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Biomedical subjects

Y W Lam

Publications and source records attributed to Y W Lam.

At least 37 records · Page 2Linked to original sources
PubMed1998

Reversible metabolism of clozapine and clozapine N-oxide in schizophrenic patients.

1. To characterize the interconversion process between clozapine and its metabolite clozapine N-oxide (CNO), eight healthy male schizophrenics were administered a single dose of clozapine or CNO in a randomized crossover manner. 2. Using a general pharmacokinetic model for the interconversion process, the mean total clearances of clozapine and CNO were 28.45 L/hr and 45.30 L/hr, respectively. These values were similar to the values obtained by the usual model-independent method of pharmacokinetic analysis. 3. When administered clozapine, mean CNO plasma concentrations of 17.7 +/- 16.4 ng/ml were slightly lower than the other clozapine metabolite-desmethylclozapine (DCLOZ) plasma levels of 24.4 +/- 8.6 ng/ml at the 12 hour time point. When CNO was administered, plasma concentrations at the 12 hour time point of clozapine were twice the amount of CNO (28.1 +/- 8.9 ng/ml vs 14.4 +/- 8.8 ng/ml). 4. DCLOZ plasma concentrations were detected in all patients upon clozapine administration. Upon CNO administration, only one patient had detectable plasma DCLOZ levels. 5. The interconversion process of clozapine and CNO could partially account for the wide interpatient variability reported for clozapine plasma concentrations in schizophrenic patients.

Adult↗
PubMed1998

Voltage-sensitive dyes for monitoring multineuronal activity in the intact central nervous system.

Optical monitoring of activity provides new kinds of information about brain function. Two examples are discussed in this article. First, the spike activity of many individual neurons in small ganglia can be determined. Second, the spatiotemporal characteristics of coherent activity in the brain can be directly measured. This article discusses both general characteristics of optical measurements (sources of noise) as well as more methodological aspects related to voltage-sensitive dye measurements from the nervous system.

Action Potentials↗
PubMed1997

Plasma alpha-one acid glycoprotein and haloperidol concentrations in schizophrenic patients.

Thirty six schizophrenic patients were randomly assigned to placebo or haloperidol treatment for 6 weeks. Blood samples to measure plasma alpha-one acid glycoprotein (AAG), haloperidol and reduced haloperidol concentrations were obtained at baseline and weeks 2, 4, and 6. Blood samples were obtained 10-12 h after the evening dose and prior to the morning dose. Haloperidol and reduced haloperidol was assayed by HPLC with electrochemical detection. Plasma AAG levels were assayed by radial immunodiffusion. Patients were clinically assessed by the Brief Psychiatric Rating Scale (BPRS) and Abnormal Involuntary Movement Scale at baseline and weeks 2, 4, and 6. BPRS scores did not significantly decrease during placebo treatment, although a slight drop in plasma AAG levels was found. Haloperidol produced a significant decrease in BPRS scores and plasma AAG levels. Mean plasma haloperidol levels were 12.9 +/- 14.7 ng/ml at week 6. Significant correlations between decreasing BPRS scores and plasma AAG levels were not found with only a strong trend at week 2 (r = 0.445, p = 0.073). The role of AAG and psychotropic drug disposition in psychiatric patients requires further evaluation.

Adult↗
PubMed1997

Principles of drug administration in renal insufficiency.

Normal renal function is important for the excretion and metabolism of many drugs. Renal diseases which affect glomerular blood flow and filtration, tubular secretion, reabsorption and renal parenchymal mass alter drug clearances and lead to the need for alterations in dosage regimens to optimise therapeutic outcome and minimise the risk of toxicity. Renal disease is increasing and the cost of care has risen progressively over the past decade. Part of these costs is related to inappropriate drug therapy and excessive drug use. Although there are a variety of methods for evaluating the various aspects of renal function, the most practical and commonly used clinical measure of renal function is estimated creatinine clearance (CLCR) as a marker for glomerular filtration. This is useful since alterations in drug clearance are proportional to alterations in CLCR, and this relationship is used as the basis for changing doses and dosage intervals for drugs which are largely renally excreted. Two populations, neonates and the elderly, are at risk of inappropriate drug dosage due to physiological changes in renal function. Estimated CLCR may not be the best method of evaluating renal function in these patients, and dosage regimens should be carefully considered. Renal insufficiency and concurrent drug therapy used in these populations can either increase or decrease drug absorption, depending on the particular agent. Drug distribution may be altered in renal insufficiency due to pH-dependent protein binding and reduced protein (primarily albumin) levels. Interestingly, renal disease may affect hepatic as well as renal drug metabolism; the exact mechanisms for these changes are not well understood. The most important quantitative pharmacokinetic change is excretion. Glomerular filtration and tubular process may both be affected but not to the same extent, and the type of renal disease may differentially affect filtration and excretion. Drug removal by dialysis is dependent on a number of factors, including the characteristics of a particular drug and the type of dialysis and equipment used. Therapeutic outcomes may be evaluated using end-points such as plasma concentrations, patient outcomes such as reduction in fever or negative cultures, and system-wide changes such as drug-use or laboratory-use patterns.

Humans↗
PubMed1996

Lack of pharmacokinetic interaction between buspirone and haloperidol in patients with schizophrenia.

The pharmacokinetic interaction between buspirone and haloperidol was evaluated in schizophrenic patients in two different groups. In both groups, haloperidol doses (10-40 mg/day) remained constant for 6 weeks before the addition of buspirone 10 mg three times daily. Serial blood samples were obtained from the 11 patients in group I at baseline (before addition of buspirone) and after administration for 24 hours. The pharmacokinetic parameters of haloperidol were determined alone and with coadministration of buspirone. In group II, buspirone 10 mg three times daily was added to treatment with haloperidol in 27 patients. Blood samples were obtained before addition of buspirone and at weeks 2 and 6 of treatment with buspirone. Samples were obtained 10 to 12 hours after administration of the evening dose and before the morning dose. Haloperidol and its metabolite, reduced haloperidol (RH), were assayed by means of high-performance liquid chromatography with electrochemical detection. Significant changes in the pharmacokinetic parameters of haloperidol were not found in group I; a mean increase in the half-life (t1/2) of haloperidol from 21.5 to 28.1 hours was observed, but this finding was not statistically significant. Under steady-state conditions, plasma levels of haloperidol in the patients in group II did not change significantly from baseline to week 6. Plasma concentrations of RH remained unaltered in both groups. The results indicate that coadministration of buspirone does not markedly affect the pharmacokinetics or plasma concentrations of haloperidol.

Adult↗
PubMed1996

Conditioned enhancement of the early component of the rat eyeblink reflex.

Conditioned enhancement of the rat eyeblink reflex was studied using as a response measure the electromyogram (EMG) in the orbicularis oculi (oo) muscle, which is responsible for the active force generating eyelid closure. During a reflex eyeblink, the EMG evidences both a short-latency (R1) and a long-latency (R2) component, mediated by different circuits. The R2 response exhibits several experience- or use-dependent modifications. We were interested in the modifiability of the neurophysiologically simpler R1 response. Experiments were designed to determine whether the R1 response can be enhanced by a conditioned stimulus (CS) that has been explicitly paired with an aversive unconditioned stimulus (US). The R1 response was elicited by electrical stimulation of the supraorbital branch of the trigeminal nerve. Following long-delay conditioning, the CS produced a significant R1 enhancement and latency decrease that were dependent upon explicit CS-US pairings. The CS by itself produced no significant EMG response, consistent with a modulatory rather than additive effect. This is the first demonstration that the R1 response can be associatively modulated. Based on other evidence, we hypothesize that the CS-produced enhancement results from a relatively direct projection from the amygdala to the R1 circuit. As an index of aversive conditioning, R1 enhancement may prove to be a useful expression system because it offers high temporal resolution and the underlying circuitry is relatively simple-the shortest path from the fifth nerve to the muscle consisting of only two central synapses.

Animals↗
PubMed1996

Disposition of remoxipride in Chinese schizophrenic patients.

The disposition of remoxipride was evaluated in 13 male chronic schizophrenic patients. A single 150 mg dose of remoxipride was administered and blood sampling performed over the following 48 hours. The mean (SD) oral clearance and half-life of remoxipride were 74.46 (25.9) ml/min and 5.46 (0.87) hours, respectively. The mean (SD) AUC for remoxipride was 25,320 (9,820) ng.h/ml. A wide interpatient variability was observed. Compared to Caucasian studies there were no significant differences in the disposition of remoxipride.

Adult↗
PubMed1996

Serotonin selective reuptake inhibitor drug interactions and the cytochrome P450 system.

The article focuses on the effects of the serotonin selective reuptake inhibitors (SSRIs) on specific drug metabolizing isoenzymes: CYP2D6, CYP3A3/4, CYP1A2, CYP2C9, and CYP2C19. Both in vitro and in vivo data regarding the inhibition potential of the SSRIs at each of these isoenzyme systems are reviewed. In general, the magnitude of the in vivo interactions between the SSRIs and substrates for these isoenzyme systems mirrors to a large extent their in vitro inhibitory potencies. However, in vitro work is limited owing to pharmacokinetic considerations, the effect of metabolites on the isoenzymes, and the likelihood that several isoenzymes are co-responsible for the metabolism of a substrate.

Antidepressive Agents↗
PubMed1995

Intra- and interethnic variability in reduced haloperidol to haloperidol ratios.

Steady-state haloperidol and reduced haloperidol concentrations were measured in 250 schizophrenic patients from 4 ethnic groups: 39 Blacks, 66 Caucasians, 82 Chinese, and 63 Mexican Americans. The distribution of the reduced haloperidol to haloperidol concentration (RH/HL) ratios was bimodal in all ethnic groups, with the antimode determined by probit plot as 0.46, 0.51, 0.36, and 0.76, respectively. With these antimodes, the proportion of patients with low RH/HL ratios were 41%, 42%, 73%, and 57% in the four ethnic groups, respectively. Compared with the other three ethnic groups, in the Chinese patients the ratio was lower. The mean RH/HL ratio in the Chinese was 0.34 compared with 0.81 to 0.87 in the non-Chinese groups. In 53 patients who were treated with two or more haloperidol dosage regimens, steady-state haloperidol and reduced haloperidol drug concentrations obtained from the different regimens were positively correlated with the haloperidol dose (R = .79 and R = .62, respectively). Our data suggest not only the existence of a bimodal distribution in the RH/HL ratio, but also that the antimode separating the low and high ratio subgroups is different among the various ethnic groups.

Adult↗
PubMed1995

Cell type- and differentiation stage-dependent expression of PML domains in rat, detected by monoclonal antibody HIS55.

Using mouse monoclonal antibody (mAb) HIS55, we identified a nuclear antigen (ag) that exhibited a staining pattern of discrete foci. Such foci could be detected in cells of many mammalian species. These nuclear foci were not associated with nuclear membrane, nucleoli, or mitotic chromosomes. In isolated rat liver nuclei, HeLa cells, and normal human and rat lymph nodes, staining of HIS55 colocalized with that of 5E10. 5E10 recognizes PML nuclear domains, multimolecular complexes of unknown function containing the product of PML gene and at least two other components. HIS55 foci were expressed widely in many tissues but the expression level varied in a cell type-specific manner, with the number of HIS55 nuclear foci ranging from 0 (as in neurons) to over 100 (as in megakaryocytes) and the size ranging from fine (as in cortical thymocytes) to very large (as in urethra epithelium). HIS55 ag expression level also varied among cells of the same lineage, as observed in embryonic development of rat and in the hemopoietic system of adult rat. The expression level of HIS55 foci roughly correlated with the overall rate of protein synthesis of cells, supporting a role of PML domains as transcription regulatory units. The expression of HIS55 foci, however, did not correlate with the growth index of cell populations. Our observations on normal tissues agreed with the hypothesis that PML domain expression is regulated by external, possibly site-dependent factors. We further supported this by demonstrating that PML domains in rat ventral prostate epithelia were upregulated upon castration.

Animals↗
PubMed1995

Disposition and covalent binding of ibuprofen and its acyl glucuronide in the elderly.

Ibuprofen is an over-the-counter nonsteroidal anti-inflammatory drug with a low incidence of severe adverse reactions. It is metabolized by oxidation to carboxyibuprofen and hydroxyibuprofen and by conjugation to an acyl glucuronide. In vitro studies have indicated that ibuprofen glucuronide is labile and reactive, forming covalent adducts with proteins. To verify the formation of ibuprofen-protein adducts in vivo, the pharmacokinetics of ibuprofen glucuronide and its covalent binding to plasma proteins were studied in five elderly patients who received long-term administration of oral doses of ibuprofen. Plasma levels of ibuprofen glucuronide were low relative to those of ibuprofen; the ratio of area under the plasma concentration versus time curve for the glucuronide relative to the parent drug was only 4%. Covalent binding of ibuprofen to plasma protein was observed in all patients, correlating well with the area under the plasma concentration versus time curve of ibuprofen glucuronide (r = 0.966). Compared with reports for other nonsteroidal anti-inflammatory drugs that form acyl glucuronides, plasma levels of ibuprofen-protein adduct are low during long-term administration. The observed lower reactivity in vivo is probably attributable to the greater stability of ibuprofen glucuronide relative to other acyl glucuronides.

Administration, Oral↗
PubMed1995

Roxithromycin disposition in patients on continuous ambulatory peritoneal dialysis.

Roxithromycin is a macrolide antibiotic with a spectrum of activity similar to erythromycin. Roxithromycin has been shown to have a favourable pharmacokinetic profile with more reliable absorption and higher, prolonged plasma and tissue concentrations compared with erythromycin. The pharmacokinetics and dialysis clearance of roxithromycin were studied in twelve patients with end-stage renal disease on continuous ambulatory perionteal dialysis. Following a single 300 mg oral dose, multiple blood, dialysate and urine samples were collected over 48 h and assayed for roxithromycin by a microbiological method. Peak plasma concentrations were attained between 0.5 and 5 h, and ranged from 2.3 to 6.8 mg/L. The mean elimination half-life was 20.6 +/- 8.7 h, compared with 10 to 14 h previously reported in healthy volunteers given a single 300 mg dose. Plasma clearance relative to bioavailability (Clp/F) ranged from 37.3 to 118.3 mL/min. The percentage of the dose recovered in the dialysate and net dialysis clearance were low, ranging from 1.0 to 3.1% and 0.9 to 1.8 mL/min, respectively. Only 1% of the dose was recovered in the urine. These results demonstrate that roxithromycin is not substantially removed by continuous ambulatory peritoneal dialysis, and its elimination is prolonged in renal failure, possibly due to impaired nonrenal elimination.

Adult↗
PubMed1995

Antidepressant drug interactions and the cytochrome P450 system. The role of cytochrome P450 2D6.

The selective serotonin reuptake inhibitors (SSRIs) and venlafaxine display the following rank order of in vitro potency against the cytochrome P450 (CYP) isoenzyme CYP2D6 as measured by their inhibition sparteine and/or dextromethorphan metabolism: paroxetine > fluoxetine identical to norfluoxetine > or = sertraline > or = fluvoxamine > venlafaxine. On this basis, paroxetine would appear to have the greatest and fluvoxamine and venlafaxine the least potential for drug interactions with CYP2D6-dependent drugs. In vivo, inhibitory potency is affected by the plasma concentration of the free (unbound) drug, a potentially important consideration since many CYP2D6-metabolised drugs exhibit nonlinear (saturable) kinetics, and by the presence of metabolites, which might accumulate and interact with the CYP system. Under steady-state conditions, paroxetine and fluoxetine are approximately clinically equipotent inhibitors of CYP2D6 in vivo (as determined through their effects on desipramine metabolism); sertraline, in contrast, shows lower steady-state plasma concentrations than fluoxetine and, hence, a less pronounced inhibition of CYP2D6. Of the drugs that are metabolised by CYP2D6, secondary amine tricyclic antidepressants, antipsychotics (e.g. phenothiazines, and risperidone), codeine, some antiarrhythmics (e.g. flecainide) and beta-blockers form the focus of clinical attention with regard to their potential interactions with the SSRIs. Coadministration of desipramine and fluoxetine (20 mg/day) at steady-state produced an approximately 4-fold elevation in peak plasma desipramine concentrations, while the long half-life of the active metabolite norfluoxetine was responsible for a significant and long lasting (approximately 3 weeks) elevation of plasma desipramine concentrations after discontinuation of fluoxetine. Similarly, coadministration of desipramine with paroxetine produced an approximately 3-fold increase in plasma desipramine concentration. In contrast, coadministration of desipramine and sertraline (50 mg/day) for 4 weeks resulted in a considerably more modest (approximately 30%) elevation in plasma desipramine concentrations. Coadministration of fluoxetine (60 mg/day, as a loading dose) [equivalent to serum concentrations obtained with 20 mg/day at steady-state] with imipramine or desipramine resulted in approximately 3- to 4-fold increases in plasma area under the curve (AUC) values for both imipramine and desipramine (illustrating a significant drug interaction potential at multiple isoenzymes). Consistent with its minimal in vitro effect on CYP2D6, fluvoxamine shows minimal in vivo pharmacokinetic interaction with desipramine, but does interact with imipramine (approximately 3- to 4-fold increase in AUC) through inhibition of CYP3A3/4, CYP1A2, and CYP2C19. Thus, the extent of the in vivo interaction between the SSRIs and tricyclic antidepressants mirrors to a large extent their in vitro inhibitory potencies against CYP2D6 and other isoenzyme systems, especially if one takes into account pharmacokinetic factors.

Animals↗
PubMed1994

Disposition of clozapine and desmethylclozapine in schizophrenic patients.

The disposition of the atypical clozapine and its desmethyl metabolite were evaluated in fourteen male chronic patients. A single 100 mg dose of clozapine was administered and blood sampling performed over the following 72 hours. The mean (SD) oral clearance and half-life of clozapine were 55.4 (29.7) L/hr and 13.7 (9.9) hours, respectively. The mean (SD) AUC for clozapine and desmethylclozapine was 2389.9 (1406) and 751.1 (622.9) ng.hr/mL, respectively. The elimination of the metabolite is rate limited by its formation from cloza-pine. A wide interpatient variability in clozapine and desmethylclozapine pharmacokinetics was observed.

Adult↗
PubMed1994

Latent inhibition of the rat eyeblink response: effect of hippocampal aspiration lesions.

The effect of hippocampal aspiration lesions on latent inhibition of eyeblink conditioning in the restrained rat preparation was examined. Rats received either sham, cortical control, or hippocampal aspiration lesions. Control animals, but not animals with hippocampal lesions, showed slower conditioning after being preexposed to the conditioned stimulus (latent inhibition). Together with previous results regarding the effect of hippocampal lesions in acquisition and extinction of delay conditioning, the present study suggests that the restrained rat preparation may serve as a reliable way of investigating hippocampal participation in different classical conditioning paradigms.

Animals↗
PubMed1994

Reversible metabolism of drugs.

Many drugs undergo reversible metabolism. The basis of our understanding of this process is the reversible metabolism of prednisone (PD)-prednisolone (PL). The pharmacokinetics of reversible metabolism requires the use of four area under the curve values integrated into four equations for clearance (CL). Other variables, such as linear versus non-linear disposition, can play important roles in reversible metabolism. Of recent interest is the reversible metabolism of haloperidol which consists of an interconversion process between the parent drug haloperidol (HL) and its reduced metabolite (RH). However, the interconversion of HL-RH differs from the PD-PL model in that, whereas PD and PL are both active, RH is considered to be a therapeutically inactive, possibly toxic, metabolite. This article reviews the pharmacodynamic and pharmacokinetic properties of HL and RH and the possible clinical effects that can result from this reversible metabolism.

Animals↗
PubMed1993

Sensitive high-performance liquid chromatographic assay for the determination of chlorhexidine in saliva.

A high-performance liquid chromatographic assay was developed to determine salivary chlorhexidine concentration. Saliva sample (200 microliters) was extracted into methylene chloride. Chromatographic separation was achieved with a C18 column using a mobile phase of acetonitrile-0.05 M sodium acetate and 0.005 M heptanesulfonic acid (40:60, v/v). The standard curve was linear from 0.051 to 20.48 micrograms/ml (r2 > or = 0.997). Intra-day and inter-day coefficients of variation were < 5.5 and < or = 9%, respectively. The assay is rapid, sensitive, simple, and successfully used for quantitating salivary chlorhexidine content released from a chlorhexidine-impregnated resin worn by patients.

Chlorhexidine↗