Search PubMed⌕ Search

Biomedical subjects

Y W Lam

Publications and source records attributed to Y W Lam.

At least 55 records · Page 3Linked to original sources
PubMed1993

Prolonged haloperidol and reduced haloperidol plasma concentrations after decanoate withdrawal.

Haloperidol and reduced haloperidol plasma concentrations were measured in twelve schizophrenic patients upon cessation of haloperidol decanoate (HLD) treatment. Each patient received HLD 100 mg every 4 weeks for five injections. After the fifth injection, HLD was discontinued. Haloperidol and reduced haloperidol plasma concentrations were obtained prior to cessation and at weeks 1, 3, 4, 5, 7, 9, 11, and 13 post-injection. Haloperidol and reduced haloperidol plasma concentrations were assayed by HPLC. Both haloperidol and reduced haloperidol plasma concentrations were detectable 13 weeks post HLD discontinuation. Maximal haloperidol plasma concentrations were observed at one week post cessation and gradually declined. The mean elimination half-life for haloperidol was 27.4 +/- 8.6 days (range 19.0-47.0 days). Reduced haloperidol plasma concentrations declined very slowly. Our results show that both haloperidol and reduced haloperidol plasma concentrations can remain for extended time periods after HLD is discontinued.

Adult↗
PubMed1993

High-performance liquid chromatography determination of dextromethorphan and dextrorphan for oxidation phenotyping by fluorescence and ultraviolet detection.

To establish the usefulness of fluorescence detection to quantify urinary concentrations of dextromethorphan and dextrorphan for oxidation phenotyping, we determined the molar concentration ratio of dextromethorphan to dextrorphan in 38 subjects by UV and fluorescence detection. Dextromethorphan and dextrorphan concentrations were quantified after overnight hydrolysis of urine samples and organic solvent extraction with heptane and butanol. The compounds were separated by high-performance liquid chromatography using a phenyl column and a mobile phase consisting of acetonitrile and an aqueous mixture of 0.01 M heptane sulfonic acid and 0.01 M phosphate buffer. The eluents were detected in series by a UV detector (280 nm) and fluorescence detector (excitation 280 nm and emission 310 nm). The dextromethorphan to dextrorphan molar concentration ratio by UV and fluorescence detection was highly correlated (r = 0.997) and not statistically different (p = 0.1036). However, increased sensitivity with fluorescence detection enabled detection of lower dextromethorphan and dextrorphan concentrations when compared with UV detection. Fluorescence detection was able to detect dextromethorphan as low as 0.02 microgram/ml, which may be helpful in phenotyping individuals with extremely rapid metabolism of dextromethorphan. Fluorescence detection also produced chromatograms with significantly less interference and allows a more accurate quantitation of dextromethorphan and dextrorphan concentrations.

Chromatography, High Pressure Liquid↗
PubMed1993

Hypoxia, arterial pH and theophylline disposition.

Theophylline is a bronchodilator used extensively in the management of obstructive pulmonary disease. Factors implicated in altered theophylline clearance include smoking, age, concomitant drug intake, liver disease and left ventricular heart failure. However, evidence now suggests that theophylline clearance may be altered by changes in severity of the pulmonary obstruction, hypoxia and variation in arterial pH. The in vitro disposition of theophylline has been evaluated in isolated rat livers and mouse hepatocytes. In vivo studies have assessed the metabolism of theophylline under hypoxia in rats, rabbits and dogs. In isolated mouse hepatocytes and rat livers, low oxygen concentrations resulted in higher theophylline concentrations, a longer elimination half-life and a decrease in the production of the metabolite 1,3-dimethyl uric acid, suggesting impaired metabolism of theophylline. In rabbits, hypoxia, hypercapnia and respiratory acidosis decreased total body clearance and increased plasma theophylline concentrations. On the other hand, experiments involving dogs showed no significant changes in theophylline concentrations or pharmacokinetic parameters with hypoxia. At present, animal studies remain inconclusive. This can be attributed to the use of different animal models and variations in study methodology, including the extent and duration of hypoxia and acidaemia, concurrent acid-base disorders such as hypercapnia, as well as the severity of pulmonary obstruction. Human studies assessing alterations in theophylline disposition secondary to the hypoxia present in pulmonary disease are few and include mostly case reports and observational studies. There is evidence suggesting decreased theophylline clearance and protein binding during acute illness and some consensus can be achieved using case reports and controlled studies. There is additional evidence that drug clearance decreases with age and that elderly patients may have a decreased theophylline clearance at baseline. However, the most obvious markers appear to be the severity of pulmonary disease and the rate of change in the patient's condition. Caution should be exercised when administering theophylline to elderly patients with chronic obstructive pulmonary disease presenting with acute exacerbations of a concomitant respiratory illness, as these patients appear to be most likely to exhibit altered theophylline metabolism. Therefore, they would be at increased risk for toxicity should conventional dosages be used during an acute respiratory event.

Acid-Base Imbalance↗
PubMed1992

Pharmacokinetics of haloperidol and reduced haloperidol in Chinese schizophrenic patients after intravenous and oral administration of haloperidol.

The pharmacokinetics of haloperidol were studied in eight Chinese schizophrenic patients after intravenous administration and in six of the patients who also received oral haloperidol. After intravenous dosing, haloperidol disposition was best characterized by a three compartment model. The mean elimination half-life of 54.8 h determined by model dependent analysis was similar to the mean elimination half-life of 59.9 h determined by model independent analysis. The mean plasma clearance was 21.71/h and the mean volume of distribution during the distribution phase was 1754.3 1. After oral dosing, bioavailability of haloperidol was 35 +/- 8%, suggesting extensive first pass metabolism. Determination of reduced haloperidol concentration confirmed a previous finding of significant variability in haloperidol reductive capacity in individual patients. Comparison of area under the plasma concentration-time curve of reduced haloperidol after intravenous and oral administration of haloperidol suggests that reduction of haloperidol may only account for a small portion of first pass metabolism of haloperidol. However, conversion of reduced haloperidol back to haloperidol necessitates the monitoring of both haloperidol and reduced haloperidol concentrations in clinical practice.

Administration, Oral↗
PubMed1992

Comparison of haloperidol and reduced haloperidol plasma levels in four different ethnic populations.

1. Plasma haloperidol and reduced haloperidol concentration were measured in four ethnic populations. 2. Plasma samples were obtained under steady-state conditions and obtained 10-12 hours post bedtime dose and prior to the morning dose. 3. Haloperidol and reduced haloperidol plasma levels were assayed by radioimmunoassay and liquid chromatography. 4. A wide interpatient variability between haloperidol dose and plasma concentration was observed for each ethnic group. 5. The Chinese group differed from the other ethnic populations. 6. A nonlinear relationship was observed between haloperidol and reduced haloperidol plasma levels in each ethnic group. Further, the relationship of haloperidol to reduced haloperidol plasma levels differed for each ethnic group. These results suggest that various ethnic groups could metabolize haloperidol and reduced haloperidol differently.

Black or African American↗
PubMed1992

Interindividual variabilities in haloperidol interconversion and the reduced haloperidol/haloperidol ratio.

Metabolism of haloperidol in humans includes N-dealkylation to inactive metabolites and reduction to reduced haloperidol; reduced haloperidol is also oxidized back to haloperidol. A single 0.5 mg/kg (0.00133 mmol/kg) oral dose of haloperidol and reduced haloperidol was administered to seven Chinese schizophrenics in a randomized crossover manner separated by a 2-week interval. The clearance values for the different metabolic pathways of haloperidol and reduced haloperidol were determined. There were differences up to 10-fold in both oxidation and reduction capacities. There were also interindividual variabilities in the elimination of reduced haloperidol (0.37 +/- 0.20 L/hr/kg) and the N-dealkylation pathway (0.74 +/- 0.36 L/hr/kg). Four weeks after the single-dose study, the same patients also received haloperidol (10 mg) twice daily for 4 weeks. The reduced haloperidol to haloperidol concentration ratio (0.40 +/- 0.16) after the 4-week therapy is related to individual variabilities in the interconversion process and the N-dealkylation pathway of haloperidol.

Adult↗
PubMed1991

Effect of probenecid on the pharmacokinetics and pharmacodynamics of procainamide.

Renal tubular transport of organic anions and cations is assumed to be mutually exclusive. However, results of a number of in vitro and in vivo studies suggest an interaction between the organic anion, probenecid, and various organic cations in the proximal renal tubule. To evaluate the clinical importance of such an interaction, the authors investigated the pharmacokinetics and pharmacodynamics of procainamide, an organic cation with a low therapeutic index that is excreted in part by active secretion in the proximal tubule, in the presence and absence of probenecid. In a randomized crossover study, six healthy subjects received a single 750-mg IV dose of procainamide, with and without prior probenecid administration (2 g orally). Blood and urine samples were obtained and pharmacokinetic parameters of procainamide were determined in each treatment period. QT intervals were measured from ECG recordings that were obtained at blood collection times for pharmacodynamic evaluation. Coadministration of probenecid did not result in any significant change in the overall disposition of procainamide. In particular, renal clearance was not significantly different (488 +/- 95 mL/min without probenecid vs. 478 +/- 69 mL/min in the presence of probenecid). Our data suggest an interaction between probenecid and procainamide in the proximal renal tubule does not exit. Reasons for this lack of interaction are discussed.

Adult↗
PubMed1991

Ethnic comparison of haloperidol and reduced haloperidol plasma levels: Taiwan Chinese versus American non-Chinese.

Steady-state haloperidol (HAL) and reduced HAL (RHAL) plasma levels were measured in Chinese and non-Chinese schizophrenic patients. The patients (n = 38) were matched according to age (+/- 1 yr) and by HAL dose. In general, Chinese patients had higher mean plasma HAL levels and lower RHAL/HAL ratios compared to non-Chinese patients (23.6 +/- 14.9 ng/ml versus 17.1 +/- 10.1 ng/ml, p less than 0.05; 0.52 +/- 0.44 versus 0.82 +/- 0.62, p less than 0.05). Six groups were formed according to HAL dose (number per group): 10 mg/day (6); 20 (11); 30 (11); 40 (4); 50 (3); and 60 (3). No significant differences were found in age, weight and dose/weight. In each dose group, HAL plasma levels were generally higher in the Chinese patients than in the non-Chinese patients, though significance was only detected in the 30 mg group (26.1 +/- 7.0 ng/ml versus 18.5 +/- 5.1 ng/ml, p = 0.035) and a slight trend in the 40 mg group (36.0 +/- 15.0 ng/ml versus 23.5 +/- 10.4 ng/ml, p = 0.074). RHAL/HAL ratios were generally lower in the Chinese patients than in the non-Chinese patients, with a strong trend toward the significance level in the 20 mg and 30 mg groups (0.22 +/- 0.13 versus 0.58 +/- 0.57, p = 0.066 and 0.43 +/- 0.26 versus 0.71 +/- 0.34, p = 0.062). This study further suggests the possibility of different metabolic rates between Chinese and non-Chinese patients. Possible differences in the enzyme systems which relate to the metabolism of HAL and RHAL between Chinese and non-Chinese populations are discussed.

Adult↗
PubMed1990

Reversible metabolism of haloperidol and reduced haloperidol in Chinese schizophrenic patients.

Haloperidol disposition has been associated with reversible metabolism: it is reversibly reduced to its metabolite, reduced haloperidol, which has less pharmacologic activity than the parent compound. To characterize the interconversion process, six healthy male schizophrenics were administered a single dose of 10 mg haloperidol or reduced haloperidol in a randomized crossover manner. Using a general pharmacokinetic model for the interconversion process, the clearances of haloperidol and reduced haloperidol are 1.15 +/- 0.32 l/h/kg and 0.76 +/- 54 l/h/kg, respectively. These clearances are similar to that obtained by the usual mammillary model analysis. With a single 10 mg dose administration of either drug, about 23% of the biotransformation of haloperidol involves the reduction pathway. Back conversion from the reduced metabolite to the parent drug through oxidation contributes even less to the total biotransformation of reduced haloperidol. This action of interconversion or saturation under chronic drug administration is unknown. Reversible metabolism of haloperidol could partially account for the wide therapeutic range for haloperidol as reported in the literature.

Adult↗
PubMed1990

The pharmacokinetics of teicoplanin in varying degrees of renal function.

The pharmacokinetics of teicoplanin, a new glycopeptide antibiotic with activity against aerobic gram-positive bacteria, were characterized after intravenous administration of a single 3 mg/kg dose in five healthy volunteers and six patients with various degrees of stable renal insufficiency. Serum and urine samples were collected during a 15-day period and drug concentrations were assayed microbiologically. The mean elimination half-life of teicoplanin was 162.6 +/- 69.8 hours in healthy volunteers and was prolonged with decreased renal function. The mean plasma and renal clearances of teicoplanin in healthy subjects were 11.4 +/- 1.5 ml/min and 10.0 +/- 1.0 ml/min, respectively. Both values decreased in patients with renal failure and correlated significantly with measured creatinine clearances (r2 = 0.938 and 0.884, respectively). A nomogram for dosage adjustment in patients with varying degrees of renal failure is presented.

Adult↗
PubMed1990

Drug interactions in hypertensive patients. Pharmacokinetic, pharmacodynamic and genetic considerations.

Antihypertensive treatment has proven benefits, and the number of patients being treated with these drugs is significant. Hypertensive patients may have other medical illnesses for which they receive medications, and interactions between antihypertensive agents and other drugs is likely. Some of these interactions may lead to undesirable effects or even loss of blood pressure control. However, drug interactions can also be beneficial when 2 antihypertensive drugs with different pharmacological actions are prescribed in combination and with a clear therapeutic objective in mind. Clinicians should be aware of the mechanisms and the consequences of the different types of interaction in hypertensive patients, so that a desired pharmacological response can be achieved with the fewest side effects in the patients.

Antihypertensive Agents↗
PubMed1989

Pharmacodynamics and pharmacokinetics of haloperidol and reduced haloperidol in schizophrenic patients.

Twelve male chronic schizophrenic inpatients, neuroleptic-free for at least 4 weeks, were given an oral test dose of 10 mg haloperidol (HAL) and reduced HAL (RHAL) in a random order, with a 2-week interval. Two weeks after the last test dose, the patients were given HAL, 5 mg orally twice daily for 7 days. Blood samples were drawn at baseline and between 0.5 and 24 hr after the test doses, and during HAL treatment as well. Plasma drug concentrations and homovanillic acid (HVA) levels were measured with high-performance liquid chromatography using electrochemical detection. HAL, but not RHAL, produced increments in plasma HVA (pHVA) levels at 24 hr after a test dose. pHVA levels remained higher than baseline during HAL treatment. Detectable interconversion between HAL and RHAL was observed in eight patients. The capacity of the reductive drug-metabolizing enzyme system, however, was greater than that of the oxidative processes. The plasma RHAL:HAL ratios on days 6 and 7 were higher than and positively correlated with those at Tmax after a single dose of HAL and were negatively correlated with the HAL:RHAL ratios at Tmax after a single dose of RHAL. Thus, both reductive and oxidative drug-metabolizing systems probably contribute to individual differences in plasma RHAL:HAL ratios in HAL-treated schizophrenic patients.

Adult↗
PubMed1989

Pharmacokinetics of haloperidol.

Haloperidol has been used extensively for the treatment of psychotic disorders, and it has been suggested that the monitoring of plasma haloperidol concentration is clinically useful. Different assay methodologies have been used in research and clinical practice to examine the relationship between response and plasma concentration of the drug. Chemical assays such as high pressure liquid chromatography (HPLC) and gas-liquid chromatography (GLC) have good precision and sensitivity; radioimmunoassay (RIA) is generally more sensitive, but less precise and specific. Radioreceptor assay quantifies dopaminereceptor blocking activity but does not provide results comparable with those of HPLC, GLC and RIA. Large doses of haloperidol can safely be given intravenously and intramuscularly for rapid neuroleptisation; the bioavailability of this agent administered orally ranges from 60 to 65%. However, there is large interindividual, but not intraindividual, variability in plasma haloperidol concentrations and most pharmacokinetic parameters. This interindividual variability could be partially explained by the reversible oxidation/reduction metabolic pathway of haloperidol: it is metabolised via reduction to reduced haloperidol, which is biologically inactive. Different extents of enterohepatic recycling, and ethnic differences in metabolism, could also account for the observed variability in haloperidol disposition. Although not conclusive from different clinical studies, it appears that a plasma haloperidol concentration range of 4 micrograms/L to an upper limit of 20 to 25 micrograms/L produces therapeutic response. The role of reduced haloperidol in determining clinical response is not clear, although in some studies a high reduced haloperidol/haloperidol concentration ratio has been suggested to be associated with therapeutic failure. Measurements of red blood cell or cerebrospinal fluid haloperidol concentration have also been proposed as determinants of therapeutic response, but results from different studies are inconsistent, and do not seem to provide a significant advantage over plasma concentration monitoring. Physiological parameters such as prolactin and homovanillic acid levels have been evaluated, with the latter showing some promise that warrants further investigation. Haloperidol decanoate can be characterised by a flip-flop pharmacokinetic model because its absorption rate constant is slower than the elimination rate constant. Its plasma concentration peaks on day 7 after intramuscular injection. The elimination half-life is about 3 weeks, and the time to steady-state is about 3 months.

Drug Interactions↗
PubMed1988

Stereoselectivity: an issue of significant importance in clinical pharmacology.

Many drugs have one or more asymmetric centers and are administered as a racemate containing an equal mixture of enantiomers with different pharmacologic properties, routes, and rates of disposition in humans. For example, S-warfarin is more potent than R-warfarin, and is metabolized by different pathways. The S-enantiomer is primarily oxidized, and the R-enantiomer is metabolized by both oxidation and reduction. Nevertheless, because of the difficulty in separating and analyzing individual enantiomers, most pharmacokinetic and pharmacodynamic studies on drugs have been performed without considering the stereochemical factors. This is unfortunate, because a nonstereoselective approach to the study of chiral drugs precludes insight into potential valuable information that may be relevant to drug development and evaluation. On the other hand, when the pharmacologic properties (including activity, disposition, and interaction with the other enantiomer) of enantiomers have been defined, manipulation of the enantiomeric ratio or use of the pure enantiomer can be pursued to optimize therapeutic efficacy.

Drug Interactions↗
PubMed1988

Effect of protein binding on serum bactericidal activities of ceftazidime and cefoperazone in healthy volunteers.

The effect of protein binding on antibiotic efficacy is controversial. The pharmacologic effect of an antibiotic is believed to be related to its unbound concentration at the site of infection. It is unknown whether antibiotics with a low degree of serum protein binding are clinically superior to antibiotics that are highly protein bound. In a randomized, crossover investigation, the serum bactericidal activities of a single dose of ceftazidime (30 mg/kg) and cefoperazone (30 mg/kg) were studied in six healthy volunteers against three clinical isolates of Pseudomonas aeruginosa for which both antibiotics had similar MICs and MBCs. Serum samples were collected over 12 h. The total and unbound antibiotic concentrations were determined by high-pressure liquid chromatography. Mean peak total concentrations of ceftazidime and cefoperazone in serum were 101.7 +/- 18.6 and 264.1 +/- 149.6 micrograms/ml, respectively. Due to its lower protein binding (21 +/- 6%), ceftazidime had significantly higher unbound concentrations in serum than did the highly bound cefoperazone (91.5 +/- 2%). Mean peak unbound concentrations were 78.5 +/- 12.5 and 24.2 +/- 17.8 micrograms/ml for ceftazidime and cefoperazone, respectively. The unbound concentration of ceftazidime at each sampling time was higher than that of cefoperazone. Although total concentrations were consistently higher than the MICs, serum containing cefoperazone showed minimal bactericidal activity against the isolates. In contrast, despite lower total concentrations, ceftazidime had greater antibacterial activity than cefoperazone. Serum bactericidal activity was more closely related to unbound rather than total antibiotic concentrations. Our data support the concept that only the unbound drug is microbiologically active.

Adult↗