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Biomedical subjects

L K Cheng

Publications and source records attributed to L K Cheng.

At least 19 recordsLinked to original sources
PubMed2006

Computational simulations of the human magneto- and electroenterogram.

Many functional pathologies of the small intestine are difficult to diagnose clinically without an invasive surgical intervention. Often such conditions are associated with a disruption of the normal electrical activity occurring within the musculature of the small intestine. The far field electrical signals on the torso surface arising from the electrical activity within the small intestine cannot be reliably measured. However, it has been shown that abnormal electrical activity in the small intestine can be distinguished by recording the magnetic fields of intestinal origin immediately outside the torso surface. We have developed an anatomically-based computational model to simulate slow wave propagation in the small intestine, the resulting cutaneous electrical field and the magnetic field outside the torso. Using both a one-dimensional and a three-dimensional model of the duodenum we investigate the degree of detail that is required to realistically simulate this far field activity. Our results indicate that some of the qualitative behavior in the far field activity can be replicated using a one-dimensional model, although there are clear situations where the greater level modeling detail is required.

Action Potentials↗
PubMed2006

Multiscale modelling of human gastric electric activity: can the electrogastrogram detect functional electrical uncoupling?

During recent years there has been a growing interest in the assessment of gastric electrical health through cutaneous abdominal recordings. The analysis of such recordings is largely limited to an inspection of frequency dynamics, and this has raised doubts as to whether functional gastric electrical uncoupling can be detected using this technique. We describe here a computational approach to the problem in which the equations governing the underlying physics of the problem have been solved over an anatomically detailed human torso geometry. Cellular electrical activity was embedded within a stomach tissue model, and this was coupled to the torso using an equivalent current source approach. Simulations were performed in which normal and functionally uncoupled (through the introduction of an ectopic antral pacemaker) gastric slow wave activity was present, and corresponding cutaneous electrogastrograms were produced. These were subsequently analysed using the currently recommended techniques, and it was found that the functionally uncoupled situation was indistinguishable from normal slow wave activity using this approach.

Computer Simulation↗
PubMed2005

Rapid construction of a patient-specific torso model from 3D ultrasound for non-invasive imaging of cardiac electrophysiology.

One of the main limitations in using inverse methods for non-invasively imaging cardiac electrical activity in a clinical setting is the difficulty in readily obtaining high-quality data sets to reconstruct accurately a patient-specific geometric model of the heart and torso. This issue was addressed by investigation into the feasibility of using a pseudo-3D ultrasound system and a hand-held laser scanner to reconstruct such a model. This information was collected in under 20 min prior to a catheter ablation or pacemaker study in the electrophysiology laboratory. Using the models created from these data, different activation field maps were computed using several different inverse methods. These were independently validated by comparison of the earliest site of activation with the physical location of the pacing electrodes, as determined from orthogonal fluoroscopy images. With an estimated average geometric error of approximately 8 mm, it was also possible to reconstruct the site of initial activation to within 17.3 mm and obtain a quantitatively realistic activation sequence. The study demonstrates that it is possible rapidly to construct a geometric model that can then be used non-invasively to reconstruct an activation field map of the heart.

Cardiac Pacing, Artificial↗
PubMed2004

An anatomical model of the gastric system for producing bioelectric and biomagnetic fields.

Between 60 and 70 million people in the United States are affected by gastrointestinal disorders. Many of these conditions are difficult to assess without surgical intervention and accurate noninvasive techniques to aid in clinical assessment are needed. Through the use of a superconducting quantum interference device (SQUID) gradiometer, the weak magnetic field generated as a result of muscular activity in the digestive system can be measured. However, the interpretation of these magnetic recordings remains a significant challenge. We have created an anatomically realistic biophysically based mathematical model of the human digestive system and using this model normal gastric electrical control activity (ECA) has been simulated. The external magnetic fields associated with this gastric ECA have also been computed and are shown to be in qualitative agreement with recordings taken from normal individuals. The model framework thus provides a rational basis from which to begin interpreting magnetic recordings from normal and diseased individuals.

Digestive System Physiological Phenomena↗
PubMed2001

Noninvasive electrical imaging of the heart: theory and model development.

The aim of this work is to begin quantifying the performance of a recently developed activation imaging algorithm of Huiskamp and Greensite [IEEE Trans. Biomed. Eng. 44:433-446]. We present here the modeling and computational issues associated with this process. First, we present a practical construction of the appropriate transfer matrix relating an activation sequence to body surface potentials from a general boundary value problem point of view. This approach makes explicit the role of different Green's functions and elucidates features (such as the anisotropic versus isotropic distinction) not readily apparent from alternative formulations. A new analytic solution is then developed to test the numerical implementation associated with the transfer matrix formulation presented here and convergence results for both potentials and normal currents are given. Next, details of the construction of a generic porcine model using a nontraditional data-fitting procedure are presented. The computational performance of this model is carefully examined to obtain a mesh of an appropriate resolution to use in inverse calculations. Finally, as a test of the entire approach, we illustrate the activation inverse procedure by reconstructing a known activation sequence from simulated data. For the example presented, which involved two ectopic focii with large amounts of Gaussian noise (100 microV rms) present in the torso signals, the reconstructed activation sequence had a similarity index of 0.880 when compared to the input source.

Algorithms↗
PubMed1997

Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin.

In our laboratory, primary human hepatocytes are being investigated as an in vitro experimental system for the evaluation of pharmacokinetic drug-drug interactions. Our study here represents the first reported study that directly compares the cytochrome P450 isozyme 3A (CYP3A) induction potential of three antimicrobials derived from rifamycin B, namely, rifampin, rifapentine and rifabutin. Two endpoints of CYP3A activity, testosterone 6 beta-hydroxylation and midazolam 1-hydroxylation have been used. Results obtained with hepatocytes from four different human donors show consistently that rifampin and rifapentine are potent inducers of CYP3A, while a significantly lower induction potential is observed for rifabutin. The relative induction potency of the three antimicrobials (rifampin > rifapentine >> rifabutin) is consistent with the available human in vivo data. For CYP1A measured as ethoxyresorufin O-deethylase activity, CYP2C8/9 measured as tolbutamide 4-hydroxylation activity, CYP2D6 measured as dextromethorphan O-demethylation, and AZT glucuronidation, there is either no effect or, where induction is found to be statistically significant in these other endpoints, the maximum induction values are consistently < 100% of the control. Our results suggest that CYP3A is the major CYP induced by these rifamycin B derivatives. These studies illustrate the application of human hepatocytes in the evaluation of the structure-activity relationships in CYP induction for this class of chemicals and as an in vitro screen for drug-drug interaction potential via CYP induction.

Antibiotics, Antitubercular↗
PubMed1995

Human metabolism of dolasetron mesylate, a 5-HT3 receptor antagonist.

Dolasetron mesylate is a selective and potent 5-HT3 receptor antagonist. This drug is currently in development for the treatment of nausea and vomiting in chemotherapy. The metabolism of dolasetron mesylate was studied in six healthy male volunteers who were given a single 300 mg oral dose of [14C]dolasetron mesylate. An average of 59% of the total radioactivity was recovered in the urine and 25% in the feces. Metabolites were quantitated in urine samples taken up to 36 hr postdose. Reduced dolasetron (RD) accounted for 17-54% of the dose in urine. Hydroxylated metabolites of RD made up no more than 9% of the dose in urine. Most of the remaining urinary radioactivity consisted of conjugated metabolites of RD and hydroxy RD. Hydrolysis of selected urine samples showed that the glucuronide of RD was the most abundant conjugate in urine. A small percentage of the dose (< 1%) in urine was identified as the N-oxide of RD. Analysis of urine samples by chiral HPLC indicated that the R(+):S(-) ratio of RD was approximately 9:1.

Adult↗
PubMed1995

Metabolism of terfenadine associated with CYP3A(4) activity in human hepatic microsomes.

Terfenadine (Seldane) undergoes extensive metabolism to form azacyclonol and terfenadine alcohol. Terfenadine alcohol is subsequently metabolized to azacyclonol and terfenadine acid. Although testosterone 6 beta-hydroxylation [CYP3A(4)] has been shown to be the principal enzyme involved in the first step in terfenadine's biotransformation (formation of azacyclonol and terfenadine alcohol), the enzymes catalyzing the subsequent metabolic steps in the conversion of terfenadine alcohol to azacyclonol and terfenadine acid have not been identified. The purpose of these studies was to determine the role of cytochrome P450 isoforms in the biotransformation of terfenadine and terfenadine alcohol. To this end, both terfenadine and its alcohol were incubated with 10 individual human liver microsomal samples that have been characterized for major isozyme activities. The metabolites and parent drugs were quantified by HPLC. The formation of azacyclonol and terfenadine alcohol from terfenadine is confirmed to be catalyzed predominantly by CYP3A(4) isozyme, and the ratio of the rate of terfenadine alcohol formation to that of azacyclonol is 3:1. Involvement of the CYP3A(4) in terfenadine metabolism was further confirmed by the following studies: a) inhibition of terfenadine alcohol formation by ketoconazole and troleandomycin, two specific inhibitors of CYP3A(4), and b) time course of terfenadine alcohol formation by cloned human CYP3A(4). When terfenadine alcohol was used as substrate, both the terfenadine acid and azacyclonol formation were also catalyzed by CYP3A(4) isozyme. However, the rate of formation of the terfenadine acid metabolite is almost 9 times faster than that of azacyclonol. The net ratio of terfenadine acid to azacyclonol is 2:1.

Alcohols↗
PubMed1990

Determination of a new anti-allergenic agent, 1-[4-[3-[4-[bis-(4-fluorophenyl)hydroxymethyl]-1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone, and its active acidic metabolite in plasma by high-performance liquid chromatography.

High-performance liquid chromatographic (HPLC) methods were developed for the analysis of two compounds in a series of new antiallergenic agents, 1-[4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone and its active acidic metabolite in plasma. The methods utilize ultraviolet or fluorescence detection, liquid-liquid extraction or solid-phase extraction and reversed-phase HPLC. The drugs were quantitated in samples from bioavailability studies performed in dogs. Calibrations were in the ng/ml concentration range for both compounds in plasma.

Animals↗
PubMed1990

Pharmacodynamics and pharmacokinetics of AHR-11748, a new antiepileptic agent, in rodents.

AHR-11748, the desmethyl metabolite of fluzinamide (an effective antiepileptic), was active in preventing maximal seizures induced in mice or rats by electroshock and threshold seizures induced in mice by Metrazol, bicuculline, and picrotoxin. The compound showed a profile of anticonvulsant activity similar to those of phenobarbital and valproic acid and different from those of phenytoin and ethosuximide. ED50s were less than those of valproic acid, but greater than those of phenobarbital. Analysis of plasma and whole brain homogenates of mice indicated that AHR-11748 has an apparent terminal half-life (t1/2, beta) of 1.0 h. The brain:plasma ratio of AHR-11748 was 3.4:1 from 0.5 h to 6 h.

Administration, Oral↗
PubMed1990

Bromfenac, a new nonsteroidal anti-inflammatory drug: relationship between the anti-inflammatory and analgesic activity and plasma drug levels in rodents.

Bromfenac [2-amino-3-(4-bromobenzoyl)benzenacetic acid, sodium salt sesquihydrate] exhibited potent analgesic and anti-inflammatory activity in mice and rats. In a mouse model of pain (acetylcholine abdominal constriction), bromfenac showed a rapid onset of activity (20 min) that persisted for at least 4 hr. In a rat model of inflammation (carrageenan foot edema), a single oral dose of bromfenac, 0.316 mg/kg, produced significant anti-inflammatory activity up to 24 hr after dosing. Bromfenac was readily absorbed after oral administration, peak plasma levels being achieved at the earliest time tested: 20 min in the mouse and 30 min in the rat. The plasma half-life of bromfenac in rats is less than 4 hr. Since the anti-inflammatory activity persisted for 20 to 24 hr in spite of its short plasma half-life, it appears that there is no direct correlation between duration of activity and plasma drug level.

Analgesia↗
PubMed1988

Bioavailability of potassium from three dosage forms: suspension, capsule, and solution.

A crossover study was performed in 28, healthy, male volunteers to determine the bioavailability of potassium from a suspension containing microencapsulated potassium chloride compared with that from a marketed microencapsulated potassium chloride capsule and a marketed potassium chloride solution. The 20-day study consisted of four, five-day periods. In three of the periods, a single, 40-mEq dose of one of the potassium formulations was administered; no drug treatment was given in the remaining period so that the amount of potassium contributed by dietary sources could be determined. Meals were served that provided controlled amounts of potassium and sodium. Bioavailability was represented by cumulative amount of K+ excreted in urine 24 and 48 hours after drug administration. The rate of absorption was calculated from excretion rates during each of the intervals of urine collection on Days 4. The pattern of excretion exhibited by the solution indicated rapid absorption and elimination. The potassium from the suspension and the capsules was excreted more slowly and over a longer period, indicating that the potassium content from these formulations was not being dumped. No statistically significant differences between the suspension and the capsules were found. The extent of absorption of K+ was similar from all three products, and the potassium from the suspension was found to be fully bioavailable when compared with the liquid and the capsule.

Adult↗
PubMed1984

Simultaneous determination of fluzinamide and three of its active metabolites in plasma by high-performance liquid chromatography.

A sensitive and selective high-performance liquid chromatographic method has been developed for a new anticonvulsant, fluzinamide, and three of its active metabolites. This method requires only 0.5 ml of plasma, and it involves a single extraction with a mixture of hexane--dichloromethane--butanol (55:40:5). The plasma extract is chromatographed on a 10-micron, C18 reversed-phase column and quantitated by ultraviolet absorbance at 220 nm. The concentration--response curves for all four compounds are linear from 0.05 micrograms/ml to at least 10 micrograms/ml. The extraction efficiency of this method is greater than 90%. The accuracy and precision of the method were tested by analyzing spiked unknown samples that had been randomly distributed across the concentration range. The mean concentrations found were within +/- 9% of the various amounts added with a standard deviation of +/- 3.5%. This method has been successfully applied to the analysis of samples obtained from fluzinamide-dosed dogs, healthy unmedicated volunteers, and patients who were at steady state with phenytoin, carbamazepine, and fluzinamide.

Anticonvulsants↗