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Biomedical subjects

K Chan

Publications and source records attributed to K Chan.

At least 91 records · Page 5Linked to original sources
PubMed2000

Pharmacokinetics of diclofenac sodium in chronic active hepatitis and alcoholic cirrhosis.

The objective of this study was to assess the pharmacokinetics of diclofenac sodium and its five metabolites following administration of a 150 mg oral dose to healthy subjects and patients with either chronic active hepatitis of varying morphology or alcoholic cirrhosis. Six healthy subjects, 6 chronic active hepatitis patients, and 6 alcoholic cirrhosis patients were enrolled in this prospective, open-label, parallel study. Blood samples were drawn at 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 312, and 480 hours, and urine samples were collected for 144 hours after administration of a single oral dose of diclofenac sodium. The mean area under the serum concentration-time curve extrapolated to infinity, oral clearance, half-life, maximal concentration, and time to peak concentration for diclofenac and its metabolites were determined and compared using analysis of variance. Cirrhotics had a mean +/- SD diclofenac AUC value (19,114 +/- 6806 ng.h/ml) significantly different (p < 0.02) from hepatitis patients (6071 +/- 1867 ng.h/ml) and healthy subjects (7008 +/- 2006 ng.h/ml), whereas healthy subjects and hepatitis patients had similar values. Comparable results were found for 4'-hydroxydiclofenac. The AUC values for 3'-hydroxydiclofenac and 3'-hydroxy-4'methoxydiclofeanc were significantly different when healthy subjects were compared to cirrhotics. However, hepatitis subjects were not significantly different from either group. The results indicate that hepatitis does not alter the pharmacokinetics of diclofenac. Alcoholic cirrhosis increased the mean diclofenac AUC approximately three times compared to normal subjects, indicating that one-third of the usual dose in cirrhotics would produce equivalent AUC values in normal subjects and subjects with alcoholic cirrhosis. However, since pharmacodynamic measurements were not made and no increase in untoward or side effects was noted in the alcoholic cirrhosis patients after a single dose, maintenance doses should be titrated to patients response.

Adult↗
PubMed2000

Sputum elastase in steady-state bronchiectasis.

STUDY OBJECTIVES: To study the correlations between sputum elastase output with clinical and sputum inflammatory and microbial factors in steady-state bronchiectasis. DESIGN: Prospective recruitment of patients with bronchiectasis (17 women; 48.5 +/- 16.5 years old; FEV(1)/FVC, 1.3 +/- 0.6/2.1 +/- 0.9) for assessment of 24-h sputum output of elastase, bacteria, leukocytes, interleukin (IL)-1beta, IL-8, tumor necrosis factor-alpha, and leukotriene B(4). Clinical variables assessed concomitantly included 24-h sputum volume, lung spirometry, number of lung lobes affected by bronchiectasis, and exacerbation frequency. SETTING: Consecutive recruitment of outpatients (n = 30) in steady-state bronchiectasis. MEASUREMENTS AND RESULTS: Twenty-four-hour sputum elastase output correlated with 24-h sputum volume (r = 0.79, p = 0.0001); number of bronchiectatic lung lobes (r = 0.54, p = 0.0026); percent predicted FEV(1) (r = -0. 48, p = 0.0068); percent predicted FVC (r = -0.49, p = 0.001); and leukocyte output (r = 0.75, p = 0.0001). There was no correlation between the sputum output of bacteria with either inflammatory or enzymatic factors (p > 0.05). CONCLUSION: Our data highlight the importance of elastase and the possibility of independent roles for enzymatic, inflammatory, and microbial components in the pathogenesis of bronchiectasis. Further research on novel therapy targeting each of these components should be pursued.

Adult↗
PubMed2000

Phase I trial of exisulind (sulindac sulfone, FGN-1) as a chemopreventive agent in patients with familial adenomatous polyposis.

Exisulind (sulindac sulfone; FGN-1), a metabolite of sulindac without known effects on prostaglandin synthesis, can promote apoptosis and inhibit tumorigenesis in preclinical systems. We performed a Phase I trial of this compound in patients with familial adenomatous polyposis (FAP) to examine the tolerability and safety of this drug in the cancer chemoprevention setting. Six patients each were treated with exisulind at doses of 200, 300, and 400 mg p.o. twice a day. Reversible hepatic dysfunction was noted in four of six patients treated at the 400-mg p.o., twice-a-day dose level, but in only one to two of six patients treated at each of the lower dose levels. The serum half-life of exisulind was 6-9 h; little drug accumulation was noted over time. A nonsignificant trend toward increased apoptosis in polyps was noted at the maximum tolerated dose, but no decrease in polyp numbers or significant effects on cellular proliferation was noted. After treatment, polyps tended to display a "halo" appearance grossly and mucinous differentiation histologically. The maximum safe dose of exisulind is 300 mg p.o. twice a day in patients with subtotal colectomies. Reversible hepatic dysfunction limits further dose escalation. A decrease in polyp numbers could not be demonstrated, but the trend toward increased apoptosis at the MTD and the observation of mucinous change histologically suggest that further investigation of drugs of this class might be warranted.

Adenomatous Polyposis Coli↗
PubMed1999

Nrf2 is essential for protection against acute pulmonary injury in mice.

Nrf2 is a member of the "cap 'n' collar" family of transcription factors. These transcription factors bind to the NF-E2 binding sites (GCTGAGTCA) that are essential for the regulation of erythroid-specific genes. Nrf2 is expressed in a wide range of tissues, many of which are sites of expression for phase 2 detoxification genes. Nrf2(-/-) mice are viable and have a normal phenotype under normal laboratory conditions. The NF-E2 binding site is a subset of the antioxidant response elements that have the sequence GCNNNGTCA. The antioxidant response elements are regulatory sequences found on promoters of several phase 2 detoxification genes that are inducible by xenobiotics and antioxidants. We report here that Nrf2(-/-) mice are extremely susceptible to the administration of the antioxidant butylated hydroxytoluene. With doses of butylated hydroxytoluene that are tolerated by wild-type mice, the Nrf2(-/-) mice succumb from acute respiratory distress syndrome. Gene expression studies show that the expression of several detoxification enzymes is altered in the Nrf2(-/-) mice. The Nrf2(-/-) mice may prove to be a good in vivo model for toxicological studies. As oxidative damage causes DNA breakage, these mice may also be useful for testing carcinogenic agents.

Animals↗
PubMed1999

Synthesis, structure-activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 1. Thiazolone and oxazolone series.

Selective cyclooxygenase-2 (COX-2) inhibitors have been shown to be potent antiinflammatory agents with fewer side effects than currently marketed nonsteroidal antiinflammatory drugs (NSAIDs). Initial mass screening and subsequent structure-activity relationship (SAR) studies have identified 4b (PD138387) as the most potent and selective COX-2 inhibitor within the thiazolone and oxazolone series of di-tert-butylphenols. Compound 4b has an IC50 of 1.7 microM against recombinant human COX-2 and inhibited COX-2 activity in the J774A.1 cell line with an IC50 of 0.17 microM. It was inactive against purified ovine COX-1 at 100 microM and did not inhibit COX-1 activity in platelets at 20 microM. Compound 4b was also orally active in vivo with an ED40 of 16 mg/kg in the carrageenan footpad edema (CFE) assay and caused no gastrointestinal (GI) damage in rats at the dose of 100 mg/kg but inhibited gastric prostaglandin E2 (PGE2) production in rats' gastric mucosa by 33% following a dose of 100 mg/kg. The SAR studies of this chemical series revealed that the potency and selectivity are very sensitive to minor structural changes. A simple isosteric replacement led to the reversal of selectivity.

Administration, Oral↗
PubMed1999

Synthesis, structure-activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 2. 1,3,4- and 1,2,4-thiadiazole series.

Two isoforms of the cyclooxygenase (COX) enzyme have been identified: COX-1, which is expressed constitutively, and COX-2, which is induced in inflammation. Recently, it has been shown that selective COX-2 inhibitors have antiinflammatory activity and lack the GI side effects typically associated with NSAIDs. Initial mass screening and subsequent SAR studies have identified 6b (PD164387) as a potent, selective, and orally active COX-2 inhibitor. It had IC50 values of 0.14 and 100 microM against recombinant human COX-2 and purified ovine COX-1, respectively. It inhibited COX-2 activity in the J774A.1 cell line with an IC50 of 0.18 microM and inhibited COX-1 activity in platelets with an IC50 of 3.1 microM. The choline salt of compound 6b was also orally active in vivo with an ED40 of 7. 1 mg/kg in the carrageenan footpad edema (CFE) assay. In vivo studies in rats at a dose of 100 mg/kg showed that this compound inhibited gastric prostaglandin E2 (PGE2) production in gastric mucosa by 77% but caused minimal GI damage. SAR studies of this chemical series revealed that the potency and selectivity are very sensitive to minor structural changes.

Administration, Oral↗
PubMed1999

High performance DNA sequencing, and the detection of mutations and polymorphisms, on the Clipper sequencer.

The Visible Genetics Clipper sequencer is a new platform for automated DNA sequencing which employs disposable MicroCel cassettes and 50 microm thick polyacrylamide gels. Two DNA ladders can be analyzed simultaneously in each of 16 lanes on a gel, after labeling with far-red absorbing dyes such as Cy5 and Cy5.5. This allows a simultaneous bidirectional sequencing of four templates. We have evaluated the Clipper sequencer, by cycle-sequencing of an M13 single-stranded DNA standard, and by coupled amplification and sequencing (CLIP) of reverse-transcribed human immunodeficiency virus (HIV-1) RNA standards and clinical patient samples. (i) Limitations of instrument. We have examined basic instrument parameters such as detector stability, background, digital sampling rate, and gain. With proper usage, the optical and electronic subsystems of the Clipper sequencer do not limit the data collection or sequence-determination processes. (ii) Limitations of gel performance. We have also examined the physics of DNA band separation on 50 microm thick MicroCel gels. We routinely obtain well-resolved sequence which can be base-called with 98.5% accuracy to position approximately 450 on an 11 cm gel, and to position approximately 900 on a 25 cm gel. Resolution on 5 and 11 cm gels ultimately is limited by a sharp decrease in spacing between adjacent bands, in the biased reptation separation regime. Fick's (thermal) diffusion appears to be of minor importance on 6 cm or 11 cm gels, but becomes an additional resolution-limiting factor on 25 cm gels. (iii) Limitations of enzymology. Template quality, primer nesting, choice of DNA polymerase, and choice between dye primers and dye terminators are key determinants of the ability to detect mutations and polymorphisms on the Clipper sequencer, as on other DNA sequencers. When CLIP is used with dye-labeled primers and a DNA polymerase of the F667Y, delta(5'--> 3' exo) class, we can routinely detect single-nucleotide mutations and polymorphisms over the 0.35-0.65 heterozygosity range. We present an example of detecting therapeutically relevant mutations in a clinical HIV-1 RNA isolate.

Bacteriophage M13↗
PubMed1999

Toxicity of ifosfamide and its metabolite chloroacetaldehyde in cultured renal tubule cells.

Renal injury is a common side effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that the ifosfamide metabolite chloroacetaldehyde may contribute to this nephrotoxicity. The present study examined the effects of ifosfamide and chloroacetaldehyde on rabbit proximal renal tubule cells in primary culture. The ability of the uroprotectant medication sodium 2-mercaptoethanesulfonate (mesna) to prevent chloroacetaldehyde-induced renal cell injury was also assessed. Chloroacetaldehyde (12.5-150 microM) produced dose-dependent declines in neutral red dye uptake, ATP levels, glutathione content, and cell growth. Coadministration of mesna prevented chloroacetaldehyde toxicity while pretreatment of cells with the glutathione-depleting agent buthionine sulfoximine enhanced the toxicity of chloroacetaldehyde. Ifosfamide (1000-10,000 microM) toxicity was detected only at concentrations of 4000 microM or greater. Analysis of media collected from ifosfamide-treated cell cultures revealed the presence of several ifosfamide metabolites, demonstrating that renal proximal tubule cells are capable of biotransforming this chemotherapeutic agent. This primary renal cell culture system should prove useful in studying the cause and prevention of ifosfamide nephrotoxicity.

Acetaldehyde↗
PubMed1999

Hematopoietic stem cell transplantation for childhood myeloid malignancies after high-dose thiotepa, busulfan and cyclophosphamide.

Seventeen children with advanced myeloid malignancies (induction failure, relapse, myelodysplasia, secondary AML, or CR >1) received thiotepa 750 mg/m2 i.v., busulfan 12 mg/kg or 640 mg/m2 p.o., and cyclophosphamide 120 mg/kg i.v. as a preparative regimen for allogeneic or autologous hematopoietic stem cell (HSC) transplantation. Of the 15 allogeneic transplants, eight were from matched siblings, one was from a mismatched sibling, and six were from unrelated donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine or tacrolimus and methotrexate. Regimen-related toxicity was common but tolerable, affecting mainly the skin and gastrointestinal tract. Three patients died early and were not evaluable for engraftment; engraftment occurred in the remaining patients. Nine patients with active disease at the time of transplant were evaluable for response; all achieved remission. With a median follow-up of 40 months (range, 10-71 months), nine patients are alive and disease-free. The 3-year actuarial event-free survival was 51% (95% confidence interval (CI) 27-76%). Seven patients died of transplant-related complications: infection (n = 4), chronic GVHD (n = 1), veno-occlusive disease, VOD, (n= 1) and pulmonary alveolar hemorrhage (n = 1). Only one patient had leukemia relapse and died. We conclude that the use of high-dose thiotepa, busulfan and cyclophosphamide is an effective conditioning regimen for childhood myeloid malignancies and may be tested in patients with less advanced disease (eg CR1).

Adolescent↗
PubMed1999

A comparative study on the efficacy of levofloxacin and ceftazidime in acute exacerbation of bronchiectasis.

A prospective randomized study was performed in order to compare the efficacy of oral levofloxacin, a new S- isomer of ofloxacin, with intravenous ceftazidime in the empirical treatment of acute exacerbations of bronchiectasis. Consecutive patients with acute exacerbation of bronchiectasis were recruited at a tertiary referral centre and were randomized to receive 10 days' treatment with either oral levofloxacin (300 mg b..d.) or ceftazidime (1 g i.v.t.d.). Body temperature, cough score, dyspnoea score, sputum purulence and volume and white blood cell and neutrophil count were assessed on day 1 and day 10. Thirty-five patients (mean age 61 yrs, 15 males) completed the study; 17 of these were in the levofloxacin group. There was no significant difference in the distribution of sputum pathogens or clinical parameters between the two groups at entry to and completion of the study. Both groups of patients showed significant improvement in 24-h sputum volume, sputum purulence score, cough score and dyspnoea score (p<0.001) but there was no significant difference between these two groups at entry to or on completion of the study (p>0.05). The results of this study suggest that oral administration of levofloxacin is as effective as parenteral ceftazidime in the empirical treatment of exacerbations in bronchiectasis.

Acute Disease↗
PubMed1999

Activity of enzymes catalyzing formation of beta-L-fucosyl phosphate and GDP-beta-L-fucose in amphibian tissues and their application in chemo-enzymic synthesis of GDP-beta-L-fucose.

Amphibian oviduct and liver were shown to contain enzymes that catalyze the formation of GDP-beta-L-fucose from GDP-alpha-D-mannose or L-fucose. The conversion of L-fucose into beta-L-fucopyranosyl phosphate was achieved on a preparative scale using high-activity fucokinase in toad liver extracts. For chemo-enzymic preparation of GDP-beta-L-fucose, a convenient modification for pyrophosphate synthesis through phosphomorpholidate which does not require anhydrous conditions is suggested.

Animals↗
PubMed1999

Sarcoidosis presenting in infancy: a rare occurrence.

Sarcoidosis is infrequent in children. Clinical features of sarcoidosis occurring in children 8-15 years old include pulmonary, lymphnodes and ocular involvement. The picture is similar to that of adult-sarcoidosis. Sarcoidosis in infants, however, is rare and it differs from the adult disease. Sarcoidosis occurring in infancy has features clinically similar to that of juvenile rheumatoid arthritis. The case presented here is that of an infant who developed sarcoidosis at the age of 3 months. Her illness had all the features of a multisystem illness except for the hilar or parenchymal lung involvement. Because of the complicated and unusual illness the diagnosis of sarcoidosis was not established till the child was five years old. She received corticosteroids and immunosuppressive treatment in varying doses for a long time. Now at the age of 18, the patient's disease seems to have undergone a complete remission.

Adrenal Cortex Hormones↗
PubMed1998

Cockroach allatostatin-immunoreactive neurons and effects of cockroach allatostatin in earwigs.

A monoclonal antibody to allatostatin I of the cockroach Diploptera punctata was used to demonstrate the presence of allatostatin-immunoreactive cells and fiber tracts in the neuroendocrine system of the earwig Euborellia annulipes. The corpora cardiaca cells were not immunoreactive, nor were the neurosecretory endings of fiber tracts from the brain to the corpora cardiaca. No immunoreactive material was detected in the corpus allatum, although the corpus allatum contained neurosecretory endings, and some cells of the brain, including medial and lateral protocerebral cells, showed immunoreactivity. In addition, the recurrent and esophageal nerves were allatostatin-positive. The last abdominal ganglion contained immunoreactive somata, and immunoreactive axons of the proctodeal nerve innervated the rectum, anterior intestine, and posterior midgut. We did not detect reactive endocrine cells in the midgut. Allatostatin I at concentrations of 10(-5) and 10(-7) M did not inhibit juvenile hormone biosynthesis by E. annulipes corpora allata in vitro. This was true for glands of low activity from 2-day females and brooding females, as well as for relatively high activity glands from 10-day females. In contrast, 10(-7) M allatostatin I significantly and reversibly decreased hindgut motility. Motility was decreased in hindguts of high endogenous motility from 2-day females and in those of relatively low activity from brooding females. These results support the notion that a primary function of allatostatin might be to reduce gut motility.

Animals↗
PubMed1998

Metabolic disposition of 14C-bromfenac in healthy male volunteers.

The metabolic disposition of 14C-bromfenac, an orally active, potent, nonsteroidal, nonnarcotic, analgesic agent was investigated in six healthy male subjects after a single oral 50-mg dose. The absorption of radioactivity was rapid, producing a mean maximum plasma concentration (Cmax) of 4.9 +/- 1.8 microg x equiv/mL, which was reached 1.0 +/- 0.5 hours after administration. Unchanged drug was the major component found in plasma, and no major metabolites were detected in the plasma. Total radioactivity recovered over a 4-day period from four of the six subjects averaged 82.5% and 13.2% of the dose in the urine and feces, respectively. Excretion into urine was rapid; most of the radioactivity was excreted during the first 8 hours. Five radioactive chromatographic peaks, a cyclic amide and four polar metabolites, were detected in 0- to 24-hour urine samples. Similarity of metabolite profiles between humans and cynomolgus monkeys permitted use of this animal model to generate samples after a high dose for structure elucidation. Liquid chromatography/mass spectrometry (LC/MS) analysis of monkey urine samples indicated that the four polar metabolites were two pairs of diastereoisomeric glucuronides whose molecular weight differed by two daltons. Enzyme hydrolysis, cochromatography, and LC/MS experiments resulted in the identification of a hydroxylated cyclic amide as one of the aglycones, which formed a pair of diastereoisomeric glucuronides after conjugation. Data also suggested that a dihydroxycyclic amide formed by the reduction of the ketone group that joins the phenyl rings formed the second pair of diastereoisomeric glucuronides. Further, incubation of various reference standards in control (blank) urine and buffer with and without creatinine indicated that the hydroxy cyclic amide released from enzyme hydrolysis can undergo ex vivo transformations to a condensation product between creatinine and an alpha-keto acid derivative of the hydroxy cyclic amide that is formed by oxidation and ring opening. Further experiments with a dihydroxylated cyclic amide after reduction of the keto function indicated that it too can form a creatinine conjugate.

Adolescent↗
PubMed1998

Internal mammary artery to coronary artery bypass in paediatric cardiac surgery.

The internal mammary artery is regarded as the optimal conduit for coronary artery bypass grafting in adults. Use of this conduit in paediatric surgery is rare and has been reported mainly in patients with Kawasaki's disease. We report five patients who required internal mammary-coronary artery grafting due to adverse anatomical disposition of the coronary artery. In two cases an internal mammary graft was required during correction of transposition of the great arteries. The other cases involved correction of a left coronary artery arising anomalously from the pulmonary artery. Late angiography shows satisfactory growth and patency of the conduits.

Coronary Angiography↗
PubMed1998

Discriminant validity of the Medical Outcomes Study cognitive function scale in HIV disease patients.

Human immunodeficiency virus (HIV) infection results in a chronic course of disease progression and eventual death. With this disease progression comes decreases in health-related quality of life and cognitive function in many patients. We evaluated the construct and discriminant validity of the Medical Outcomes Study four-item and six-item cognitive function scale in a sample of 162 patients with HIV disease. The patients were assessed at baseline and after 4 months with the cognitive function scale, a cognitive functioning transition item, the Reitan trail making test (TMT) and the Centers for Epidemiologic Studies Depression (CES-D) scale. The results found that the four- and six-item cognitive function scales varied by HIV disease stage, CD4 count, self-reported change in cognitive function, TMT-based cognitive impairment and depression. The differences in the cognitive function scores were attenuated, but still remained statistically significant even after controlling for depression. The cognitive function scales predict cognitive impairment based on the TMT. The results support the construct validity of these self-report cognitive function scales.

Adult↗