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Biomedical subjects

A H Lau

Publications and source records attributed to A H Lau.

At least 19 recordsLinked to original sources
PubMed1992

Clinical pharmacokinetics of metronidazole and other nitroimidazole anti-infectives.

Metronidazole was first introduced for the treatment of trichomoniasis. Its therapeutic use has subsequently been expanded to include amoebiasis, giardiasis and, more recently, anaerobic infections. Most of the early pharmacokinetic studies employed nonspecific assays such as microbiological and chemical assays. These assays were not able to differentiate the parent drug from the metabolites or other interfering substances. Pharmacokinetic data obtained through the use of specific chromatographic techniques provide the basis for this review of recent pharmacokinetic findings concerning metronidazole and other nitroimidazole antibiotics. When given intravenously or orally at usual recommended doses, metronidazole attains concentrations well above the minimum inhibitory concentrations for most susceptible micro-organisms. The drug has an oral bioavailability approaching 100%. Rectal and vaginal administration results in a smaller amount of drug absorption and lower serum concentrations. Metronidazole has limited plasma protein binding but can attain very favourable tissue distribution, including into the central nervous system. The drug is extensively metabolised by the liver to form 2 primary oxidative metabolites: the hydroxy and acetic acid metabolites. The kidney is responsible for the elimination of only a small amount of the parent drug; however, normal excretion of the 2 metabolites is dependent on the integrity of kidney function. The metabolism of metronidazole was found to vary among patient groups. Preterm and term infants have lower total body clearance (CL) and prolonged elimination half-lives. However, children older than 4 years old were observed to have pharmacokinetic parameters similar to those in adults. Reduced CL was also observed in children who are malnourished. Elderly patients have reduced renal excretion of both the parent drug and hydroxy metabolite. Pharmacokinetic parameters in pregnant patients were not significantly different from those in nonpregnant women; however, the drug is distributed into breastmilk and the infant will be exposed to the drug through the nursing mother. Patients undergoing gastrointestinal surgery or having enteric diseases and those who are hospitalised or critically ill also have altered pharmacokinetics. Metabolism of the drug is reduced in patients with liver dysfunction, giving delayed production of metabolites. In contrast, renal failure has little effect on the elimination of the parent drug, but affects the excretion of the metabolites more significantly. Haemodialysis was found to remove a substantial amount of the metronidazole while the effect of peritoneal dialysis was more limited. Energy and protein deficient diets as well as occupational exposure to gasoline did not alter metronidazole pharmacokinetics. However, the effect of alcohol consumption on metronidazole CL requires further study.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1991

Mycotic (Aspergillus) arteritis resulting in fatal subarachnoid hemorrhage: a case report.

A seventy-one year-old Japanese man suffering from carcinoma of the common bile duct died from subarachnoid hemorrhage secondary in intracranial mycotic arteritis (MA). Repeated cultures of the discharge from the draining tubes, the tip of intravenous hyperalimentation catheters, blood, sputum, and urine failed to grow any fungus. Autopsy disclosed MA due to Aspergillus at the terminal portion of the right internal carotid artery close to the posterior communicating artery.

Aged↗
PubMed1991

Pharmacokinetics of intravenous metronidazole at different dosages in healthy subjects.

Metronidazole is effective in the treatment of trichomoniasis and serious anaerobic infections. Individual doses given clinically ranged from 250 mg to 2.0 gm. Most of the available pharmacokinetic data were obtained when the drug was administered at the low end of the dosage range. Several other studies were done using assays that were subject to interference by metabolites. We therefore conducted this investigation to evaluate the pharmacokinetics of metronidazole at different dosage levels in normal subjects in a crossover manner using a specific HPLC assay. Nine male normal volunteers were each administered 250 mg, 1.0 gm and 2.0 gm of intravenous metronidazole in a crossover manner. Serial blood samples were obtained immediately before and at 0, 15, 30, 60, 90 minutes, 2, 4, 6, 10, 24 and 32 hours after the dose. Serum concentrations of metronidazole and its metabolites were determined by HPLC. The half-lives, elimination rate constants, volumes of distribution and areas under the concentration-time curve were calculated. Analysis of variance revealed a statistically significant difference between the low dose (250 mg) and the high dose (1.0 gm and 2.0 gm) effect on the calculated pharmacokinetic parameters. In addition, the production and the elimination of the metronidazole hydroxy metabolite were also found to be reduced when higher doses of the drug were administered. These findings revealed that the pharmacokinetics of metronidazole and its hydroxy metabolite are altered when higher doses of the drug are given; the metabolic transformation of the parent drug is also expected to be reduced.

Adult↗
PubMed1989

Removal of cephalosporins by continuous arteriovenous ultrafiltration (CAVU) and hemofiltration (CAVH).

Cephalosporins are used with increasing frequency for sepsis treatment in patients receiving CAVU and CAVH. The different cephalosporins share the same basic molecular structure, yet they exhibit varied extent of plasma protein binding. Different amounts of the antibiotics may be removed by the ultrafiltration procedure because of these variations of physicochemical properties. We evaluated the sieving of eight new cephalosporins across the hemofilter membrane using an in vitro model. Bovine blood was perfused through polysulfone membranes at blood and ultrafiltrate flow rates of 100 and 20 ml/min respectively. Arterial plasma, venous plasma and ultrafiltrate drug concentrations were used to determine sieving coefficients. The sieving coefficients correlated well with the ultrafiltrate-arterial plasma drug concentration ratio (r = 0.679-0.972) but poorly with the extent of protein binding. Factors other than protein binding may therefore affect the drug sieving. Based on the findings, it was predicted that 0.2-21.9% of the daily cephalosporin dose may be removed by the CAVU and CAVH treatment. The need to alter drug dosages depends on the techniques of the ultrafiltration and hemofiltration procedure, the kinetics of the cephalosporins in patients, the sensitivity of the pathogen and the nature of the infection.

Animals↗
PubMed1988

Transient encephalopathy related to rapidly and markedly elevated blood pressure in acute stage of hypertensive cerebral hemorrhage--relationship to hypertensive encephalopathy--a case report.

A seventy-two-year-old man with hypertensive cerebral hemorrhage acutely developed severe headache, nausea, vomiting, agitation, and disorientation with abrupt rise in blood pressure on the sixth day after the onset. At that time, there were no remarkable changes in focal neurologic deficits, and repeated brain CT scans revealed a small hematoma located in the right basal ganglia without further enlargement or herniation. Blood chemistry and arterial gas analysis were within the normal ranges except for a slight rise in blood urea nitrogen. Similar episodes occurred three times within two days, and each time the cerebral symptoms disappeared in accordance with lowering of blood pressure by antihypertensive therapy. Complication of hypertensive encephalopathy was strongly suggested. The authors discuss the pathophysiology of this encephalopathy in relation to cerebral hemorrhage.

Aged↗
PubMed1987

Pharmacokinetics of metronidazole in patients with alcoholic liver disease.

The pharmacokinetics of metronidazole was evaluated in eight patients with alcoholic liver disease. Metronidazole (7.5 mg/kg) was administered to each patient intravenously. Serial blood samples were obtained after the dose. Serum metronidazole concentrations were determined by high-performance liquid chromatography. The following pharmacokinetic parameters (mean +/- standard deviations) were obtained: half-life, 18.31 +/- 6.06 h; elimination rate constant, 0.042 +/- 0.013 h-1; volume of distribution, 0.77 +/- 0.16 liters/kg; and total body clearance, 0.51 +/- 0.11 ml/min per kg. Compared with subjects with normal liver function, patients with liver disease showed a reduction in drug elimination rate and total body clearance. The half-life of metronizadole in serum and volume of distribution were increased. Large variations of these parameters were also observed among the patients. On the basis of these observations, a reduced dose of metronidazole should be given to patients with alcoholic liver disease to avoid accumulation of metronidazole and its metabolites. Monitoring of drug concentration in serum may also be necessary to optimize therapy.

Adult↗
PubMed1986

Evaluation of a potential drug interaction between sucralfate and aspirin.

Recent studies have demonstrated a cytoprotective effect of sucralfate on gastric mucosa in patients receiving aspirin. The potential drug interaction between sucralfate and aspirin was evaluated in a randomized crossover manner in 12 healthy men. Subjects were initially given a single dose of aspirin alone or in combination with sucralfate for 2 days. The drug dosing schedule was then reversed after 1 week. Sixteen blood samples were drawn after each aspirin dose for HPLC assay of aspirin and its metabolites. Pharmacokinetic parameters were calculated for aspirin, salicylic acid, and salicyluric acid. None of these parameters demonstrated any statistically significant differences between the two treatment groups. The combined use of sucralfate and aspirin is therefore not likely to result in a clinically significant pharmacokinetic drug interaction. The systemic therapeutic effect of aspirin is not expected to be altered when sucralfate is used concurrently in patients receiving chronic aspirin therapy.

Adsorption↗
PubMed1986

Hemodialysis clearance of metronidazole and its metabolites.

Metronidazole is now being used with increasing frequency for various infectious conditions in patients with renal failure. It is commonly administered to septic patients who have developed acute renal failure requiring hemodialysis. The hemodialysis clearances of metronidazole and its metabolites were evaluated in nine renal failure patients on maintenance hemodialysis. The mean +/- standard deviation clearance and the extraction ratio were 106.9 +/- 16.3 ml/min and 0.65 +/- 0.08, respectively, when regenerated cellulose dialysis membrane was used. The clearance and the extraction ratio with the use of cuprophan membrane were 72.1 +/- 17.3 ml/min and 0.44 +/- 0.12, respectively. The clearances and extraction ratios for the metabolites were similar to those of the parent drug. For both metronidazole and the hydroxy metabolite, the clearance and the extraction ratio demonstrated a statistically significant difference between the regenerated cellulose membrane and the cuprophan membrane. In summary, metronidazole and its metabolites were found to be highly dialyzable with different clearances depending on the specific type of membrane used. However, owing to the relatively wide therapeutic index of the drug, dosage supplementation may be necessary only in seriously ill patients to ensure therapeutic effect.

Acute Kidney Injury↗
PubMed1986

Rapid estimation of total body clearance of theophylline in patients receiving intravenous aminophylline infusion.

The method of Chiou to rapidly estimate theophylline total body clearance using two serum concentration data during the early stage of intravenous aminophylline infusion was evaluated in 16 patients with acute exacerbation of asthma or chronic obstructive pulmonary disease. The observed serum concentrations at later times were compared with those predicted. The mean prediction error for serum concentrations was 4.93% with a standard deviation of 20.06%. These results indicate that this simple method of Chiou may offer a reliable rapid estimation of total body clearance for dosage individualization in patients receiving intravenous aminophylline infusion.

Adult↗
PubMed1985

Effect of ultrafiltration on peritoneal dialysis drug clearances.

To determine the effect of dialysate osmolarity on peritoneal dialysis drug transfer, peritoneal dialysis clearances of theophylline, phenobarbital, and tobramycin were determined in 10 rabbits using dialysate containing 1.5 and 4.25% glucose. Urea and creatinine clearances were also obtained for comparison. Under similar dialysis conditions, the peritoneal clearances of the three drugs remained unchanged for the two types of dialysate. In contrast, the peritoneal clearances of urea and creatinine were significantly higher with the use of 4.25% glucose dialysate (p less than 0.001). Thus, peritoneal dialysis clearances of theophylline, phenobarbital and tobramycin are not significantly affected by hypertonicity-induced ultrafiltration during acute peritoneal dialysis.

Animals↗
PubMed1985

Effect of peritoneal dialysis on serum concentrations of three drugs commonly used in pediatric patients.

The use of peritoneal dialysis in young infants bears the theoretical advantage that the relative size of their peritoneal surface area is twice that of adults. The movement of drugs across the peritoneum is affected by the physiochemical properties of the drug molecules and the pathophysiologic condition of the patient. It is observed that the peritoneal dialysis clearances of phenobarbital, amikacin and cefazolin in infants were 1.07-1.33, 0.54-0.86 and 0.40-1.02 ml/min, respectively. The dosage determination in the dialysis patients receiving these drugs is discussed.

Amikacin↗
PubMed1984

Comparison of a fluorescent immunoassay with an enzyme immunoassay and a radioimmunoassay for gentamicin.

A fluorescent immunoassay (FIA) for gentamicin was evaluated and compared with an enzyme multiplied immunoassay (EMIT) and a radioimmunoassay (RIA) for gentamicin. Pooled human serum that contained low, medium, and high concentrations of gentamicin sulfate (approximately 2.5, 5, and 10 micrograms/ml of gentamicin) were analyzed for actual gentamicin concentration by FIA. Samples were assayed 10 times during the same day to evaluate within-run precision and on 10 different days to evaluate between-run precision. Serum samples obtained from patients receiving gentamicin therapy were analyzed for gentamicin concentration using FIA and EMIT, and separate serum samples were analyzed using FIA and RIA. Results were compared by regression analysis. Within-run coefficients of variation were 8.47%, 6.84%, and 2.62%, respectively, for the low, medium, and high concentrations of gentamicin, and the respective between-run coefficients of variation were 10.81%, 6.31%, and 1.64%. The correlation coefficient for the comparison of FIA with EMIT was 0.943, and the correlation coefficient for the comparison of FIA with RIA was 0.970. The fluorescent immunoassay is a reliable method for determining the concentration of gentamicin in serum. Although the results obtained by FIA correlate well with those obtained by EMIT and RIA, variability exists between concentrations determined by each of these methods.

Evaluation Studies as Topic↗
PubMed1979

Chloramphenicol pharmacokinetics in hospitalized patients.

The apparent body clearance of chloramphenicol was investigated in 21 hospitalized adult patients on 27 occasions. Apparent body clearance was found to be significantly lower (1.99 +/- 1.49 ml/min per kg) in patients with total serum bilirubin concentrations of >1.5 mg/100 ml than in patients with serum bilirubin concentrations of </=1.5 mg/100 ml (3.57 +/- 1.72 ml/min per kg; P < 0.001). Serum protein binding of chloramphenicol was lower in cirrhotic patients (42.2 +/- 6.8% bound) than in normal adults (53.1 +/- 5.2% bound; P < 0.001). Low binding of chloramphenicol was also found in the serum of premature neonates (32.4 +/- 8.2% bound; P < 0.001). Reduced binding in neonates implies the need for a lower therapeutic range of total chloramphenicol concentration (3.5 to 13.9 mug/ml) compared with the usual adult range (5 to 20 mug/ml). Finally, three case reports are presented which demonstrate marked abnormalities and intrasubject variation in chloramphenicol clearance.

Adolescent↗
PubMed1979

Relationship between serum and saliva chloramphenicol concentrations.

The relationship between serum and saliva chloramphenicol (CAP) concentrations was evaluated in 27 paired specimens collected from 20 hospitalized patients during therapy with the drug. A significant (R = 0.80, P < 0.001) but variable relationship was found to exist. Serum protein binding of CAP was also evaluated (43.7 +/- 5.7% bound; N = 24). Differences in CAP binding did not apparently account for a significant portion of the variability in the observed saliva/serum CAP concentration ratios. The degree of variation observed indicated that saliva CAP concentrations could not be relied upon for the prediction of serum CAP concentrations.

Adult↗
PubMedDate not supplied

Vascular access thrombosis during recombinant human erythropoietin therapy.

The increased incidence of vascular access thrombosis (VAT) associated with recombinant human erythropoietin (r-HuEPO) therapy is multifactorial and controversial. Sixty-three hemodialysis patients who received > or = 12 weeks of r-HuEPO therapy were prospectively followed for the incidence of VAT. Those who experienced VAT (Group 1) were compared with those who did not (Group 2). The patients initially received r-HuEPO 50 U/kg intravenously three times a week. The dose was adjusted for a target hematocrit (t-Hct) of 30-33%. Twenty-five of the 63 patients (40%) experienced VAT (Group 1). These patients were older (mean, 54.0 +/- 14.0 years versus 47.3 +/- 15.0 years, p = 0.08). There was no difference between Groups 1 and 2 with respect to the baseline Hct level (21.5 +/- 2.9% versus 21.4 +/- 4.3%), the number of patients who achieved t-Hct (20 versus 28), and the mean time to reach t-Hct (18.6 +/- 15.1 weeks versus 16.9 +/- 16.2 weeks). However, 20 of 25 Group 1 patients (80%) were diabetic compared with only 18 of 38 Group 2 patients (47%, p = 0.0169, by Fisher's exact test). In addition, the types of vascular access differed markedly between the two groups: arteriovenous (AV) grafts/AV fistulae/Permcaths, Group 1: 21/3/1 versus Group 2: 15/21/2, p = 0.0018. It was concluded that the occurrence of VAT in r-HuEPO treated patients was not related to the patient's hematologic response to the drug, but rather, it depended upon the integrity of the patient's vasculature and the type of vascular access used.

Adult↗