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Biomedical subjects

M Chung

Publications and source records attributed to M Chung.

At least 19 recordsLinked to original sources
PubMed1992

Inhibition of myogenesis by okadaic acid, an inhibitor of protein phosphatases, 1 and 2A, correlates with the induction of AP1.

Recently, we demonstrated that okadaic acid, an inhibitor of protein phosphatases 1 and 2A, inhibits myogenesis by extinguishing the expression of MyoD1 and inducing the expression of Id. Since it has been reported that transformation by c-fos also inhibits myogenesis through inhibition of MyoD1 expression, we examined the effects of okadaic acid on the activation of the c-fos and jun family of proto-oncogenes in an attempt to understand the mechanism by which okadaic acid inhibits the myogenic differentiation. Treatment of C2C12 cells in growth medium with okadaic acid increased expression of the mRNAs for the c-fos family continuously and for the jun family to a lesser extent. In contrast, in differentiation medium, the induction of c-fos, c-jun, and fos B mRNAs by okadaic acid was transient, whereas fra-1, jun D, and jun B mRNAs were induced continuously, suggesting that okadaic acid regulates the expression of the c-fos and jun family through complex regulatory mechanisms depending on the state of differentiation of the cells. Transfection of c-jun and c-fos promoter-chloramphenicol acetyltransferase constructs demonstrated that the effects of okadaic acid on the induction of c-fos and c-jun are mediated through the activation of promoter elements. These results suggest that some of the targets of protein phosphatases 1 and 2A may include transcription factors capable of forming AP1 complexes and that these factors may play an important role during myogenic differentiation.

Base Sequence↗
PubMed1991

Purification and partial characterization of stonustoxin (lethal factor) from Synanceja horrida venom.

1. The lethal factor of the stonefish (Synanceja horrida) venom, designated as the stonustoxin, was purified to homogeneity by a two-step procedure on Sephacryl S-200 High Resolution (HR) gel permeation and DEAE Bio-Gel A anion exchange chromatography. 2. Stonustoxin has a native mol. wt of 148,000 and an isoelectric point of 6.9. 3. SDS-polyacrylamide gel electrophoresis revealed two subunits (designated alpha and beta) with mol. wts of 71,000 and 79,000, respectively. 4. The amino acid composition of both subunits and the N-terminal amino acid sequence of the beta subunit were also determined. 5. Purified stonustoxin had an LD50 of 0.017 microgram/g which is 22-fold more potent than that of the crude venom. 6. The toxin exhibited potent haemolytic activity in vitro and edema-inducing activity with a minimum edema dose (MED) of 0.15 micrograms in mouse paw. The edema effect was not antagonized by diphenhydramine.

Amino Acid Sequence↗
PubMed1991

Screening for frailty: criteria and predictors of outcomes.

OBJECTIVE: To determine the reliability of rapid screening by clinically derived geriatric criteria in predicting outcomes of elderly hospitalized patients. DESIGN: Prospective cohort study of 985 patients screened at the time of hospital admission and followed for 1 year with respect to the outcomes of mortality, hospital readmission, and nursing home utilization. SETTING: Palo Alto Veterans Affairs Medical Center, a tertiary care teaching hospital. SUBJECTS: Male patients 65 years of age and older admitted to the Medical and Surgical services during the period from October 1, 1985 through September 30, 1986. RESULTS: Patients were grouped by specific screening criteria into three groups of increasing frailty: Independent, Frail, and Severely Impaired. Each criterion focused on a geriatric condition and was designed to serve as a marker for frailty. Increasing frailty was significantly correlated with increasing length of hospital stay (P less than 0.0001), nursing home utilization (P less than 0.0001), and mortality (P less than 0.0001). Multivariate analyses revealed that the clinical groups were more predictive of mortality and nursing home utilization than were age or Diagnosis-Related Groups (DRGs). Rehospitalization was unrelated to age, clinical group, or DRG, suggesting that utilization may not be driven by the clinical factors measured in this study. CONCLUSIONS: Rapid clinical screening using specific geriatric criteria is effective in identifying frail older subjects at risk for mortality and nursing home utilization. Our findings suggest that geriatric syndromes are more predictive of adverse outcomes than diagnosis per se. This well operationalized screening process is inexpensive as well as effective and could easily be introduced into other hospital settings.

Activities of Daily Living↗
PubMed1990

Effect of haemodialysis on the pharmacokinetics of cetirizine.

The pharmacokinetics of Cetirizine, a histamine H1-receptor antagonist, were investigated in five renal failure patients undergoing chronic haemodialysis therapy. The patients received one 10 mg cetirizine dihydrochloride capsule 3 h before haemodialysis. Concentrations of cetirizine in serum and dialysate were determined by HPLC. The maximum serum cetirizine concentration and the time to reach that maximum were 285 micrograms.l-1 and 2.0 h, respectively. The terminal disposition half-life of cetirizine in these patients was 19.3 h. The haemodialysis clearance of cetirizine was 14.0 ml. min-1. Although this is approximately 33% of the apparent total body clearance of cetirizine in subjects with normal renal function, the fraction of the dose removed by dialysis was only 9.4%. Thus, since haemodialysis does not produce a clinically significantly alteration in cetirizine elimination, no supplemental dose should be necessary after dialysis.

Adult↗
PubMed1989

Characterization of tumor necrosis factor-alpha receptors in human and rat thyroid cells and regulation of the receptors by thyrotropin.

Administration of recombinant human tumor necrosis factor-alpha (TNF) to rats and mice produces a model of nonthyroid illness in which there is impairment of hypothalamic-pituitary thyroid function, including reduced serum concentrations of T4 and T3, reduced thyroid radioiodine uptake, and reduced response to TSH. In this study, we tested the binding and effects of TNF on FRTL-5 cells and on four human thyroid carcinoma cell lines. The TSH-stimulated [125I]iodide uptake by FRTL-5 cells was inhibited by TNF in a dose-dependent manner. The four human thyroid carcinoma cell lines (NPA, MRO, ARO, WRO) have TSH receptors but did not respond to TSH in regard to iodide uptake and thymidine incorporation. Both human thyroid carcinoma cells and FRTL-5 cells contain specific receptors for TNF. Scatchard analysis showed that the receptor numbers and dissociation constants in human thyroid carcinoma cells and FRTL-5 cells were, respectively; 2.4 x 10(4), 5.4 nM (WRO); 8 x 10(3), 3.4 nM (MRO); 4 x 10(3), 1 nM (ARO); 7 x 10(3), 1 nM (NPA); 3 x 10(3), 1 nM (FRTL-5), and 9 x 10(3), 1 nM (FRTL-5 cells treated with TSH). The results indicate that TNF affects thyroid cell function through binding to the TNF receptor and that the number of TNF receptors is regulated by TSH.

Animals↗
PubMed1988

Multiple-dose pharmacokinetics and toleration of intravenously administered cefoperazone and sulbactam when given as single agents or in combination.

The multiple-dose pharmacokinetics and toleration of cefoperazone (3 g every 12 h) and sulbactam (1.5 g every 12 h) were studied when these antimicrobial agents were administered continuously over 7 days as a 15-min infusion of individual agents and as a 3/1.5-g cefoperazone-sulbactam combination. Fourteen male volunteers participated in an open, three-way crossover study of Latin Square design with a 1-week washout period between phases. On days 1 and 7 of each phase, serial serum samples and urine were collected for drug assay over a 12-h period. Hematological and clinical chemistry determinations were made within 10 days before the first antibiotic dose and for each treatment phase just before the first dose, on day 4 of treatment, and within 24 h of the last dose. For cefoperazone as a single agent on days 1 and 7, the average maximal concentration in serum (Cmax) was approximately 430 micrograms/ml, the terminal elimination half-life (t1/2) was 1.8 h, and the average percentage of dose excreted unchanged in the urine (%Ur) was 30%. For sulbactam as a single agent, the Cmax was approximately 90 micrograms/ml, the t1/2 was 1 h, and the %Ur was 89% on days 1 and 7. When comparing individual versus simultaneous drug administration, the only pharmacokinetic alteration observed was a statistically significant but minor (about 10%) decrease in sulbactam renal clearance, on both days 1 and 7, resulting in a similar decrease in total body clearance (CL). The area under the curve, apparent volume of distribution by the area method (V), t1/2, and Cmax were not significantly altered. Although cefoperazone pharmacokinetic parameters were not significantly altered when comparing single-agent to combination drug administration, the area under the curve was slightly lower and CL, nonrenal clearance, and V were modestly higher from day 1 to day 7. Because Cmax and t1/2 were unaffected, these minor day effects would not be of clinical significance. Intravenous administration of cefoperazone and sulbactam given as individual agents compared with the combination did not show pharmacokinetic differences that are likely to produce clinically relevant effects. The combination of cefoperazone and sulbactam was well tolerated, and the safety profile of the combination was similar to that either drug given alone under the conditions of this study.

Adult↗
PubMed1987

Clinical pharmacokinetics of nifedipine gastrointestinal therapeutic system. A controlled-release formulation of nifedipine.

The pharmacokinetics of nifedipine following intravenous administration can be represented by an open two-compartment model with a terminal elimination half-life of about two hours. Nifedipine is extensively biotransformed to inactive metabolites, and the total body clearance (450 to 700 ml/minute) is primarily due to hepatic metabolism. Nifedipine undergoes significant tissue distribution in that the steady-state volume of distribution (0.62 to 0.77 liter/kg) is more than twice the volume of distribution of the central compartment (0.25 to 0.29 liter/kg). Although nifedipine is almost completely absorbed from the gastrointestinal tract, oral bioavailability ranges from 45 to 68 percent because of first-pass metabolism. Nifedipine given three times daily shows no accumulation in plasma and no changes in pharmacokinetic behavior during a one-week study period. Pharmacokinetic studies on the gastrointestinal therapeutic system (GITS) show that the bioavailability of the GITS dosage form (relative to the capsule) is about 65 percent after a single dose, but increases to about 86 percent at steady-state because of residual absorption more than 24 hours after dosing. Linear pharmacokinetics are seen following administration of single oral doses of nifedipine GITS as indicated by dose-proportional increases in the area under the plasma drug concentration-time curve over the range of 30 to 180 mg. Administration of the GITS dosage form in the presence of food slightly increases the rate of drug absorption, but does not influence the extent of drug bioavailability. Dose-dumping has not been observed, even with dosing after a meal containing a high level of fat. The GITS tablets provide zero-order delivery of nifedipine, and drug absorption persists beyond the dosing interval of 24 hours. Thus, the GITS dosage form will permit once-a-day dosing and maintain the desired, constant plasma drug concentration with minimal fluctuation.

Biological Availability↗
PubMed1987

Human CSF-1: molecular cloning and expression of 4-kb cDNA encoding the human urinary protein.

A 4-kilobase complementary DNA (cDNA) encoding human macrophage-specific colony-stimulating factor (CSF-1) was isolated. When introduced into mammalian cells, this cDNA directs the expression of CSF-1 that is structurally and functionally indistinguishable from the natural human urinary CSF-1. Direct structural analysis of both the recombinant CSF-1 and the purified human urinary protein revealed that these species contain a sequence of at least 40 amino acids at their carboxyl termini which are not found in the coding region of a 1.6-kilobase CSF-1 cDNA that was previously described. These results demonstrate that the human CSF-1 gene can be expressed to yield at least two different messenger RNA species that encode distinct but related forms of CSF-1.

Amino Acid Sequence↗
PubMed1987

Effects of parenteral and enteral nutrition on postnatal development of the small intestine and pancreas in the rabbit.

Although TPN is used frequently in young infants, little information is available regarding its effect on postnatal development of the gut. The effect of total parenteral nutrition (TPN) and intragastric (IG) alimentation on ontogeny of the small intestine was examined in infant rabbits starting at 10-12 days. Animals were killed at 17-19 days. Body weight, organ weight and weight of segments of proximal, mid and distal small intestine were measured. Intestinal mucosa was scraped, weighed and homogenized for estimation of protein, DNA and disaccharidases. Na+ transport was examined in short-circuited jejunum. Weight gain was similar in controls, sham-treated and TPN animals, but was significantly reduced in IG animals. TPN induced precocious development of sucrase and maltase activity and glucose-stimulated Na+ transport, despite causing a significant decrease in mucosal weight and DNA and pancreatic amylase. IG alimentation also induced precocious development of sucrase, maltase and glucose-stimulated Na+ transport. Thus TPN, despite producing mucosal atrophy and decreased pancreatic exocrine development, stimulates accelerated postnatal maturation of the small intestine.

Animals↗
PubMed1987

The comparative pharmacokinetics of H1-receptor antagonists.

H1-receptor antagonists appear to be absorbed rapidly after oral administration, with peak serum concentrations being reached one to three hours after a dose. For most of these drugs, the absolute bioavailability is unknown because no intravenous formulations are available for comparative purposes. The serum elimination half-life values of these agents are variable: a few hours for terfenadine and triprolidine; about 9 hours for cetirizine, azatadine, and loratadine; from 20 to 25 hours for hydroxyzine, chlorpheniramine, and brompheniramine; and from 5 to 14 days for astemizole. Few pharmacokinetic studies of H1-receptor antagonists in children have been reported. However, it is known that chlorpheniramine, hydroxyzine, cetirizine, and terfenadine have shorter elimination half-life values in children than in adults. Regardless of the age of patients, for most of the H1-receptor antagonists the apparent volumes of distribution and total body clearances appear to be large (3.4 to 18.5 L/kg and 4.4 to 32.1 mL/min/kg, respectively). Cetirizine is an exception, with values of 0.8 L/kg and 0.5 mL/min/kg. Urinary excretion of unchanged antihistamine is higher after cetirizine (60% of dose) than any other H1 blocker. For H1-receptor antagonists with long half-life values, steady state may not be reached for several days (chlorpheniramine and brompheniramine) or several weeks (astemizole), and significant accumulation of drug occurs if the dosing interval is more frequent than every half-life. There is no evidence for the introduction of metabolism of H1-receptor antagonists, even after months of treatment.

Adult↗
PubMed1987

Pharmacokinetics of cetirizine in the elderly and patients with renal insufficiency.

The disposition of cetirizine, a new H1-receptor antagonist, was evaluated in 30 healthy adults of various ages and in 15 adults with various degrees of renal insufficiency. The purpose of the evaluation was to determine whether dosage schedules of cetirizine will require modification in the elderly or patients with renal insufficiency. We found that the elimination half-life of cetirizine was prolonged in patients with mild and moderate renal insufficiency, compared with age-matched individuals with normal renal function (19.0 +/- 3.3 and 20.9 +/- 4.4 hours, vs 7.4 +/- 3.0 hours, respectively). However, the mean apparent steady-state volume of distribution did not differ significantly between these subject groups (range 0.41 to 0.47 L/kg). Total body clearance and renal clearance of the drug were both significantly lower in the patients with renal insufficiency. In elderly subjects, the elimination half-life of cetirizine was significantly prolonged compared with younger adults, and apparent total body clearance was significantly reduced. Again, there was no significant difference in the volume of distribution between the groups. Linear regression showed good correlations between the disposition characteristics of cetirizine and age as well as creatinine clearance. However, we found no relationship between age and the ratio of apparent total body clearance of cetirizine to creatinine clearance. Thus the disposition of cetirizine is independent of age but dependent on renal function. The relationship between apparent total body clearance of cetirizine and creatinine clearance was significant only in patients with creatinine clearances greater than 40 mL/min. Progressive decrements in creatinine clearance were not associated with similar changes in the pharmacokinetic parameters of cetirizine.

Adult↗
PubMed1987

The metabolism and pharmacokinetics of 14C-cetirizine in humans.

This study investigated the metabolism and pharmacokinetics of cetirizine, a new H1-receptor antagonist. Single oral doses of 14C-cetirizine dihydrochloride (10 mg) in aqueous solution were administered to six healthy male volunteers. The drug was rapidly absorbed: The peak mean concentration of radioactivity (359 ng-equivalents/mL) and of unchanged drug (341 ng/mL) were achieved within one hour. Mean concentrations of cetirizine declined biexponentially and had a mean elimination half-life of 7.4 hours. The drug was excreted quite rapidly, with 60% of the dose recovered in the 24-hour urine. An additional 10% was excreted in urine over the next four days. Approximately 10% of the dose was excreted in feces over the five-day study period. The dose was excreted mainly as the unchanged drug. Examination of the radioactive compounds present in the plasma, and excreted in the urine and feces indicate that there is little metabolism of cetirizine. One minor metabolite, formed by oxidative O-dealkylation of the cetirizine side chain, was detected in plasma and feces.

Adult↗
PubMed1987

Influence of ethacrynic acid on outflow facility in the monkey and calf eye.

Living monkeys were perfused via the anterior chamber by the two step constant pressure technique with the sulfhydryl (SH)-reactive diuretic, ethacrynic acid (ECA) at dosages from 0.1 to 1.0 mM. Above 0.37 mM a reproducible increase in outflow facility (C) was observed. At 0.5 mM C increased 115% with ECA compared to a 22% increase in control eyes (n = 9; P less than 0.01). In three monkeys simultaneous perfusion of ECA with cysteine in 10% excess prevented this effect. In enucleated calf eyes at dosages ranging from 0.1 to 0.5 mM ECA a similar increase in outflow facility was demonstrated. Simultaneous perfusion of 0.1 mM ECA with 0.5 mM cysteine blocked this increase in facility. At high dosages (6 mM) of ECA a decrease in C of 35% was observed (P less than 0.01, n = 8). Electron microscopic studies of the perfused monkey eyes did not readily explain the observed facility effects of ECA, except for the occurrence of a small number of breaks in the inner wall endothelium of Schlemm's canal. The juxtacanalicular meshwork appeared normal. Moderate to profound trabecular endothelial cell swelling was observed with ECA alone and with simultaneous cysteine. Morphologic studies performed 4 and 11 weeks after repetitive acute exposure to ECA indicated that the tissues of the outflow pathway appeared normal. The importance of this work is that it points to a new class of drugs that may be used someday to treat glaucoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Rising multiple-dose pharmacokinetics of labetalol in hypertensive patients.

Labetalol, a drug possessing both alpha- and beta-adrenergic blocking activities, is used in the treatment of hypertension. The current study was undertaken to elucidate the steady-state pharmacokinetics of labetalol following a rising oral multiple-dosage regimen. Twelve patients received oral labetalol every 12 hours for 18 days. An initial dose of 100 mg was increased at three-day intervals to 200, 300, 400, and 600 mg q12h. Selected blood samples were taken at various times following drug administration at each dose level and analyzed for labetalol levels by a specific high-performance liquid chromography assay. The pharmacokinetics of labetalol are best described by a two-compartment open model with first-order absorption. The half-lives of the absorption, distribution, and elimination phases are 0.6, 1.3, and 8.3 hours, respectively. The steady-state plasma drug concentrations are predictable from the pharmacokinetic data and are in good agreement with the observed values. Steady-state levels are reached by the third day at each dose level studied and increase proportionally with dose.

Adult↗
PubMed1985

Comparative bioavailability and pharmacokinetics of three formulations of albuterol.

Albuterol sulfate, alpha'[[1,1-dimethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol sulfate, is a relatively selective beta-2-adrenergic bronchodilator used for the relief of bronchospasm. The bioavailability of two 4-mg tablet formulations, differing in their inactive excipients, and a syrup formulation, was evaluated. The three dosage forms were orally administered to 12 normal male volunteers in a randomized three-way crossover study. Plasma samples were collected at frequent time points through 12 h and analyzed for albuterol content by a specific GC-MS method. The drug was rapidly absorbed from all three formulations. Maximum drug concentrations were comparable for the three formulations and were obtained between 1.8-2.0 h. The areas under the plasma concentration-time curves were 68-78 h X ng/mL. The drug elimination phase half-live (t1/2 beta) ranged from 4.8 to 5.5 h. Analysis of the data showed that the bioavailability of albuterol from a tablet formulation is equivalent to that from a solution.

Administration, Oral↗
PubMed1985

Clinical pharmacology of netilmicin in preterm and term newborn infants.

Sixty-four neonates, with gestational age ranging from 27 1/2 to 40 weeks, postnatal age from 1 to 15 days, and birth weight from 800 to 3400 gm, were given netilmicin 2.5 mg/kg intramuscularly two or three times per day according to postnatal age, for 5 to 14 days. Serum concentrations were measured before and 1 hour after a dose at least twice during treatment. The serum washout profile of the drug was observed in 22 neonates after discontinuation of therapy. Renal function was studied in 37 infants by measuring serum creatinine concentrations and in 27 by urinary excretion of N-acetyl-glucosaminidase during and up to 15 days after therapy. Behavioral and impedance audiometry, and in infants failing those, auditory brainstem evoked response tests, were performed between 6 and 12 months of age. In 23.5% of the neonates, trough serum levels were greater than 3 micrograms/ml. The serum washout followed a multiexponential decay, accounting for distributional, rapid (initial), and slow (tissue) elimination phases. Linear regression analysis performed between each kinetic parameter and gestational age or birth weight showed that initial elimination half-life, steady-state volume of distribution, and total body clearance were significantly correlated with both variables. Netilmicin did not cause detectable renal or auditory damage.

Acetylglucosaminidase↗