Jacobus Burggraaf

Continuous intravenous furosemide in haemodynamically unstable children after cardiac surgery

Objective: The commonly used continuous intravenous (IV) furosemide dosing schedule after cardiac surgery in children is largely empirical and may not be optimal. This may even be more marked in children after cardiac surgery who are haemodynamically unstable, and in whom transient renal insufficiency may occur. A study was performed to obtain an impression regarding which clinically applicable measures may be used to design a rational scheme for continuous IV furosemide therapy in children after cardiac surgery. Subjects and methods: Twelve paediatric patients (5F/7xa0M, age 0–33xa0weeks) post-cardiac surgery, who were to receive 3xa0days of continuous IV furosemide treatment, were included in an open study. Blood and urine samples were taken for furosemide, creatinine, and electrolyte levels, and fractionated urinary output was measured. Furosemide in blood and urine was measured using high performance liquid chromatography (HPLC). Results: The mean starting dose of continuous IV furosemide was 0.093 (±0.016) mg/kg per hour. The mean dose was increased to 0.175 (±0.045) mg/kg per hour per hour on day 2, and changed to 0.150 (±0.052) mg/kg per hour on day 3. Infusion rates were increased from day 1 to day 2 in ten cases, and decreased from day 2 to day 3 in three cases. Serum furosemide levels never exceeded ototoxic levels. The urinary furosemide excretion rate was inversely related to serum creatinine levels. Conclusions: This study extends the observation of the beneficial effects of continuous IV furosemide also to those children who are haemodynamically unstable after cardiac surgery. However, as the effects of furosemide are dependent on renal function, it can be hypothesised that the dosing schedule may be optimised. Contrary to the currently used dosage schedule in which the dose of furosemide is gradually increased over time, it may be more rational to start with a higher dose and adapt this dose (downward) guided by the observed effect (urine output). Because the infusion rate was increased to 0.2xa0mg/kg per hour in nine out of 12 patients on day 2 and was never increased further, this suggests that a starting rate of 0.2xa0mg/kg per hour may be optimal.

Influence of obesity and body fat distribution on growth hormone kinetics in humans

We studied the kinetics of exogenous recombinant 22-kDa human growth hormone (rhGH) in premenopausal women with upper body obesity (UBO), lower body obesity (LBO), or normal body weight. A bolus of 100 mU rhGH was administered during a continuous infusion of somatostatin to suppress endogenous GH secretion. GH kinetics were investigated with noncompartmental analysis of plasma GH curves. GH peak values in response to GH infusion and plasma half-life of GH were not significantly different between normal weight and obese subjects. In contrast, GH clearance was 33% higher in LBO women and 51% higher in UBO women compared with clearance in normal weight controls. The difference in clearance between LBO and UBO was not statistically significant. Altered GH clearance characteristics contribute to low circulating GH levels in obese humans. Body fat distribution does not appear to affect GH kinetics.We studied the kinetics of exogenous recombinant 22-kDa human growth hormone (rhGH) in premenopausal women with upper body obesity (UBO), lower body obesity (LBO), or normal body weight. A bolus of 100 mU rhGH was administered during a continuous infusion of somatostatin to suppress endogenous GH secretion. GH kinetics were investigated with noncompartmental analysis of plasma GH curves. GH peak values in response to GH infusion and plasma half-life of GH were not significantly different between normal weight and obese subjects. In contrast, GH clearance was 33% higher in LBO women and 51% higher in UBO women compared with clearance in normal weight controls. The difference in clearance between LBO and UBO was not statistically significant. Altered GH clearance characteristics contribute to low circulating GH levels in obese humans. Body fat distribution does not appear to affect GH kinetics.

Ciclosporin kinetics in children after stem cell transplantation

AIMSnTo develop a limited sampling strategy to determine ciclosporin systemic exposure [area-under-the-curve(AUC)]. This is meant to be the first step in a future study of the relationship between AUC and the biological effects of ciclosporin.nnnMETHODSnThe pharmacokinetics of ciclosporin was investigated prospectively following stem cell transplantation (SCT) in 17 children, aged 1.8-16.1 years. Ciclosporin was given twice daily, intravenously over a short infusion of 2 h duration during the early post-SCT period, or orally later on, when oral medication was well tolerated. Parameter estimation was performed using nonlinear mixed effect modelling as implemented in the NONMEM program. Individual empirical Bayes estimates of clearance and distribution volume were correlated with the demographic variables.nnnRESULTSnPharmacokinetics was described adequately with a two-compartment model with lag time (population estimates: CL = 11.3 l h(-1); V(c) = 16.5 l; V(p) = 59.9 l; t(1/2) absorption = 0.78 h, t(lag) = 0.6 h). The AUCs, determined for the combination of trough level with one time point between 2 and 3 h after dosing, correlated very well with the reference AUC (r(2) = 0.97). No correlation was found between clearance and distribution volume, and the demographic patient variables length, body weight, age and glomerular filtration rate.nnnCONCLUSIONnA two-point limited sampling strategy, in combination with a Bayesian fitting procedure using the pharmacokinetic population model described, can adequately determine the AUC of ciclosporin. Since no correlation between clearance and body weight was found, dosing ciclosporin per kg bodyweight is not supported by the results of this study. We suggest starting with a fixed dose, followed by AUC determination and dose adjustment.

Development of an optimal furosemide infusion strategy in infants with modeling and simulation

The optimal dosing strategy for continuous intravenous furosemide infusion is unknown in pediatric patients. Eighteen patients less than 1 year old were studied after cardiac surgery during routine clinical care. The current strategy starts with a continuous infusion of 0.1 mg/kg · h, which may be adapted.

The sugar absorption test in the evaluation of the gastrointestinal intolerance to bisphosphonates : Studies with oral pamidronate

Some bisphosphonates induce gastrointestinal side effects, but the localization in the gastrointestinal tract and the underlying mechanism are unknown. The feasibility of the sugar absorption test was investigated to assess the gastrointestinal effects of oral enteric‐coated pamidronate. The sugar absorption test measures the urinary excretion of lactulose, mannitol, and sucrose after oral intake. Increases in the lactulose/mannitol ratio and sucrose excretion indicate increased small intestinal permeability and gastroduodenal disease, respectively.

Population Pharmacokinetic Model Characterizing 24-Hour Variation in the Pharmacokinetics of Oral and Intravenous Midazolam in Healthy Volunteers.

Daily rhythms in physiology may affect the pharmacokinetics of a drug. The aim of this study was to evaluate 24‐hour variation in the pharmacokinetics of the CYP3A substrate midazolam. Oral (2 mg) and intravenous (1 mg) midazolam was administered at six timepoints throughout the 24‐hour period in 12 healthy volunteers. Oral bioavailability (population mean value [RSE%] of 0.28 (7.1%)) showed 24‐hour variation that was best parameterized as a cosine function with an amplitude of 0.04 (17.3%) and a peak at 12:14 in the afternoon. The absorption rate constant was 1.41 (4.7%) times increased after drug administration at 14:00. Clearance (0.38 L/min (4.8%)) showed a minor 24‐hour variation with an amplitude of 0.03 (14.8%) L/min and a peak at 18:50. Simulations show that dosing time minimally affects the concentration time profiles after intravenous administration, while concentrations are higher during the day compared to the night after oral dosing, reflecting considerable variation in intestinal processes.

Modeling the Influence of Growth Hormone on Lipolysis

Lipolysis (the breakdown of fat) is generally estimated using stable isotopes, where the rate of appearance (Ra) of glycerol is calculated using Steeles equations. These equations are based on single-compartment differential equations for tracer and tracee where rate of change is approximated by the change in concentration from one time point to the next. We demonstrate an alternative approach to estimate metabolic processes, and to determine relationships between hormones and their actions. Growth hormone (GH) or saline was administered in a double-blind randomized crossover design to eight normal weight (NW) and eight obese (OB) subjects, and differences in the effects of GH on lipolysis were investigated. The relationship between the plasma GH concentration and glycerol Ra (as an index of lipolysis) was described using PK/PD modeling. The model incorporated the plasma GH, glycerol and D5-glycerol concentration profiles, and two sequential effect compartments to account for the delay in response. The estimated time-profile of glycerol Ra was compared with estimates obtained using Steeles equations. NONMEM (Version V) FOCE was used for parameter estimation, four differential equations were used, and glycerol and D5-glycerol were estimated simultaneously. The model adequately described both primary variables (glycerol) and derived variables (glycerol Ra as obtained using Steeles equations). Modeling allowed the assessment of potential differences in GH sensitivity in the two groups, and indicated the importance of GH in lipolysis.

Creating a culture of thoughtful prescribing

Background: In the Netherlands 170,000 patients yearly fall victim to poor communication between health care professionals, with 44% of patients receiving inappropriate therapy as a result. Evidence indicates that this problem may be due to physicians learning to communicate therapeutic content by unstructured means during training. Aim: To introduce a structured format for creating and communicating therapeutic plans; to provide for students opportunities practice and feedback on their abilities. Methods: We developed the Individualized Therapy Evaluation and Plan (ITEP) for therapeutic decision-making and communication based on the subjective objective assessment and plan note. The therapeutic plans from students of the 2003 cohort were assessed with one simple and one complex case using a 15-point criteria form. Over the next 3 years students were given more practice using the ITEP and the average score on the complex case was tracked and compared to the 2003 cohort. Results: In cohort 2003, 82% of the students satisfactorily completed the simple case, while only 32% did so with the complex case. In subsequent years, the average scores on the complex case significantly improved from 3.8 to 6.8 with increasing practice. Conclusions: Students can select a simple drug regimen, but without practice using the ITEP will not help to deal with multiple disease states.

Levofloxacin-Induced QTc Prolongation Depends on the Time of Drug Administration.

Understanding the factors influencing a drugs potential to prolong the QTc interval on an electrocardiogram is essential for the correct evaluation of its safety profile. To explore the effect of dosing time on drug‐induced QTc prolongation, a randomized, crossover, clinical trial was conducted in which 12 healthy male subjects received levofloxacin at 02:00, 06:00, 10:00, 14:00, 18:00, and 22:00. Using a pharmacokinetic‐pharmacodynamic (PK‐PD) modeling approach to account for variations in PKs, heart rate, and daily variation in baseline QT, we find that the concentration‐QT relationship shows a 24‐hour sinusoidal rhythm. Simulations show that the extent of levofloxacin‐induced QT prolongation depends on dosing time, with the largest effect at 14:00 (1.73 (95% prediction interval: 1.56–1.90) ms per mg/L) and the smallest effect at 06:00 (−0.04 (−0.19 to 0.12) ms per mg/L). These results suggest that a 24‐hour variation in the concentration‐QT relationship could be a potentially confounding factor in the assessment of drug‐induced QTc prolongation.

A Comparison of the Gastrointestinal Effects of the Nitrogen‐Containing Bisphosphonates Pamidronate, Alendronate, and Olpadronate in Humans

B (PCPs) are used in the treatment of skeletal disorders such as Paget disease, bone tumors, skeletal metastases, and osteoporosis. Bisphosphonates have been associated with gastrointestinal complaints, such as abdominal discomfort, nausea, and vomiting. These nonspecific gastrointestinal complaints, of which the exact nature has not yet been determined, have been observed frequently and in clinical practice are not seldom associated with premature cessation of PCP therapy. It has been suggested that N-PCPs, PCPs with a nitrogen (N) atom in the bioactive moiety of the molecule, cause more of these side effects compared with other PCPs. Previously, we have shown in in vitro experiments that at equimolar concentrations the primary amino-substituted N-PCP pamidronate and alendronate are more toxic for intestinal epithelium than is the tertiary amino-substituted N-PCP olpadronate. In addition, results from other studies suggest that primary amino-substituted PCPs cause more gastrointestinal side effects than do tertiary amino-substituted PCPs. The nonspecific gastrointestinal side effects caused by N-PCPs are related to oral administration of the drug and do not occur after intravenous dosing, suggesting that the effects are related to a local gastrointestinal mechanism rather than a systemic effect. Several techniques can be used to investigate the gastrointestinal effects of PCPs. Endoscopy is a widely used method to show gastric and intestinal abnormalities. The incidence of gastrointestinal complaints in clinical practice was higher than expected from endoscopic studies evaluating PCPs. The gastrointestinal abnormalities causing these complaints may be localized more distally in the gastrointestinal tract than can be evaluated with endoscopy. To investigate the gastrointestinal effects of N-PCPs, we used the sugar absorption test (SAT). Increased permeability is often the first sign of intestinal damage that precedes ulceration. Gastrointestinal permeability can be measured with the SAT. The SAT is able to detect early onset of gastrointestinal damage, and it appears logical to relate these first signs of intestinal damage to nonspecific gastrointestinal complaints. Indeed, in a recent study using the SAT, we were able to show that oral enteric-coated pamidronate increased intestinal but not gastroduodenal permeability and that the SAT is an appropriate method to evaluate gastrointestinal effects of PCPs in humans. The aim of this study was to compare the gastrointestinal effects of pamidronate, alendronate, and olpadronate administered at clinically relevant doses using the SAT. In addition, we compared the possible BRIEF REPORTS/CLINICAL STUDIES