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W Tong

Publications and source records attributed to W Tong.

At least 19 recordsLinked to original sources
PubMed1996

A comparative molecular field analysis study of N-benzylpiperidines as acetylcholinesterase inhibitors.

A series of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives and of N-benzylpiperidine benzisoxazoles has been investigated using the comparative molecular field analysis (CoMFA) approach. These compounds have been found to inhibit the metabolic breakdown of the neurotransmitter acetylcholine (ACh) by the enzyme acetylcholinesterase (AChE) and hence alleviate memory deficits in patients with Alzheimer's Disease by potentiating cholinergic transmission. Development of the CoMFA model considered two separate alignments: (i) alignment I which emphasized the electrostatic fitting of the subject compounds and (ii) alignment II which emphasized their steric fitting. In addition, the inhibitor compounds were considered both as neutral species and as N-piperidine-protonated species. The resulting 3D-QSAR indicates a strong correlation between the inhibitory activity of these N-benzylpiperidines and the steric and electronic factors which modulate their biochemical activity. A CoMFA model with considerable predictive ability was obtained.

Acetylcholinesterase↗
PubMed1996

Effect of particle size on molten states of starting powder and degradation of the relevant plasma-sprayed hydroxyapatite coatings.

Crystallinity of hydroxyapatite (HA) coatings is an important parameter to evaluate their stability. Variation of the size distribution of the starting powder is one way to alter crystallinity of coatings. The fundamental reason might be the variation of molten states of HA powders with different particle sizes. In the experiments, HA particles sized between 1 and 180 microns were divided into six groups by sieving. It was observed that the trend of crystallinity of coatings on particle size is not linear but fluctuates. The fluctuation of crystallinity was caused by the alteration of molten states of HA powders with different size distributions. It is concluded that the molten state of starting powder also fluctuated with particle size but the trend was different from that of crystallinity. Coatings sprayed with different particle sizes were immersed in deionized water for 1 month. After immersion, severe degradation and break-up were observed on the surface of coatings with the highest crystallinity, which were sprayed with large sized HA powders. It may be the high porosities in these coatings that cause the severe degradation. This shows that high crystallinity is not necessarily related to high stability of coatings and microstructure is of great importance when stability of coatings is considered.

Biocompatible Materials↗
PubMed1996

Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: a phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer.

PURPOSE: A phase II trial of paclitaxel infused over 96 hours in patients with metastatic breast cancer with demonstrated disease progression (PD) during short-infusion taxane treatment was performed to evaluate schedule-dependent activity with prolonged drug exposure. The tolerability of this strategy and its pharmacokinetic profile and pharmacodynamic correlates were also investigated. PATIENTS AND METHODS: Paclitaxel was administered to 26 patients with metastatic breast cancer at 120 to 140 mg/m2 intravenously over 96 hours. Twenty-three patients had demonstrated PD while receiving prior 3-hour paclitaxel, two during 1-hour docetaxel, and one during infusions of docetaxel and then paclitaxel. Twenty-one patients (81%) had no prior response to the short taxane infusion (primary resistance) and five (19%) had prior partial responses (PRs) of brief duration before PD (secondary resistance). Plasma paclitaxel concentrations were assessed at 24, 48, 72, and 96 hours. RESULTS: After delivery of 195 cycles, seven of 26 assessable patients (26.9%; 95% confidence interval, 11.6% to 47.8%) had major objective responses, with a median response duration of 6 months (range, 1 to 13). The predominant toxicities were neutropenia (76% grade > or = 3) and stomatitis (15% grade > or = 3). Despite omission of premedications, no significant hypersensitivity reactions occurred. The median steady-state paclitaxel concentration (Css) in 23 assessable patients was 0.047 mumol/L (range, .023 to .176). Patients who experienced grade 4 neutropenia had significantly decreased paclitaxel clearance and higher Css than those with grade 1 to 3 neutropenia (P < .05). Pretreatment elevation of hepatic transaminases was associated with delayed clearance (P < .01) and increased myelo-suppression and mucosal toxicity. CONCLUSION: Paclitaxel demonstrates activity against metastatic breast cancer when administered over 96 hours to patients with disease that recently had progressed during short taxane exposure. Delayed paclitaxel clearance and consequent increased toxicity occurred in patients with hepatic dysfunction. The activity observed supports preclinical data that suggest variability in efficacy and resistance patterns to paclitaxel based on duration of exposure.

Adult↗
PubMed1995

Tumor necrosis factor-alpha-dependent activation of a RelA homodimer in astrocytes. Increased phosphorylation of RelA and MAD-3 precede activation of RelA.

Rel proteins are important intracellular mediators of cytokine-induced signal transduction. To understand how cytokines affect different cell populations in the brain, we have characterized Rel activation in astrocytes. A RelA homodimer is uniquely activated in cytokine-stimulated astrocytes. Cytokine-dependent phosphorylation of the RelA inhibitor MAD-3 occurred on discrete peptides prior to its dissociation from RelA. A transient hyperphosphorylation of RelA was also induced. Antioxidant treatment inhibited both RelA activation and phosphorylation of the RelA.MAD-3 complex. These results demonstrate that cytokine-dependent activation of the RelA homodimer involves phosphorylation of both RelA and its associated inhibitor. The sole activation of a RelA homodimer suggests that cytokines will activate a unique set of Rel-regulated genes in astrocytes.

Animals↗
PubMed1995

Stimulation of group II phospholipase A2 mRNA expression and release in an immortalized astrocyte cell line (DITNC) by LPS, TNF alpha, and IL-1 beta. Interactive effects.

Astrocytes are immunoactive cells in brain and have been implicated in the defense mechanism in response to external injury. Previous studies using cultured glial cells indicated the ability of astrocytes to respond to bacteria endotoxin and cytokines, resulting in the release of phospholipase A2. In this study, we examined the interactive effects of lipopolysaccharides (LPS), interleukin 1 beta (IL-1 beta) and tumor necrosis factor (TNF alpha) to stimulate phospholipase A2 (PLA2) in an immortalized astrocyte cell line (DITNC) with many properties of type I astrocytes. Northern blot analysis using oligonucleotide probes derived from the cDNA encoding the rat spleen group II PLA2 indicated the ability of DITNC cells to respond to all three factors in the induction of gene expression and the release of PLA2. After an initial lag time of 2 h, PLA2 release was proportional to time, reaching a plateau by 12 h. This event occurred at a time period preceding any signs of cell death. Cycloheximide at 1.25 microM completely inhibited cytokine-induced PLA2 release. When suboptimal amounts of TNF alpha were added to the DITNC culture together with IL-1 beta or LPS, a synergistic increase in the induction of PLA2 release could be observed. On the other hand, combination of IL-1 beta and LPS resulted only in an additive increase in PLA2 release. Antibodies to IL-1 beta and TNF alpha completely neutralized the effects of these two agents on PLA2 release. However, neither antibody was able to inhibit the PLA2 release induced by LPS, suggesting that the effect of LPS was not complicated by the release of IL-1 beta or TNF alpha. Taken together, results show that the immortalized astrocyte cell line (DITNC) can be used for studies to elucidate the molecular mechanism underlying the cytokine signaling cascade and subsequent induction of PLA2 synthesis.

Animals↗
PubMed1995

Foscarnet and ganciclovir pharmacokinetics during concomitant or alternating maintenance therapy for AIDS-related cytomegalovirus retinitis.

INTRODUCTION: The use of foscarnet and ganciclovir as a combination treatment for cytomegalovirus retinitis is increasing because of limitations associated with single agent therapy. METHODS: The pharmacokinetics of foscarnet and ganciclovir were determined in 13 patients receiving either concomitant therapy (regimen A) or daily alternating therapy (regimen B) for maintenance of cytomegalovirus disease. For regimen A, 60 mg/kg intravenous foscarnet and 3.75 mg/kg ganciclovir were sequentially administered daily; for regimen B, 120 mg/kg foscarnet and 6 mg/kg ganciclovir were administered on alternating days. For both regimens, serial blood sampling for pharmacokinetic analysis was performed for each drug alone (day 1 or 2) and after 2 weeks of combination therapy. Plasma samples for foscarnet and ganciclovir analysis were performed by means of high-performance liquid chromatography. Pharmacokinetic analysis was performed with noncompartmental methods. RESULTS: For regimen A, the plasma clearance (CL) of foscarnet did not change in the presence of ganciclovir, averaging 0.12 +/- 0.08 and 0.11 +/- 0.02 L/hr/kg on study days 2 and 14, respectively (p = 0.34). The volume of distribution (VSS) and mean residence time (MRT) also did not change significantly. CL and MRT of foscarnet did not change for regimen B, although a slight increase in VSS was observed before (0.38 +/- 0.05 L/kg) and after (0.46 +/- 0.07 L/kg) alternating therapy (p = 0.03). Ganciclovir CL did not change for either regimen, with mean values of 0.21 +/- 0.10 and 0.25 +/- 0.10 L/hr/kg (regimen A, p = 0.17) and 0.32 +/- 0.10 and 0.34 +/- 0.11 L/hr/kg (regimen B, p = 0.24). MRT and VSS were also not significantly different. CONCLUSION: These plasma data suggest that further dosage adjustments are unnecessary for or alternating maintenance therapy.

AIDS-Related Opportunistic Infections↗
PubMed1995

Amorphorization and recrystallization during plasma spraying of hydroxyapatite.

X-ray diffraction was used to characterize the dependence of mean crystallite size and crystallinity on the thickness of coatings. A fall in mean crystallite size but a rise in crystallinity with increased thickness was observed. The reason might be due to the differences in cooling rate of partially molten particles of hydroxyapatite. The thicker the coating, the longer the cooling time. The longer cooling time was beneficial to the occurrence of recrystallization. It was found that the critical thickness of recrystallization (rc) was about 20 microns.

Biocompatible Materials↗
PubMed1995

Phase I trial of high-dose tamoxifen as a modulator of drug resistance in combination with daunorubicin in patients with relapsed or refractory acute leukemia.

Tamoxifen and its main metabolite N-desmethyltamoxifen (NDMTmx) have been shown to increase intracellular daunorubicin (DNR) levels in human leukemia cell lines that display the multidrug resistant (MDR) phenotype. We designed a phase I dose escalation study of Tmx (200-700 mg/day p.o. for 7 days) in combination with a fixed dose of DNR (50 mg/m2 intravenously on days 5, 6 and 7) in patients with advanced leukemia to determine whether this combination could be given safely and whether plasma levels of 10 microM, the effective in vitro MDR modulator concentration, could be achieved. Pharmacologic studies of Tmx, NDMTmx and DNR, and its main metabolite daunorubicin-ol (DNR-ol) were performed as was determination of P-glycoprotein (Pgp) using a monoclonal antibody that recognizes an external epitope of the molecule. A total of 14 patients (median age 50, range 22-67) were treated at the following dose levels: 200 mg/day: three patients; 400 mg/day: four patients; 550 mg/day: three patients; and 700 mg/day: four patients. Two patients with relapsed AML achieved remission. Toxicity of the combination was similar to that seen with DNR alone and no severe hepatic, cardiac or retinal toxicity was noted. Plasma Tmx levels approached 7 microM at the two highest dose levels studied; plasma levels of NDMTmx were slightly less. The area under the curve for DNR and its main metabolite daunorubicin-ol (DNR-ol) did not show significant changes with escalation of Tmx dose. This phase I study suggests that concentrations of Tmx high enough to reverse the MDR phenotype can be approached and that the combination of high-dose Tmx with a standard dose of DNR has an acceptable toxicity profile. More evaluation in phase II studies is necessary to define further its role as an MDR modulator.

Adult↗
PubMed1995

[Isolation of fusarium and extraction of its toxin from buckwheat grown in an area with "endemic breast enlargement" disease].

Fusarium was isolated and its toxin was extracted from the buckwheat grown in an epidemic area with "endemic breast enlargement" disease. The toxin was determined with thin layer chromatography and mass spectrography. Results showed there were more than four kinds of mould, including fusarium, isolated from buckwheat grown in the endemic disease area. All the buckwheat grown in the area were infected with mould and 34% with fusarium. Three kinds of toxin were extracted from the buckwheat, with rates of flow of 0.23, 0.47 and 0.90, respectively, in thin layer chromatography. And, zearalenone was extracted from the buckwheat and identified by mass spectrography.

Animals↗
PubMed1994

A phase I trial of intrahepatic verapamil and doxorubicin. Regional therapy to overcome multidrug resistance.

BACKGROUND: Verapamil can modulate multidrug resistance in vitro, but only at levels that are not tolerable when administered systemically. Regional strategies of drug administration may permit the delivery of high concentrations of a drug to specific areas with lower systemic levels. Colorectal cancers typically express the multidrug resistance phenotype. METHODS: A Phase I trial was performed to determine the maximum tolerable dose (MTD) and dose limiting toxicities of verapamil by hepatic artery infusion, together with doxorubicin, to patients with hepatic metastases of colorectal cancer. Fourteen patients with metastatic colorectal cancer received a 14-hour intrahepatic infusion of verapamil. Six hours after the start of the infusion, a fixed dose of doxorubicin (50 mg/m2) was given, also via the hepatic artery, over a 30-minute period. Patients were followed by cardiac telemetry but were not in an intensive care setting, and no invasive monitoring was used. All patients had received prior intrahepatic chemotherapy. RESULTS: The MTD of intrahepatic verapamil on this schedule in this patient population was 1.2 mg/kg/hour. Hypotension was the dose limiting toxicity. No major objective responses were noted in this heavily pretreated patient population. A dose of 1.0 mg/kg/hour is recommended for Phase II trials. CONCLUSIONS: Based on estimations of normal hepatic artery blood flow, the estimated concentration of verapamil delivered to the hepatic tumors at 1.0 mg/kg/hour is 3.6 micrograms/ml (7.3 microM), which is comparable to concentrations at which an in vitro reversal of MDR is seen. This study demonstrates that the systemic toxicities of an MDR reversal agent can be overcome by regional drug delivery, establishing this approach as an important model system for further study of MDR modulation.

Adenocarcinoma↗
PubMed1994

A phase I trial of immediate postoperative intraperitoneal floxuridine and leucovorin plus systemic 5-fluorouracil and levamisole after resection of high risk colon cancer.

BACKGROUND: The purpose of this study was to evaluate the toxicity of immediate postoperative intraperitoneal (IP) floxuridine (FUdR) and leucovorin (LV) after resection of high risk colon cancer, and to determine the appropriate dose of intravenous fluorouracil (FU) plus levamisole during concurrent intraperitoneal therapy. METHODS: The authors conducted a tertiary referral Comprehensive Cancer Center Phase I Trial in patients with resected colon cancer at high risk for recurrence. After resection of all gross disease, intraperitoneal treatment was administered twice daily for 3 days every 2 weeks for three cycles (Days 1-3, 15-17, 29-31). Intravenous FU daily for 5 days was administered on days 29-33 concurrently with the third cycle of intraperitoneal therapy. Fluorouracil doses during the last cycle of intraperitoneal therapy were escalated; intraperitoneal FUdR and LV doses and weekly intravenous FU doses (starting on Day 58) were fixed. RESULTS: Twenty-six patients with resected high risk colon cancer were treated. Three had Dukes' B2, 16 Dukes' C, and 7 Dukes' D (M1) resected tumors. Intraperitoneal therapy was well tolerated with no increase in operative morbidity and no operative mortality. Two patients had > or = Grade 3+ toxicity during IP therapy alone. There were no treatment related deaths. During concurrent intraperitoneal and intravenous chemotherapy, the maximum tolerated dose of FU was 300 mg/m2/day for 5 days. The recommended dose for Phase II or III trials is 200 mg/m2/day for 5 consecutive days. Pharmacokinetic analysis indicated that using the doses used in this trial, measurable systemic concentrations of FUdR and LV were obtained during IP therapy. This may have contributed to observed toxicity with intravenous FU doses of 300-400 mg/m2. With a median duration of follow-up of 18 months, four patients had recurrence of disease. No peritoneal recurrences have been noted to date. CONCLUSIONS: Immediate postoperative IP FUdR and LV are well tolerated after resection of high risk colon cancer. The recommended dose of intravenous FU beginning on Day 29 (concurrent with the last dose of IP therapy) is 5FU 200 mg/m2 for 5 consecutive days. The remaining year of adjuvant fluorouracil and levamisole can be administered with standard dose attenuation. Although follow-up is short, the lack of recurrent peritoneal metastases is encouraging. Additional trials with this approach are warranted in patients with high risk colorectal cancer.

Adult↗
PubMed1994

Phosphorylation of lipids in rat primary glial cells and immortalized astrocytes (DITNC).

Phosphatidylinositol 4,5-bisphosphate, a substrate in the signal transduction pathway involving phospholipase C, is synthesized in cell membranes by phosphorylation of phosphatidylinositol (PI) and phosphatidylinositol 4-phosphate (PI-4-P). Incubation with [gamma-32P]adenosine triphosphate of membranes isolated from primary glial cells in culture and from an immortalized astrocyte cell line (DITNC) and subsequent separation of the lipids by high-performance thin-layer chromatography revealed a number of labeled lipid bands. Further analysis of the deacylated products by high-performance liquid chromatography indicated the presence of two PI-4-P bands and a band corresponding to lysoPIP (PIP, PI phosphate). The two PI-4-P bands were more prominent in the samples from astrocyte cell membranes than from synaptic plasma membranes and plasma membranes. Analysis of the fatty acid composition of PI by gas-liquid chromatography revealed that both 20:3n-9 and 20:4n-6 were present in PI of cultured cell membranes, whereas the brain membranes contained exclusively 20:4n-6. The two PI-4-P bands in these membranes can be attributed to the presence of different molecular species of PI. Assignment of the fraction corresponding to lysoPIP was consistent with the observation that an increase in label in this lipid band occurred upon incubation of DITNC cell supernatant with lysoPI (1-stearoyl PI). This suggests that endogenous lysoPI present in the cell membranes can be phosphorylated to form lysoPIP.

Adenosine Triphosphate↗
PubMed1994

Pharmacodynamic relationship of pharmacokinetic parameters of maintenance doses of foscarnet and clinical outcome of cytomegalovirus retinitis.

The pharmacodynamic relationship between a range of foscarnet exposure measurements obtained from studying nine patients receiving ongoing maintenance therapy for cytomegalovirus retinitis and a range of efficacy values (days to retinitis progression) obtained by independent examination of serial retinal photographs from the same nine patients was analyzed. In the resulting proportional hazards models, the foscarnet area under the concentration-time curve approached statistical significance (P = 0.11) as a predictor of decreased risk of retinitis progression.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Eicosanoid production by human aortic endothelial cells in response to endothelin.

Endothelial cells actively regulate their environment by secreting humoral substances, including endothelin-1 and a variety of eicosanoids, that have local actions. To elucidate interactions among these local mediators, we measured release of cyclooxygenase and lipoxygenase pathway products of arachidonate metabolism by human aortic endothelial cells after incubation with endothelin-1. Supernatants were collected, extracted, and fractionated using high-performance liquid chromatography. Radioimmunoassays for eicosanoids were performed on the appropriate fractions. After endothelin stimulation, production of the prostacyclin metabolite 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), the thromboxane (Tx) metabolite TxB2, and prostaglandin E2 (PGE2) were increased (307 +/- 48, 320 +/- 91, and 315 +/- 74% of control, P < 0.05). Leukotriene B4 (LTB4) release was modestly increased (195 +/- 19% of control, P < 0.05). The release of 5-hydroxyeicosatetraenoic acid (5-HETE) was increased (300 +/- 57% of control, P < 0.05); production of 12-HETE and 15-HETE was unchanged. Production of eicosanoids peaked between 30 and 120 min. Preincubation with pertussis toxin prevented increased production of PGE2, LTB4, and 5-HETE after endothelin-1 stimulation; pretreatment with sphingosine had no effect. Interactions between endothelin and eicosanoids may be important components of the complex network that regulates vascular tone, coagulation, and inflammation at the local level.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1994

Trial of sequential trimetrexate, fluorouracil, and high-dose leucovorin in previously treated patients with gastrointestinal carcinoma.

PURPOSE: Trimetrexate (TMTX) is a dihydrofolate reductase inhibitor, which, like methotrexate (MTX), has been shown to potentiate fluorouracil (FU) cytotoxicity by increasing phosphoribosylpyrophosphate (PRPP) levels. We investigated the safety and efficacy of a sequential TMTX/FU/leucovorin (LV) combination. PATIENTS AND METHODS: Forty-one patients with advanced gastrointestinal carcinoma (mostly colorectal) received variable doses of TMTX followed 24 hours later by FU/LV (500 mg/m2 of each drug). Almost all patients had received previous chemotherapy. The initial 19 patients were treated on a 3-week-on/1-week-off schedule without any significant toxicity; the remaining patients were treated for 6 consecutive weeks followed by a 2-week rest period. TMTX was escalated in 30-mg/m2 increments from 20 to 110 mg/m2 in separate patient cohorts. When the 110-mg/m2 dose of TMTX was reached, the FU dose was escalated from 500 mg/m2 to 600 mg/m2. RESULTS: The partial response (PR) rate in assessable patients with colorectal cancer (all previously treated) was 20% (seven of 35; 95% confidence interval, 7% to 33%), and with other gastrointestinal cancers was one of four patients. Median survival has not been reached with a median follow-up of 13.5 months. The maximum-tolerated dose (MTD) was 110 mg/m2 for TMTX, 500 mg/m2 for FU, and 500 mg/m2 for LV on a 6-weeks-on/2-weeks-off cycle. The principal toxicities were grade 3 or 4 diarrhea, which occurred in 17% of patients, and hypersensitivity reactions, which occurred in 26% of patients. CONCLUSION: TMTX can be administered at maximal doses in combination with FU and LV without increasing toxicity. The PR rate of 20% in advanced colorectal carcinoma patients previously treated with chemotherapy is encouraging and merits further study.

Adult↗
PubMed1994

Comparative activity of tamoxifen and N-desmethyltamoxifen in human multidrug resistant leukemia cell lines.

Tamoxifen (Tmx) is one of a number of agents that can reverse the multidrug resistant (MDR) phenotype in vitro; it is unique, however, in that both the parent compound and the main metabolite, N-desmethyltamoxifen (NDMTmx), have long plasma half-lives, 7 and 14 days, respectively. To determine whether NDMTmx was as active as the parent compound in restoring sensitivity to daunorubicin (DNR) in vitro, we performed uptake and retention studies in the MDR-positive human leukemia cell lines CEM-VLB and HL-60/RV+ using laser flow cytometry to quantitate intracellular DNR concentration. Cells incubated with DNR and NDMTmx 10 microM demonstrated increased intracellular DNR levels that were very similar to those obtained with DNR and Tmx 10 microM. Cellular retention of DNR was also measured after incubation with Tmx 10 microM or NDMTmx 10 microM and resuspension in fresh medium containing Tmx or NDMTmx in order to stimulate in vivo conditions. Washout curves in both cell lines were similar with both Tmx and NDMTmx. Finally, clonogenic experiments were performed to determine whether Tmx and NDMTmx demonstrated the same degree of cytotoxicity. The combination of Tmx 10 microM plus DNR and that of NDMTmx 10 microM plus DNR each resulted in > 80% growth inhibition. These results suggest that NDMTmx is as active as Tmx in restoring sensitivity to DNR in vitro, a finding which may have important implications in clinical trials that assess the ability of Tmx to reverse the MDR phenotype.

Daunorubicin↗