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K K Chan

Publications and source records attributed to K K Chan.

At least 73 records · Page 4Linked to original sources
PubMed1998

Expression of neuronal markers in oligodendrogliomas: an immunohistochemical study.

The oligodendroglioma has been considered to be a tumour showing oligodendrocyte differentiation, but studies of the expression of oligodendrocyte markers have not conclusively demonstrated this and the pattern of differentiation of this tumour remains uncertain. Recent studies have suggested that some oligodendrogliomas may show neuronal differentiation. The aim of this study was to determine whether there was evidence of neuronal differentiation in a series of oligodendrogliomas, and, if so, to determine whether this identified a biologically or clinically distinct group. Immunohistochemistry was carried out on paraffin sections using antibodies to synaptophysin, phosphorylated and non-phosphorylated neurofilament proteins. An archival series of 32 oligodendrogliomas had been previously characterized for histological features, histological grade, Ki-67 labelling index, apoptosis index and prognosis. Six per cent of tumours showed expression of synaptophysin. Thirty-one per cent of cases showed expression of neurofilament proteins with an antibody to non-phosphorylated epitopes, but no cases were positive with antibodies to phosphorylated neurofilament epitopes. Tumours showing expression of neuronal markers did not show a difference in the distribution of histological grade or GFAP expression from those which did not express these markers, and there was no difference in labelling indices or prognosis between the two groups. In conclusion, a subset of oligodendrogliomas showed expression of neuronal lineage markers; this is discussed in relation to histogenesis and differential diagnosis. The expression of such markers did not identify a biologically or clinically distinct subgroup.

Biomarkers↗
PubMed1998

Differential in vitro hepatic and intestinal metabolism of ifosfamide in the rat.

1. Metabolism of ifosfamide (IF) in intestinal and hepatic microsomes has been investigated in the rat. The generation of three primary metabolites, 4-hydroxyifosfamide (HOIF), N2-dechloroethylifosfamide (N2D) and N3-dechloroethylifosfamide (N3D), was followed. 2. Microflora in rat small intestine showed no metabolic activity towards IF. The overall metabolic activity was higher in the hepatic microsomes than in the intestinal microsomes, and the hydroxylation pathway accounted for 53.6% of total IF metabolism in the hepatic microsomes. In contrast, hydroxylation of IF in intestinal microsomes was only 9.8% of the total monitored metabolic activity and N3-dechloroethylation of IF was a major pathway, constituting 73.0% of the monitored activity. 3. In summary, the intestinal metabolism of IF was demonstrated for the first time and these in vitro data indicate that the intestinal metabolism of IF could contribute significantly to the overall first-pass metabolism.

Animals↗
PubMed1998

Proliferation and cell death in oligodendrogliomas.

The rates of cell proliferation and of cell loss influence the growth rate of a tumour and reflect genetic changes. We studied proliferation and apoptosis in oligodendrogliomas and their relationship to progression of the tumours. Thirty-two cases of oligodendroglioma were retrieved spanning a 10-year period. The diagnosis and grade were reviewed and follow-up data obtained. Mitotic index (MI) and apoptotic index (AI) were determined from haematoxylin and eosin (H & E) stained sections. A labelling index (LI) of proliferating cells was obtained using the MIB1 antibody to the Ki-67 antigen. A further index of apoptosis was obtained using in situ end-labelling of DNA strand breaks (TUNEL index, TI). Fourteen cases were graded as II, 18 as III (1993 WHO). LI was significantly higher in grade III than in grade II tumours (P < 0.01) but the difference in apoptotic indices between grades was not significant. There was a significant (P = 0.036) positive correlation between the logarithms of TI and LI. Construction of survival curves demonstrated a significant difference in survival according to histological grade (P < 0.05). Stratification of cases by LI alone did not predict significantly different survival outcomes, and apoptotic indices did not demonstrate a relationship to survival. A positive relationship was demonstrated between proliferation and apoptosis in oligodendrogliomas. The levels of apoptosis observed indicate that this phenomenon may have an important influence on the overall rate of tumour growth.

Adolescent↗
PubMed1998

Effects of phenobarbital on stereoselective metabolism of ifosfamide in rats.

Plasma and urinary levels of ifosfamide (IF) enantiomers and their metabolites 2-dechloroethylifosfamide, 3-dechloroethylifosfamide, 4-hydroxyifosfamide, and isophosphoramide mustard were determined for control and phenobarbital-treated male Sprague-Dawley rats by using pseudoracemates and GC/MS and stable-isotope dilution analytical methods. For the control rats, the mean AUC for (S)-IF in plasma was greater than that for (R)-IF (R/S AUC ratio, 0.78) and the mean half-life of 41.8 min for (S)-IF was slightly longer than that of 34.3 min for (R)-IF. Phenobarbital pretreatment significantly decreased the AUC values for (R)-IF and (S)-IF, to 21 and 30% of the control values, respectively, and shortened plasma half-lives for both enantiomers [half-life for (R)-IF, 19.8 min; half-life for (S)-IF, 19.4 min]. The urinary excretion values for (R)-IF and (S)-IF were decreased to 41 and 30% of the control values, respectively. The overall amounts of the metabolites in urine were concomitantly increased. Additionally, there were significant reversals in both the R/S AUC ratio and the urinary excretion of 3-dechloroethylifosfamide. Moreover, the enantioselectivity for the generation of 4-hydroxyifosfamide and isophosphoramide mustard disappeared after phenobarbital treatment. These results strongly suggested that the 4-hydroxylation and dechloroethylation of IF enantiomers were mediated by different P450 isozymes or the same isozyme with different stereochemical selectivities.

Animals↗
PubMed1998

Absence of the glutathione S-transferase M1 gene increases cytochrome P4501A2 activity among frequent consumers of cruciferous vegetables in a Caucasian population.

The cancer protective effect of cruciferous vegetables has been attributed to induction of phase II enzymes. But cruciferous vegetables also induce cytochrome P4501A2 (CYP1A2), which catalyzes the metabolic activation of various procarcinogens, including aromatic amines in tobacco. Thus, frequent intake of cruciferous vegetables could also result in cancer-enhancing effects. GSTM1 is involved in the detoxification of various carcinogens, but it also enhances the excretion of isothiocyanates and possibly other enzyme inducers in cruciferous vegetables. We, therefore, hypothesized that GSTM1 null genotype might be associated with increased CYP1A2 activity among frequent consumers of cruciferous vegetables because the excretion of CYP1A2 inducers contained in these vegetables may be partially inhibited in the absence of the GSTM1 enzyme. Three hundred twenty-eight non-Hispanic white residents of Los Angeles County (265 males and 63 females) were genotyped for the presence or absence of GSTM1 alleles and phenotyped for CYP1A2 activity. Information on usual dietary habits was obtained from these subjects through in-person interviews. Among frequent (at least once a week) consumers of broccoli, GSTM1 null individuals exhibited a 21% higher geometric mean level of CYP1A2 activity relative to GSTM1 non-null individuals (5.24 versus 4.32, two-sided P = 0.01). No such difference was observed in subjects who consumed broccoli less frequently (two-sided P = 0.39). This interactive effect of GSTM1 genotype and vegetable intake on CYP1A2 activity also was observed when overall intake of the five cruciferous vegetables under study (broccoli, cabbage, cauliflower, Brussels sprouts, and mustard greens) was examined. Among weekly consumers of cruciferous vegetables, GSTM1 null individuals showed a 16% higher geometric mean level of CYP1A2 activity relative to GSTM1 non-null individuals (5.03 versus 4.33, two-sided P = 0.02), whereas no difference was evident among those who consumed cruciferous vegetables less frequently (two-sided P = 0.35). Our results suggest that cruciferous vegetables contain CYP1A2 inducers, which are deactivated in the presence of GSTM1.

Brassicaceae↗
PubMed1998

A pilot study on early post-operative morbidity and technique of inguinal node dissection in vulval carcinoma.

Inguinal lymphadenectomy is part of the management plan for most cases of vulval carcinoma. The surgical techniques have been modified over the years resulting in less destructive operations. Even so, inguinal lymphadenectomy continues to pose difficulties particularly relating to wound breakdown and lymphocyst formation. Many different methods are described, though none have undergone any comparative assessment regarding morbidity. This small study compares two methods performed on the same patients. The radical procedure included excision of the fascia lata and exposure of the femoral vessels and nerve. The anatomically-directed method was more conservative with surgery directed at removing the nodes as described in anatomical textbooks. Both methods resulted in equal lymph node retrieval, though the subjective short-term morbidity was reduced with the more conservative surgery. This approach did not result in any detrimental outcomes regarding relapse disease, though a randomised trial is required to corroborate these findings.

Carcinoma, Squamous Cell↗
PubMed1997

Synthesis and purification of NB1-palmitoyl insulin.

A procedure for synthesizing NB1-palmitoyl insulin for incorporation into liposomes for targeting to hepatocytes was developed. The amino group of the first amino acid phenylalanine on the B chain (B1) of insulin was selected for conjugation with palmitic acid in anticipation that its binding to the insulin receptor would be preserved. Two other free amino groups present in insulin, the first amino acid glycine on the A chain (A1) and the 29th amino acid lysine on the B chain (B29), were first protected with a t-butoxycarbonyloxy (t-Boc) group to yield NA1, B29-di-(t-Boc) insulin. The identity of this di-(t-Boc) insulin was confirmed by amino acid analysis as well as by enzyme hydrolysis coupled with matrix-assisted laser-desorption time of flight mass spectrometry (MALDI-TOF MS). NA1,B29-Di-(t-Boc) insulin was then reacted with the N-hydroxysuccinimide ester of palmitic acid, followed by deblocking the t-Boc groups, to yield NB1-palmitoyl insulin, the structure of which was further confirmed by MALDI-TOF MS analysis. NB1-palmitoyl insulin was found to interact with the insulin receptor on fat cells, thereby catalyzing the conversion of [14C]glucose into lipids, at reduced efficiency (30-40%).

Animals↗
PubMed1997

Depsipeptide (FR901228, NSC-630176) pharmacokinetics in the rat by LC/MS/MS.

Depsipeptide, a cyclic peptide (FR), isolated from Chrombacterium violaceum strain WB968 by Fujisawa Company during a screening program for anti-oncogene agents, possesses potent antitumor activity against human tumor cell lines and xenografts. This compound has been selected for preclinical and early clinical development by the National Cancer Institute. The pharmacokinetics and oral bioavailability of this depsipeptide in the rat were investigated in the present study. A sensitive and specific electrospray LC-tandem mass spectrometry method was first developed and validated for the analysis of this depsipeptide in plasma using t-boc-alpha-d-glutamic acid benzyl ester as the internal standard. The routine sensitivity limit was 1 or 10 ng/ml using 1.0 or 0.1 ml of plasma sample. The within-run CV values were 11.8, 17.9, 11.0, and 5.0% at 1, 10, 100, and 500 ng/ml levels, respectively, with corresponding accuracy of 94.4, 109, 95, and 97% (all n = 6). A formulation based on ethanol, normal saline and PEG400 was then developed and Fischer rats were given this formulated drug separately by intravenous and oral route. Plasma drug concentrations were measured by this method and pharmacokinetics were analyzed by the standard techniques. Plasma concentration-time profiles were found to follow a biexponential decline with a mean terminal t1/2 of 97 min and mean total clearance (CLt) of 425.3 ml/min/kg following i.v. dosing at 10 mg/kg. Following oral dosing at 50 mg/kg, the peptide was absorbed but produced erratic drug levels also with a bioavailability of 15.6%. Thus, active plasma concentrations can be produced up to 3 hrs in the rat following a single dose at 10 mg/kg and the peptide represents one of the very few orally absorbed peptides reported.

Administration, Oral↗
PubMed1997

Expanded version of PKSIM for pharmacokinetic simulations of both metabolite and parent drugs.

We recently described a computer software package for pharmacokinetic simulations called PKSIM. The programs are useful for studying drugs that display either a one-, two-, or three-compartment body model with linear or nonlinear elimination following single or multiple dosing. The practicality of PKSIM owes to its user-friendliness and flexibility to study the impact of pharmacokinetic perturbations and dosage regimens on the drug's concentration-time profile on a real-time basis. The interactive nature of PKSIM allows the test variables to be easily changed after each simulation. High-resolution graphic capabilities also permit presentation of pharmacokinetic profile in various body compartments, either individually or collectively on a single graph. The capability of PKSIM was recently extended to include simulations of both parent drug and metabolite, which adds to the value of the package. The present paper describes in detail the functions of these new features and how they can be applied to better comprehend the pharmacokinetic interdependency between the parent drug and metabolite. In addition to the dose, dosing regimen and rate of drug absorption, influences on the kinetic profiles of parent drug and metabolite by other variables such as formation rate of the metabolite, tissue distribution, tissue redistribution, elimination rates and distribution volume of both entities can be studied with minimal efforts. These new features can be particularly helpful for researchers to study prodrugs and drugs that produce active or toxic metabolites, or better understand the basic concepts of metabolite kinetics.

Biotransformation↗
PubMed1997

Suspected mitochondrial myopathy in a Jack Russell terrier.

A Jack Russell terrier with a history of progressive exercise intolerance was examined at the age of four months and again 10 months later. Clinical examination revealed a stunted, thin dog with a stilted gait. The dog had raised lactate levels before and after feeding and a raised lactate/pyruvate ratio after feeding, indicating a metabolic abnormality. Histochemical evaluation of muscle biopsies revealed subsarcolemmal accumulation of oxidative activity when stained with nicotinamide adenine dinucleotide tetrazollum reductase and ragged red fibres when stained with modified Gomori trichrome; all fibre types were involved. Ultrastructural examination of the muscle confirmed the presence of subsarcolemmal accumulations of mitochondria. Histochemical staining for the activity of enzymes of the Krebs cycle, oxidative phosphorylation and other metabolic cytosolic enzymes failed to demonstrate an abnormality. In view of the clinical picture and the biochemical and histological findings, a tentative diagnosis of mitochondrial myopathy was made. The difficulties associated with diagnosing mitochondrial disorders are discussed.

Animals↗
PubMed1997

Cupid's bow contour of the vertebral body: evaluation of pathogenesis with bone densitometry and imaging-histopathologic correlation.

PURPOSE: To investigate the Cupid's bow contour by means of bone densitometry and imaging-histopathologic correlation. MATERIALS AND METHODS: Radiographs and histologic slices were obtained in 64 cadaveric thoracolumbar spines to assess the morphology, distribution, and histopathologic features of the Cupid's bow contour. Dual-energy x-ray absorptiometry and radiography were performed in the lumbar spine in 406 healthy subjects. Bone density and body height and weight were then related to the presence of the Cupid's bow contour. The Cupid's bow contour was compared with the fish vertebra of osteoporosis and Schmorl node. RESULTS: No clinically important relationship was found between lumbar bone density, body height and weight, and prevalence of the Cupid's bow contour. Histologic examination showed thickened bone in the Cupid's bow end plate with annular fibers inserting into this region. In cadavers, the Cupid's bow contour occurred at multiple lumbar and thoracic levels, with the highest frequency in the lower lumbar spine. Lateral radiographs enabled better detection of the contour change. CONCLUSION: The Cupid's bow deformity is a developmental phenomenon that is unrelated to osteopenia or mechanical stress on the spine.

Absorptiometry, Photon↗
PubMed1997

Characterization of proflavine metabolites in rainbow trout.

Proflavine (3,6-diaminoacridine) has potential for use as an antiinfective in fish, and its metabolism by rainbow trout was therefore studied. Fourteen hours after intraarterial bolus administration of 10 mg/kg of proflavine, three metabolites were found in liver and bile, and one metabolite was found in plasma using reversed-phase HPLC with UV detection at 262 nm. Treatment with hydrochloric acid converted the three metabolites to proflavine, which suggested that the metabolites were proflavine conjugates. Treatment with beta-glucuronidase and saccharic acid 1,4-lactone, a specific beta-glucuronidase inhibitor, revealed that two metabolites were proflavine glucuronides. For determination of UV-VIS absorption and mass spectra, HPLC-purified metabolites were isolated from liver. Data from these experiments suggested that the proflavine metabolites were 3-N-glucuronosyl proflavine (PG), 3-N-glucuronosyl,6-N-acetyl proflavine (APG), and 3-N-acetylproflavine (AP). The identities of the metabolites were verified by chemical synthesis. When synthetic PG and AP were compared with the two metabolites isolated from trout, they had the same molecular weight as determined by matrix-assisted, laser desorption ionization, time-of-flight MS. In addition, they coeluted on HPLC under different mobile phase conditions. Finally, the in vitro incubation with liver subcellular preparations confirmed this characterization and provided the evidence that APG can be formed by glucuronidation of AP or acetylation of PG.

Animals↗
PubMed1997

Renal clearance of ifosfamide.

Nephrotoxicity is an important clinical side effect of the chemotherapeutic agent ifosfamide. This medication is activated by the hepatic cytochrome P450 system with potentially toxic metabolites produced through both ring hydroxylation and chloroethyl side chain oxidation pathways. Using an isolated perfused rat kidney preparation, we examined the possibility that renal metabolism of ifosfamide also occurs. Renal function before and after addition of ifosfamide to perfusate was not significantly different. After addition of ifosfamike to the perfusate, the metabolites N2-dechloroethylifosfamide, N3-dechloroethylifosfamide, and isophasphoramide mustard were recovered from urine and renal venous effluent. These results provide the first demonstration of ifosfamide metabolism by the kidney and suggest the possibility that intrarenal metabolism may contribute to nephrotoxicity.

Animals↗
PubMed1996

Spatial resolution of atrial pace mapping as determined by unipolar atrial pacing at adjacent sites.

BACKGROUND: The purpose of this study was to examine the spatial resolution of unipolar atrial pace mapping by pacing at adjacent sites within the coronary sinus and the right atrium. METHODS AND RESULTS: Unipolar pacing from each pole of a quadripolar catheter was performed in the coronary sinus (n = 29) and in the right atrium (n = 10). Pacing from the distal electrode was used to simulate the site of origin of an atrial tachycardia. These P waves were compared with the P waves generated by unipolar pacing from each of the three proximal electrodes. The P waves were analyzed for changes in amplitude, duration, and configuration. Pacing within the coronary sinus resulted in significant changes in amplitude and duration at distances of 17 and 21 mm from the distal pole, respectively. Similarly, pacing in the right atrium resulted in significant changes in amplitude and duration at distances of 17 and 32 mm from the distal pole, respectively. No significant changes in configuration were noted in the coronary sinus in any lead at packing sites < or = 32 mm from the distal pole. Configurational changes were noted in the right atrium at pacing sites 17 mm from the distal pole. CONCLUSIONS: The spatial resolution of unipolar atrial pace mapping is approximately 17 mm. These findings indicate that mapping techniques that depend on the accurate discrimination of P-wave morphology, such as pace mapping or concealed entertainment, are likely to be imprecise when used in the atria.

Adult↗
PubMed1996

Abdomino-pelvic hyperthermia and intraperitoneal carboplatin in epithelial ovarian cancer: feasibility, tolerance and pharmacology.

PURPOSE: To investigate the feasibility, toxicity, and pharmacokinetics of intraperitoneal (i.p.) carboplatin (CB) with concomitant abdomino-pelvic hyperthermia (HT) in advanced ovarian cancer patients. METHODS AND MATERIALS: Patients with residual disease mainly confined to the peritoneal cavity after platinum based chemotherapy received an initial course of i.p. CB for baseline pharmacokinetics followed by three cycles of i.p. CB with concomitant regional hyperthermia. The goal of HT was to achieve at least 45 min of intraperitoneal temperature > 42 degrees but < 50 degrees C while maintaining normal tissue temperatures < 43 degrees C and systemic body temperatures < 38 degrees C. No analgesic premedication was used. Thermometry was recorded by multisensor fiberoptic probes placed within the peritoneal cavity, bladder, vagina, and oral cavity. RESULTS: Thirteen patients received a total of 31 sessions. Our intraperitoneal temperature goal could not be achieved because of patient intolerance. At best, we could maintain intraperitoneal temperatures > 40 degrees C, for more than 40 min in 7 of 31 sessions. The average values of thermal variables were T90 = 40 degrees C, TAVE = 41 degrees C, TMIN = 38.2 degrees C, and TMAX = 42.9 degrees C. The mean maximum systemic temperature was 38 degrees C. Acute thermal toxicities requiring early interruption of hyperthermia were systemic temperature exceeding 38 degrees C (11 of 31), abdominal pain or generalized distress (20 of 31), and vomiting (2 of 31). Hematological toxicities were not increased by hyperthermia. Pharmacokinetics were consistent with enhanced clearance of CB by HT. Lower radio frequencies (< 75 MHz) achieved better heat deposition in the peritoneal cavity than higher frequencies (> 75 MHz). Two of the 13 patients (a Stage III and a Stage IV patient) are alive with no evidence of disease at 40 and 43 months from treatment. CONCLUSIONS: Intraperitoneal temperatures in the range of 40 degrees C maintained for approximately 40 min can be achieved within the described setting. The probability of successful induction of therapeutic intraperitoneal temperatures appears to be higher when frequencies below 75 MHz are used. Patients who are potentially platinum sensitive and have minimal residual disease could potentially benefit from the combined treatment under the conditions studied. However, this temperature-time range appears inadequate against platinum resistant disease, and/or bulky residual pelvic disease. Alternative approaches such as whole body hyperthermia and carboplatin are warranted to overcome some of the obstacles observed.

Adult↗
PubMed1996

Gas chromatographic-mass spectrometric assay for N-2-chloroethylaziridine, a volatile cytotoxic metabolite of cyclophosphamide, in rat plasma.

A sensitive and specific method for the quantitative analysis of N-2-chloroethylaziridine (CEA), a volatile cytotoxic metabolite of cyclophosphamide, has been developed using gas chromatography-mass spectrometry and stable isotope dilution techniques. The high volatility problem of CEA during isolation procedure was overcome by the combined use of a deuterium-labeled analog as the internal standard and a Snyder column-concentrator assembly. The assay was found to be linear from 16.7 to 2667 ng/ml in rat plasma with a routine detection limit of 5 ng/ml. The within-run precision at 33, 333 and 1333 ng/ml (n = 6) was found to be 4.8, 4.9, and 6.1%, respectively. The between-run precision was 6.4% (n = 6). The dichloromethane extraction recoveries at 33, 333, and 1333 ng/ml were found to be 101, 98, and 91%, respectively (all at n = 6). However, the overall recovery through extraction and evaporation was only 18.3, 15.2, and 27.7% at 33, 333, and 1333 ng/ml levels, respectively. The analytical method was used to evaluate the generation of CEA from its precursors in sodium phosphate buffer, in cell culture media, and the degradation of CEA in these media. In pH 7.4, 0.067 M sodium phosphate buffer at 37 degrees C, both phosphoramide mustard (PM) and nornitrogen mustard (NNM) were degraded in an apparent first-order fashion with half-lives of 24.8 and 14.5 min, respectively. The generated CEA was rather stable in this buffer and degraded with a half-life of 20 h. It was found that 32% PM and 91% NNM were converted to CEA in pH 7.4, 0.067 M sodium phosphate buffer at 37 degrees C, respectively, and 41% PM was transformed into CEA in RPMI 1640 tissue culture media containing 10% FBS at 37 degrees C. The generated CEA was very stable in the culture media with a degradation half-life of 265 h.

Animals↗
PubMed1996

QT dispersion in nonsustained ventricular tachycardia and coronary artery disease.

This study examines the relation between QT dispersion and the inducibility of ventricular tachycardia (VT) in 35 consecutive patients with coronary artery disease who underwent electrophysiologic testing for evaluation of nonsustained VT. The mean age of the patients was 66 +/- 9 years (+/- SD) and the mean left ventricular ejection fraction was 0.36 +/- 0.14. In 6 patients in whom sustained, monomorphic VT was inducible by programmed ventricular stimulation, QT dispersion was significantly greater than in the 29 patients in whom VT was not inducible (126 +/- 35 vs 67 +/- 25 ms, p < 0.001). All patients who had a QT dispersion > 120 ms had inducible sustained monomorphic VT, and no patient who had a QT dispersion < 90 ms had inducible VT. The patients who had inducible VT dis not differ significantly from those who did not with regard to age, gender, ejection fraction, RR interval, or mean QT. In conclusion, in patients with coronary artery disease who have nonsustained VT, inducibility of monomorphic VT is associated with an increase in QT dispersion. QT dispersion may be helpful in predicting which patients with nonsustained VT are and are not likely to have inducible VT by programmed stimulation.

Aged↗