Measurement of serum lamotrigine by high performance liquid chromatography using a phenyltriazine as internal standard.

Lamotrigine, an anti-epileptic drug with a phenyltriazine molecular structure, is commonly measured for therapeutic drug monitoring purposes by high performance liquid chromatography (HPLC) or gas liquid chromatography (GLC). A convenient internal standard is the structurally related phenyltriazine compound BWA725C previously obtainable from the Wellcome Foundation, UK. Irsogladine is also structurally similar to lamotrigine and was therefore tested as a possible replacement for BWA725C. A GLC procedure with thermionic detection (NPD) has been utilized routinely for lamotrigine in our drug monitoring facility. Irsogladine was unsuitable, however, because the retention times of irsogladine and a co-prescribed drug, carbamazepine, were very similar. An HPLC method utilizing a Prodigy Phenomenex ODS3 column performed well using either of the internal standards. The pH of the mobile phase had a distinct impact on the spectra of lamotrigine and BWA725C. A mobile phase at pH 3, with detection at 225 nm was required to effectively resolve lamotrigine from sulthiame and irsogladine from phenobarbitone. Comparison of the HPLC and the existing GLC method with routine patient specimens (n = 43) gave an equation, y = 0.9382x + 0.8238, R(2) = 0.9862. Irsogladine was found to be a suitable internal standard for an HPLC analysis of lamotrigine.

Acetaminophen analgesia in children: placebo effect and pain resolution after tonsillectomy.

BACKGROUND: Pharmacodynamic models of acetaminophen analgesia in children have not explored the efficacy of single oral doses greater than 40 mg/kg. METHODS: Children aged 9.0 +/- 3.0 years (+/- SD) and weight 37.9+/- 16.6 kg undergoing outpatient tonsillectomy were randomised to receive acetaminophen elixir 40 mg/kg (n = 12). high dose acetaminophen elixir 100 mg/kg (n =20) or placebo (n=30) 0.5 -1 h preoperatively. No other analgesics were given. Individual acetaminophen serum concentrations and pain scores [visual analogue scale (VAS) 0-10] were measured over a 4-8 h postoperative period. These data were pooled with data from a previous study investigating acetaminophen pharmacodynamics (n = 120) and analysed using a non-linear mixed effect model. Placebo effects and drug effects were modelled using effect-site concentration models. RESULTS: A one-compartment model with first-order input, lag time and first-order elimination was used to describe the population pharmacokinetics of acetaminophen. Pharmacokinetic parameter estimates were similar to those previously described. Pharmacodynamic population parameter estimates [population variability coefficient of variation (CV)] for a maximum analgesic effect (Emax) model, in which the greatest possible pain relief (VAS 0-10) equates to an Emax of 10, were Emax 5.17 (64%) and 50% effective concentration 9.98 mg/l (107%). The equilibration half-life (t(eq)) of the analgesic effect compartment was 53 min (217%). A placebo drug model for the effects of placebo response had a t(eq) of 1.96 h (40%), an elimination half-life of 2.06 h (50%) and a potency of 1.54 pain relief units (24%). CONCLUSIONS: High dose acetaminophen (100 mg/kg) was no more effective than 40 mg/kg and was associated with increased nausea and vomiting. A target effect compartment concentration of 10 mg/l is expected to produce a pain reduction of 2.6 units. The placebo model accounted for a maximum pain reduction of 5.6 units at 3 h. The combination of placebo effect and preoperative acetaminophen 40 mg/kg results in pain scores below 4 units for 5 h postoperatively.

A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children.

AIMS: The aims of this study were to describe paracetamol pharmacokinetics in neonates and infants. METHODS: Infants in their first 3 months of life (n = 30) were randomised to sequentially receive one of three paracetamol formulations (dose 30-40 mg kg-1) over a 2 day period. The formulations were (a) elixir, (b) glycogelatin capsule suppository and (c) triglyceride base suppository. Approximately six blood samples were taken after each dose over the subsequent 10-16 h. Data were analysed using a nonlinear mixed effect model. These neonatal and infant data were then included with data from four published studies of paracetamol pharmacokinetics (n = 221) and age-related pharmacokinetic changes investigated. RESULTS: Population pharmacokinetic parameter estimates and their coefficients of variation (CV%) for a one compartment model with first order input, lag time and first order elimination were volume of distribution 69.9 (18%) l and clearance 13.0 (41%) l h-1 (standardized to a 70 kg person). The volume of distribution decreased exponentially with a half-life of 1.9 days from 120 l 70 kg-1 at birth to 69.9 l 70 kg-1 by 14 days. Clearance increased from birth (4.9 l h-1 70 kg-1) with a half-life of 3.25 months to reach 12.4 l h-1 70 kg-1 by 12 months. The absorption half-life (tabs) for the oral preparation was 0.13 (154%) h with a lag time (tlag) of 0.39 h (31%). Absorption parameters for the triglyceride base and capsule suppositories were tabs 1.34 (90%) h, tlag 0.14 h (31%) and tabs 0.65 (63%) h, tlag 0.54 h (31%), respectively. The tabs for elixir and capsule suppository in children under 3 months were 3.68 and 1.51 times greater than children over 3 months. The relative bioavailability of rectal formulations compared with elixir were 0.67 (30%) and 0.61 (23%) for the triglyceride base and capsule suppositories, respectively. CONCLUSIONS: Total body clearance of paracetamol at birth is 62% and volume of distribution 174% that of older children. A target concentration above 10 mg l-1 in approximately 50% subjects can be achieved by a dose from 45 mg kg-1 day-1 at birth and up to 90 mg kg-1 day-1 in 5-year-old children. A reduced dose of 75 mg kg-1 day-1 in an 8-year-old child is sufficient because clearance is a nonlinear function of weight.

Gastric juice ascorbic acid is related to Helicobacter pylori infection but not ethnicity.

BACKGROUND: Maori and Pacific Island ethnic groups in New Zealand have a high risk for gastric cancer. Low levels of gastric juice ascorbic acid (vitamin C) have been suggested to be a risk factor for gastric cancer. Previous studies have shown that gastric juice ascorbic acid may be independently associated with both ethnicity and Helicobacter pylori infection. This study aimed to examine the interrelationship between H. pylori and ethnicity in New Zealand. METHODS: Gastric juice was collected into 70% perchloric acid preservative and stored at -80 degrees C. Ascorbic acid was analysed by high-performance liquid chromatography using ion-pair chromatography and electrochemical detection. Inflammation and atrophy was graded from biopsies from multiple sites in the antrum and body. Gastric juice was collected from 89 patients during routine endoscopy. RESULTS: There was a wide range of measured gastric juice ascorbic acid from 0.001 to 410 microg/mL. The median concentration of ascorbic acid for H. pylori-negative patients was 1.78 microg/mL (n = 57) and 0.12 microg/mL (n = 32) for H. pylori-positive patients (P = 0.001). Gastric juice ascorbic acid concentration was not associated with age, endoscopic diagnosis or intestinal metaplasia, but was significantly associated with the degree of acute inflammation (P = 0.01) and the presence of atrophy (P = 0.04). The median ascorbic acid concentration for European patients was 0.92 microg/mL (n = 44) and 0.09 microg/mL (n = 38) for Maori and Pacific Island ethnic groups combined (P = 0.1). Multiple step-wise regression analysis showed that only H. pylori infection was a significant factor for predicting ascorbic acid concentrations (r2 = 0.12). CONCLUSIONS: This study has confirmed that gastric juice ascorbic acid concentration is lower in the presence of H. pylori infection.

Effects of reduced-fat diets consumed ad libitum on intake of nutrients, particularly antioxidant vitamins.

OBJECTIVES: To determine whether a reduced-fat diet consumed ad libitum can achieve the recommended intakes of other macronutrients, fiber, and cholesterol and whether such a diet affects intake of other important micronutrients such as fat-soluble vitamins. DESIGN: Twelve-month, randomized, controlled trial of a reduced-fat, ad libitum diet vs usual diet. SUBJECTS: One hundred ten adults older than 40 years with glucose intolerance (2-hour blood glucose concentration = 7.0 to 11.0 mmol/L) who were selected from a previous workforce survey. INTERVENTION: Monthly small-group meetings aimed at identifying sources of dietary fat and ways to reduce fat consumption. MAIN OUTCOME MEASURES: Nutrient intakes derived from 3-day food diaries at the beginning and end of the study. Blood levels of retinol, alpha-tocopherol, and beta carotene at the end of the study. STATISTICAL ANALYSES PERFORMED: Unpaired t tests for determining changes in nutrient intake and antioxidant vitamin concentrations. Separate analyses were conducted with users of mineral and vitamin supplements and people who changed smoking status to reduce potential confounding. RESULTS: Fat intake decreased from 35% to 26% of energy in the reduced-fat diet group compared with a 2% decrease in the control group (P < .0001). Total energy intake also decreased in the 2 groups (-362 vs -59 kcal/day, P < .02). Those changes were reflected in a 3.1 +/- 4.7 kg (mean +/- standard deviation) weight loss in the intervention group compared with a 0.4 +/- 3.0 kg weight gain in the control group (P < .0001). There were no differences between groups in the changes in micronutrient intakes, except for an energy-adjusted increase in beta carotene intake in the reduced-fat diet group. Serum retinol and alpha-tocopherol concentrations were not different between the groups, but the reduced-fat diet group had higher beta carotene concentrations (P = .009). APPLICATIONS: A reduced-fat, ad libitum diet can be prescribed to improve overall macronutrient intake and achieve modest weight loss without sacrificing micronutrient intakes.

Perioperative pharmacodynamics of acetaminophen analgesia in children.

BACKGROUND: There are no adequate pharmacodynamic data relating concentrations of acetaminophen in serum to analgesia. METHODS: Children undergoing outpatient tonsillectomy were administered acetaminophen either orally, 0.5-1.0 h preoperatively (n = 20), or per rectum at induction of anesthesia (n = 100). No other analgesic agents were administered. Individual concentrations of acetaminophen in serum and pain scores (0-10) measured over a 4-h postoperative period were analyzed using a nonlinear mixed-effects model (NONMEM). RESULTS: Mean (% CV) estimates of population pharmacokinetic parameters with percent coefficient of variation, standardized to a 70-kg person, for a one-compartment model with first-order input, lag time, and first order-elimination were a volume of distribution of 60 (21) 1 and a clearance of 13.5 (46) 1/h. Rectally administered acetaminophen had an absorption half-life of 35 (63) min with a lag time of 40 min. The absorption half-life for the oral preparation was 4.5 (63) min without a detectable lag time. The relative bioavailability of the rectal compared with the oral formulation was 0.54. The equilibration half-time of an effect compartment was 1.6 (131) h. Pharmacodynamic population parameter estimates (percent coefficient of variation) for a fractional sigmoidal Emax model, in which the greatest possible pain relief equates to an Emax of 1, were Emax = 1, EC50 (the concentration producing 50% of Emax) = 3.4 (94) mg/l, and Hill coefficient = 0.54 (42). CONCLUSIONS: The pharmacodynamics of acetaminophen can be described using a sigmoidal Emax model with a low Hill coefficient. To achieve a mean posttonsillectomy pain score of 3.6 of 10, an effect compartment concentration of 10 mg/l is necessary.

Pharmacokinetics of paracetamol in adults after cardiac surgery.

The pharmacokinetics of paracetamol in adults after cardiac surgery have not been described. Twenty patients were randomized to receive either paracetamol 2 g through a nasogastric tube and as a suppository eight hours later or vice versa. Arterial blood samples were taken at 0.5, one, two, four, six and eight hours after dosing. Each patient was studied for 16 h. There were 16 males and three females. One patient was excluded because of sampling errors. The mean age was 59 (SD 8) years and the mean weight 84 kg (16). The time-concentration profiles for each individual were used to estimate pharmacokinetic parameters using a non-linear mixed effects model (NONMEM). Population parameter estimates with coefficient of variation (CV%), standardized to a 70 kg person, for a one-compartment model with first order input, lag time and first order elimination were volume of distribution 127l (28) and clearance 26.4 l/h (29) Rectal paracetamol had an absorption half-life (Tabs) of 2.02 h (31) with a lag time of 0.28 h. The absorption half-life for the oral preparation was 1.49 h (81) with a lag time of 0.17 h. The relative bioavailability of the rectal compared to the oral formulation was 0.98 (18). Concentrations after either nasogastric or rectal paracetamol 2 g were below a target concentration of 10 mg/l, which is associated with analgesia. Absorption after nasogastric administration was slow compared to healthy adults (Tabs 0.06 to 0.7 h) and the bioavailability was half that expected, due to nasogastric loss. Parameter estimates had large variability. Paracetamol is unlikely to have useful clinical impact in the majority of patients when standard doses (6 g/day) are given on day 1 after cardiac surgery.

Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children.

AIMS: Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1-2 h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children. METHODS: Concentration-time profiles in plasma and CSF after nasogastric paracetamol 40 mg kg(-1) were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two-stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70 kg person using an allometric power model. RESULTS: Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.21 h(-1) (CV 47%), volume of distribution 67.11 (CV 58%) and absorption rate constant 0.77 h(-1) (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72 h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%). CONCLUSIONS: Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1-2 h before anticipated pain or fever in children.

Evaluation of multifrequency bioimpedance spectroscopy for measurement of the extracellular water space in critically ill patients.

The purpose of this study was to compare multifrequency bioimpedance spectroscopy (BIS) estimates of extracellular water volume (ECW) in critically ill patients with measurements by bromide dilution. Stable bromide dilution and BIS were performed in 37 critically ill patients as soon as haemodynamic stability was achieved (day 0) and again 10 days later. While BIS underestimated the dilution results on each day of measurement, the 10-day changes in ECW agreed closely for the two methods (4.42 +/- 4.25 (s.d.) vs 4.43 +/- 4.84 1).

Aspects of theophylline clearance in children.

Michaelis-Menten pharmacokinetic parameters for theophylline were estimated in a three-month infant following an accidental overdose of intravenous aminophylline. Fitting of time-concentration data was performed using nonlinear regression with MKMODEL. A mixed order elimination model was superior to a first order model. Parameter estimates were standardized to a 70 kg human using an allometric power model. Parameter estimates (SE) were: maximum rate of metabolism (Vmax) 71 (42) mg.h-1, Michaelis-Menten constant (Km) 32.3 (33.5) mg.l-1, volume of distribution (Vd) 46.9 (2.6)l. This Michaelis-Menten constant is lower than that reported for adults and consequently non-linear elimination will occur at lower plasma concentrations in infants than in adults. Theophylline clearance has traditionally been reported as directly proportional to body weight. This per kilogram model gives an erroneous impression that clearance is greatest in early childhood and then decreases with age until adult rates are reached in late adolescence. Age-related clearance values reported in the literature were reviewed using an allometric 3/4 power model. This size model demonstrates that clearance increases in infancy and reaches adult rates in the first one to two years of life.

Urinary catecholamines and the diagnosis of phaeochromocytoma in Auckland.

AIM: To review the experience in Auckland with the use of urinary catecholamine measurements in the diagnosis of phaeochromocytoma. METHODS: Review of the test results of patients with proven phaeochromocytoma and retrospective analysis of the outcome of patients with increased 24-hour urinary excretion of the catecholamines noradrenaline, adrenaline and dopamine. RESULTS: Over six years the majority (16/18) of patients with proven phaeochromocytoma had raised urinary noradrenaline excretion either alone (3/16) or with raised adrenaline and/or dopamine (13/16). One phaeochromocytoma secreted adrenaline alone, none secreted dopamine alone and one had urinary catecholamine levels that were normal. Urinary adrenaline excretion was unexpectedly elevated in two patients with extra-adrenal phaeochromocytomas. Approximately 10% of 2590 24 hour urine specimens analysed over a 14 month period had an elevation of one or more catecholamine. Forty-six patients had urinary catecholamine excretion greater than twice the upper limit of normal. This group contained five of the six phaeochromocytomas diagnosed during this period. The other patients were normal (35/46, 76%) or were lost to follow up (6/46, 13%). CONCLUSIONS: In this series most patients with phaeochromocytoma (89%) had increases in the 24-hour urinary excretion of one or more than one catecholamine which exceeded twice the upper limit of normal for our laboratory with noradrenaline being most commonly affected. Increased catecholamine excretion was often seen in patients without phaeochromocytoma.

Microwave warming of 1.5% glycine solution.

The urological irrigating fluid 1.5% glycine is routinely warmed in specifically designed warming drawers prior to use. This study shows that the use of microwave energy to achieve body temperature in 2-litre bags of glycine solution is biochemically safe and that the sterility of the solution is maintained. There is a linear relationship between the temperature of the solution and time in the microwave oven, so allowing a simple formula to predict the correct heating time given variable ambient starting temperatures.

Therapeutic drug monitoring of flecainide using high-performance liquid chromatography and comparison with fluorescence polarisation immunoassay.

The therapeutic monitoring of flecainide, like the other antiarrhythmic agents, has become an integral part of the administration of this type of drug. A full description is given here of a high-performance liquid chromatographic method which has been developed and used over the past three years for the routine monitoring of flecainide. This method uses extraction into toluene using the non-fluorinated analogue of flecainide as an internal standard and then direct back-extraction into a small volume of aqueous acid without the need for solvent evaporation. A fluorescence detection instrument is chosen which avoids the use of high-cost fluorometers. Ample sensitivity is accomplished with a simple fluorometer by selecting a combination of Schott bandpass filters with high-transmittance characteristics at appropriate wavelengths. A comparison is made between this method and the newly introduced fluorescence polarisation immunoassay. The comparison shows a good agreement between the independent technologies.