the bcl-2 gene. As expected, other members of the E2F family of transcription factors such as E2F-2 and E2F-4 also transactivated the bcl-2 promoter. Our results demonstrate that E2F-1 modulates the expression of the antiapoptotic molecule Bcl-2 and suggest that up-regulation of Bcl-2 may favor the oncogenic role of E2F-1 and other members of the E2F family of transcription factors.

Binding Sites↗

PubMed2001

Inhibition of breast cancer growth in vivo by antiangiogenesis gene therapy with adenovirus-mediated antisense-VEGF.

Increased expression of VEGF in several types of tumours has been shown to correlate with poor prognosis. We used a replication-deficient adenoviral vector containing antisense VEGF cDNA (Ad5CMV-alphaVEGF) to down-regulate VEGF expression and increase the efficiency of delivery of the antisense sequence in the human breast cancer cell line MDA231-MB. Transfection of these cells with Ad5CMV-alphaVEGF in vitro reduced secreted levels of VEGF protein without affecting cell growth. Moreover, injection of the Ad5CMV-alphaVEGF vector into intramammary xenografts of these cells established in nude mice inhibited tumour growth and reduced the amount of VEGF protein and the density of microvessels in those tumours relative to tumours treated with the control vector Ad5(dl312). Our results showed that antisense VEGF(165)cDNA was efficiently delivered in vivo via an adenoviral vector and that this treatment significantly inhibited the growth of established experimental breast tumours. The Ad5CMV-alphaVEGF vector may be useful in targeting the tumour vasculature in the treatment of breast cancer.

Adenoviridae↗

PubMed2001

Nonoperative treatment versus posterior fixation for thoracolumbar junction burst fractures without neurologic deficit.

STUDY DESIGN: A prospective clinical trial was conducted. OBJECTIVE: To compare the results of nonoperative treatment versus short-segment posterior fixation using pedicle screws. SUMMARY OF BACKGROUND DATA: A previous study showed that nonoperative treatment with early mobilization produced good results, even when the posterior column was involved. METHODS: This study involved 80 patients. Inclusion criteria required the following: neurologically intact patient, single-level closed burst fracture involving T11-L2, no fracture dislocations or pedicle fractures, age of 18 to 65 years (nonpathologic adult), and no other major organ system or musculoskeletal injuries. Patients in the nonoperative group (n = 47) were allowed activity to the point of pain tolerance beginning on the day of injury using a hyperextension brace. Patients in the operative group (n = 33) underwent three-level, (one above, one at fracture level, and one below) fixation using VSP or TSRH instrumentation. The follow-up period was 2 years. RESULTS: The surgical group had less pain up to 3 months and a better Greenough Low Back Outcome Score up to 6 months, but the outcome was similar afterward. No neurologic deficit in any patient. In the nonoperative group, the kyphosis angle worsened by 4 degrees, and the retropulsion decreased from 34% to 15%. In the operative group, there was one case of superficial infection and two cases of broken screws. The kyphosis angle was improved initially by 17 degrees, but this was gradually lost. Hospital charges were four times higher in the operative group. CONCLUSIONS: Short-segment posterior fixation provides partial kyphosis correction and earlier pain relief, but the functional outcome at 2 years is similar. Early activity to the point of pain tolerance can be safely allowed.

Adult↗

PubMed2001

P-Glycoprotein and multidrug resistance-related protein expressions in relation to technetium-99m methoxyisobutylisonitrile scintimammography findings.

The purpose of this study was to retrospectively study 48 patients with infiltrating ductal breast cancer to evaluate the relationship between the degree of accumulation of technetium-99m methoxyisobutylisonitrile (Tc-MIBI) and P-glycoprotein (Pgp) or multidrug resistance-related protein (MRP) expression in breast cancer tissues. Before surgery or biopsy, all 48 patients underwent scintimammography started 10 min after the injection of Tc-MIBI. Tumor:background (T:B) ratios were calculated from the Tc-MIBI scintimammography. Immunohistochemical analysis was performed on the pathological specimens of the 48 breast tumors to determine Pgp and MRP expression. According to the results of immunohistochemical analysis, the 48 breast cancers were separated into four groups: (a) group 1, 12 cancers with both positive Pgp expression and positive MRP expression; (b) group 2, 12 cancers with positive Pgp expression and negative MRP expression; (c) group 3, 12 cancers with negative Pgp expression and positive MRP expression; and (d) group 4, 12 cancers with both negative Pgp expression and negative MRP expression. Among the four groups, the T:B ratio was lowest in group 1 (1.13+/-0.10) and highest in group 4 (2.17+/-0.14), respectively (P < 0.05). The T:B ratios of groups 2 (1.30+/-0.25) and 3 (1.32+/-0.26) were between those of groups 1 and 4. Our data confirmed that Tc-MIBI scintimammography is useful for determining Pgp and MRP expression in patients with breast cancers.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Growth suppression of human coronary vascular smooth muscle cells by gene transfer of the transcription factor E2F-1.

BACKGROUND: The transcription factor E2F-1 promotes S-phase entry and death in transformed cells and primary cardiomyocytes. We tested the hypothesis that overexpression of E2F-1 forces growth-arrested human coronary vascular smooth muscle cells (VSMCs) to enter the S phase, undergo apoptosis, and thereby regulate VSMC growth. METHODS AND RESULTS: Early-passage (</=5 passages) coronary VSMCs were transduced at an MOI of 100 with a recombinant adenovirus encoding human E2F-1. E2F-1 expression was observed by immunohistochemistry as early as 6 to 8 hours after exposure of the VSMCs to Ad.E2F-1 but not to the control vector Ad.RR. When cells were kept in growth-arrest medium, 40% of Ad.E2F-1-treated VSMCs entered the S phase by 96 hours, whereas the percentage remained <5% in Ad.RR-treated cells. Transition to the S phase in the E2F-1-transduced VSMCs was followed by apoptosis, as reflected by chromatin condensation, membrane blebbing, cell detachment, and loss of mitochondrial membrane integrity. E2F-1 overexpression resulted in positive dUTP nick end-labeling mediated by terminal deoxynucleotidyl transferase, associated with a robust increase in caspase 3-like activity. Four days after infection with Ad.E2F-1, the fraction of hypodiploid VSMCs in subG(1) increased to 75%. At 7 days, gene transfer of E2F-1 had completely suppressed the growth of VSMCs, whereas the number of Ad.RR-infected cells had increased >8 times. CONCLUSIONS: Overexpression of the transcription factor E2F-1 regulates growth of human coronary VSMCs by forcing the cells to enter the S phase and then to die. Cell death appears to involve caspase 3-like activity, which, in the VSMCs, is markedly increased by overexpression of E2F-1.

Adenoviridae↗

PubMed2001

Enantiomeric recognition of chiral 3,3-bridged-1,1'-binaphthol dimer toward alpha-phenylethylamine and alpha-amino acid ester.

The 1,1'-binaphthol-based dimers with p-phenylenebis(2-ethynyl) spacer, (+)-6 and (+)-2, were synthesized as chiral host compounds. (1)H NMR, UV-vis, and fluorescent titration were used to evaluate the enantiomeric recognition abilities of the chiral host dimers toward the guest amine 7 and alpha-amino acid ester 8. The chiral BINOL-based dimers were found to have good enantiomeric recognition ability. The computer simulation of the host-guest complex molecules was carried out to describe the conformational changes of both naphthyl ring in the molecule of chiral host dimer after complexation with the guest molecule.

Alkynes↗

PubMed2001

Liver resection for hepatocellular carcinoma in patients with end-stage renal failure.

BACKGROUND AND OBJECTIVES: Surgical resection remains the main option for curing hepatocellular carcinoma (HCC). However, liver resection in patients with end-stage renal disease (ESRD) is risky. The aim of this study is to clarify the role of liver resection for treating HCC in patients with ESRD. METHODS: A retrospective review was carried out on 468 patients who underwent liver resection for HCC between 1989 and 1999. The clinicopathological characteristics and operative results of 12 patients who had ESRD (ESRD group) were compared with those of the other 456 patients who did not have ESRD (non-ESRD group). In the ESRD group, heparin-free hemodialysis using the periodic saline-rinse method was performed during the perioperative period. RESULTS: The ESRD group had lower hemoglobin and a higher serum creatinine levels. Other patient background and tumor pathological characteristics were comparable between the two groups as well. The operative morbidity and mortality between the two groups were also similar. The 5-year disease-free survival rates for ESRD and non-ESRD groups were 35.0 and 34.2% (P = 0.31), respectively, while the 5-year actuarial survival rates were 67.8 and 53.3% (P = 0.54), respectively. CONCLUSION: With improving techniques and knowledge of dialysis, liver resection for HCC is justified in selected patients with ESRD.

Adult↗

PubMed2001

Management of acute pancreatitis: results of a 15-year experience in Taiwan.

In the past two decades, there have been great changes regarding the policy for treating acute pancreatitis. The aim of this study was to examine the chronological changes in the management of acute pancreatitis in a tertiary referral center. A retrospective review was carried out of the management approaches for acute pancreatitis in the 15 years since 1984. The patients were divided into groups according to the admission date, representing two periods: period 1, from 1984 through 1992; and period 2, from 1993 through 1999. Decision-making for treating acute pancreatitis was based mainly on Beger's criteria. The background features and treatment outcome were compared between the two periods. The severity of pancreatitis was based on the Atlanta classification system. Octreotide was available from January 1993. No differences could be found between the two periods regarding the patients' background characteristics or severity of pancreatitis. Patients in period 2 had a longer interval between the onset of pancreatitis and surgery, and a lower incidence of pancreatectomy. Although the surgical morbidity, mortality, and reoperation rates were not significantly different between the two periods, more patients with severe acute pancreatitis in period 2 received nonsurgical treatment, and a lower mortality rate was also noted. With improvements in critical care, increasing experience, and better surgical techniques, even patients with severe acute pancreatitis can be treated by nonsurgical means. However, aggressive surgical intervention is necessary for patients who have signs of infected necrosis and whose disease is not controllable by conservative methods.

Adult↗

PubMed2001

Delivery of cell cycle genes to block astrocytoma growth.

Current therapies for glioblastoma multiforme are ineffective. Therefore, novel therapies that target specific differences between normal and malignant cells are urgently needed. Abnormalities of cell-cycle related genes are a common feature of cancer in general and astrocytic tumors in particular. The role of these proteins is to help to regulate cell proliferation, differentiation and apoptosis. Restoring wild-type activity of critical regulators of the cell cycle to astrocytic tumors generally results in modification of the growth properties, and often the viability, of the cancer cells. Transfer of p53 induces growth arrest and, more importantly, apoptosis. Restoration of the Rb pathway results in either reversible growth arrest or senescence. Expression of E2F-1 induces transient increase of proliferation followed by massive apoptosis. Overexpression of MMAC/PTEN arrests cell cycle progression in G1 and promotes anoikis. Current knowledge of the functions of these cell-cycle controllers can be used to design small peptides and drugs to induce cell-cycle related anti-cancer effect. Inactivation of the p53 and Rb pathways in cancer cells is also being used to engineer mutant viruses that are able to replicate exclusively in cancer cells.

Animals↗

PubMed2001

Improving operative safety for cirrhotic liver resection.

BACKGROUND: Liver resection in a patient with cirrhosis carries increased risk. The purposes of this study were to review the results of cirrhotic liver resection in the past decade and to propose safe strategies for cirrhotic liver resection. METHODS: Based on the date of operation, 359 cirrhotic liver resections in 329 patients were divided into two intervals: period 1, from September 1989 to December 1994, and period 2, from January 1995 to December 1999. The patient backgrounds, operative procedures and early postoperative results were compared between the two periods. The factors that influenced surgical morbidity were analysed. RESULTS: In period 2, patient age was higher and the amounts of blood loss and blood transfused were lower. Although postoperative morbidity rates were similar, blood transfusion requirement, postoperative hospital stay and mortality rate were significantly reduced in period 2. No death occurred in 154 consecutive cirrhotic liver resections in the last 38 months of the study. Prothrombin activity and operative time were independent factors that influenced postoperative morbidity. CONCLUSION: With improving perioperative assessment and operative techniques, most complications after cirrhotic liver resection can be treated with a low mortality rate. However, more care should be taken if prothrombin activity is low or there is a long operating time.

Adult↗

PubMed2001

Introduction of mutant p53 into a wild-type p53-expressing glioma cell line confers sensitivity to Ad-p53-induced apoptosis.

Transient expression of the tumor suppressor gene p53 via adenoviral-mediated gene transfer induces apoptosis in glioma cells expressing mutant p53, while causing cell cycle arrest in cells with wild-type p53. To determine whether a change in p53 status of a wild-type p53-expressing cell line such as U-87 MG would alter its apoptotic resistant phenotype in response to Ad-p53 infection, we generated cell lines U-87-175.4 and U-87-175.13 via retroviral-mediated gene transfer of the p53 (175H) mutant into the U-87 MG parental line. Control cell lines U-87-Lux.6 and U-87-Lux.8 were also generated and express the reporter gene luciferase. Both U-87-175.4 and U-87-175.13, but not control cell lines, exhibited morphology characteristic of apoptosis after Ad-p53 infection. Furthermore, expression of other p53 mutants (248W, 273H) in U-87 MG also sensitized cells to Ad-p53-induced apoptosis. Apoptosis was confirmed by TUNEL and cell cycle analysis. Several p53 response genes were examined in cells infected with Ad-p53, and among these, BCL2, p21WAF1/CIP1, CPP32/caspase 3, and PARP showed differences in expression between U87-175 and U87-Lux cell lines. Taken together, our data demonstrate that the introduction of p53 mutants in U-87 MG promotes an apoptotic response in association with adenoviral-mediated wild-type p53 gene transfer. These results underscore the importance of glioma p53 genotype for predicting tumor response to p53-based gene therapy.

Adenoviridae↗

PubMed2001

Co-expression of E2F-2 enhances the p53 anti-cancer effect in human glioma cells.

Gliomas are highly resistant to conventional treatment. Improved knowledge of the molecular defects of glioma cells offers new avenues for the development of gene therapy strategies. Transfer of the p53 gene has proven effective in suppressing proliferation in human glioma cell lines. However, several human glioma cell lines are resistant to p53-induced cell death. The E2F family of transcription factors are pivotal for the regulation of cell-cycle and cell-death related genes in gliomas. In the present study, we sought a more effective strategy for glioma treatment by examining the therapeutic potential of the simultaneous transfer of p53 and E2F-2 to gliomas. Trypan blue cell viability assays and flow cytometric cell-cycle analysis demonstrated that the transfer of both p53 and E2F-2 induced cell death in D-54 MG, a p53-resistant glioma cell line. In addition, transfer of E2F-2 did not interfere with the apoptotic properties of exogenous wild-type p53 in U-251 MG cells. Finally, the expression of E2F-2 in D-54 MG cells suppressed the expression of the apoptotic molecule mdm-2 induced by exogenous p53 in these cells. These results show that co-expression of E2F-2 and p53 enhances the anti-cancer effect of p53 in gliomas.

Actins↗

PubMed2001

Adenovirally-mediated transfer of E2F-1 potentiates chemosensitivity of human glioma cells to temozolomide and BCNU.

The therapeutic efficacy of standard cancer treatments such as chemotherapy may be improved if they are combined with gene-therapy. Less than 30% of patients with glioblastoma multiforme respond to adjuvant chemotherapy. Actively dividing cells are generally more sensitive to chemotherapy than are non-dividing cells. To determine whether forced cell-cycle progression selectively sensitizes tumor cells to alkylating agents, we examined the effects of overexpressing the E2F-1 protein (a positive regulator of cell-cycle progression) on the sensitivity of two malignant human glioma cell lines, U-251 MG and D-54 MG, to BCNU and temozolomide. Treating these cells with 20-35 microM BCNU or 20-30 microM temozolomide resulted in 50% growth inhibition (IC50) within 4 or 6 days, respectively. By contrast, cells that were first induced to overexpress E2F-1 protein by infection with an adenoviral vector had IC50s that were 37-50% lower. Conversely, transferring the cyclin-dependent kinase inhibitors p16 and p21 to the cells, also by adenoviral infection, produced 3 to 4-fold increases in chemoresistance. Cell-cycle analyses showed that the combination of E2F-1 overexpression and treatment with BCNU or temozolomide increased the proportion of cells in S phase, but the combination of p16 or p21 overexpression and drug treatment reduced the proportion of cells in S phase. These observations suggest that overexpression of genes that positively control cell-cycle progression may be useful for increasing the sensitivity of glioma cells to alkylating agents.

Adenoviridae↗

PubMed2001

Human progesterone receptor shows differential sensitivity to carboxyl group modifying agents when bound to agonist and antagonist ligands.

BACKGROUND: Modulation of human uterine progesterone receptor (PR) in relation to its binding to synthetic steroids with known agonist (R5020) and antagonist (triamcinolone acetonide, T.A.) properties was studied in the presence of the specific carboxyl group modifiers, N,N'-dicyclohexylcarbodiimide (DCCD) and 1-ethyl-3-carbodiimide hydrochloride (EDC). METHODS: Uterine cytosol was treated with DCCD or EDC. The amounts of total bound were detected using the steroid binding measurements. The formation and transformation of progesterone-receptor complexes (PRc) were analyzed using sedimentation rate analysis. RESULTS: Our studies show that the modification of the COOH group differentially influences the properties of mammalian PR binding with either R5020 or T.A. DCCD and EDC affect the steroid binding of PR by decreasing the binding sites, not by the changing the affinity. CONCLUSION: Our studies indicate the importance of the carboxyl group in steroid binding by PR. This implies that both aspartic acid and glutamic acid residues, which have the carboxyl group, may play an important role when PR binds with steroid ligands.

Cytosol↗

PubMed2001

Pharmacokinetics of enantiomers of trans-tramadol and its active metabolite, trans-O-demethyltramadol, in human subjects.

AIM: To study the stereoselectivity in pharmacokinetics of the enantiomers of trans-tramadol (trans-T) and its active metabolite, trans-O-demethyltramadol (M1) in human subjects. METHODS: Trans-T hydrochloride sustained-release tablets were taken orally by 12 healthy male volunteers. After a multiple dosage schedule, the serum concentrations of (+)-trans-T, (-)-trans-T, (+)-M1, and (-)-M1 were determined in serum by high performance capillary electrophoresis (HPCE). RESULTS: (+)-Trans-T, (-)-trans-T, (+)-M1 and (-)-M1 in human serum were separated by HPCE. The linear range was 2.5-320 microg/L for the enantiomers of trans-T, and 2.5-50 microg/L for the enantiomers of M1. For the enantiomers of trans-T and M1, the intra-day and inter-day RSD were less than 15 % and 20 %, and the relative recoveries were 94.3 %-106.2 % and 90.4 %-107.8 %, respectively; the limit of quantitation was 1.25 microg/L. The serum concentrations of the enantiomers of trans-T reached a steady state in 12 subjects on d 4 after the initial administration. The steady state serum concentrations of (+)-trans-T were higher than that of (-)-trans-T at every sampling points in the subjects. The differences were significant in the main pharmacokinetic parameters between (+)-trans-T and (-)-trans-T except Tmax. The serum concentrations of (-)-M1 were higher than that of (+)-M1 in most subjects and at most sampling time points. There were significant differences in Cmax and Cmin between the enantiomers of M1. CONCLUSION: The pharmacokinetics of trans-T and M1 was found to be stereoselective. (+)-Trans-T was shown to be absorbed completely, but eliminated more slowly. The pharmacokinetic stereoselectivity of M1 was different among human subjects.

Adolescent↗