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Aims 5-Fluorouracil (5-FU) is widely used in combination chemotherapy, and literature suggests pharmacokinetic-guided dosing to improve clinical efficacy and reduce toxicity. This study aimed to determine the pharmacokinetic exposure of both 5-FU and its metabolite, 5,6-dihydrofluorouracil (DHFU), in patients with gastrointestinal malignancy and to establish a simplified strategy to assist in therapeutic drug management for dose optimization. Methods This was a prospective, observational study, performed in 27 patients diagnosed with gastrointestinal malignancy who were prescribed 5-FU. Multiple samples were collected per patient over the slow bolus (15-20 min) and continuous infusion period (over 44 h) in doses 1 and 3, and the concentrations of 5-FU and DHFU were measured. Results A higher proportion of patients had exposures within the therapeutic range in dose 3 (50%) as compared to dose 1 (37.5%) with 5-FU. There was an association between delayed time to maximum concentration of DHFU and a high maximum concentration of 5-FU. A limited sampling strategy was developed with 4 samples, 2 during the bolus period and 2 during the continuous period (at 18 h and the end of infusion), which accurately predicted the total area under the curve of 5-FU. Conclusion Using body surface area-based dosing with 5-FU, 50-60% of patients were outside of the therapeutic range. In the absence of genotype testing, measurement of the metabolite DHFU could be a phenotypical measure of dihydropyrimidine dehydrogenase enzyme activity. A limited sampling strategy was developed in patients who were prescribed a combination regimen of slow bolus, followed by a 44-hour continuous infusion of 5-FU to assist in the therapeutic drug management of patients.

Melioidosis is an emerging infectious disease of major public health importance. We describe a patient who presented with septicaemic melioidosis with multi-organ dysfunction. He had only marginal response on standard doses of meropenem. Therapeutic drug monitoring (TDM) revealed suboptimal concentration of meropenem following which drug dose was increased, with which he showed rapid clinical improvement and microbiological clearance. Melioidosis presents with multisystem involvement with disseminated abscess, standard dosing of meropenem may not be sufficient in achieving therapeutic levels and TDM with increased dosing in these critically ill patients will improve outcome.

Pharmacokinetics of meropenem differ widely in the critically ill population. It is imperative to maintain meropenem concentrations above the inhibitory concentrations for most of the interdose interval. A population pharmacokinetic/pharmacodynamic model was developed to determine the probability of target attainment for 3-hour and 30-minute infusion regimens in this population.This study was performed in an intensive care setting among adult patients who were initiated on meropenem at a dose of 1000 mg. Multiple blood specimens were collected at predetermined time points during the interdose period, and meropenem concentrations were measured using high performance liquid chromatography. Using Pmetrics, a pharmacokinetic/pharmacodynamic model was developed and validated. Monte Carlo simulation was performed, and probability of target attainment (100% Tminimum inhibitory concentration (MIC), with a probability0.9) for doubling MICs was determined for different regimens of meropenem.A 2-compartment multiplicative gamma error model best described the population parameters from 34 patients. The pharmacokinetic parameters used in the final model were Ke (elimination rate constant from the central compartment), Vc (volume of distribution of central compartment), KCP and KPC (intercompartmental rate constants), and IC2 (the fitted amount of meropenem in the peripheral compartment). Inclusion of creatinine clearance (CLcreat) and body weight as covariates improved the model prediction (Ke = Ke0 × (Equation is included in full-text article.), Vc = Vc0 × Weight). The Ke and Vc [geometric mean (range)] of the individuals were 0.54 (0.01-2.61)/h and 9.36 (4.35-21.62) L, respectively. The probability of attaining the target, TMIC of 100%, was higher for 3-hour infusion regimens compared with 30-minute infusion regimens for all ranges of CLcreat.This study emphasizes that extended regimens of meropenem are preferable for treating infections caused by bacteria with higher MICs. The nonparametric analysis using body weight and CLcreat as covariate adequately predicted the pharmacokinetics of meropenem in critically ill patients with a wide range of renal function.

ObjectiveAdequate data on fentanyl pharmacokinetics in neonates are lacking. The study was performed to compare serum concentrations and clinical outcome between continuous infusion (CI) and intermittent bolus (IB) doses of fentanyl for analgesia and sedation in neonates.MethodsIn this open-label randomised controlled trial, neonates requiring 24–48 hours of mechanical ventilation and fentanyl administration were recruited. In CI regimen, 1 mcg/kg loading dose was followed by 1 mcg/kg/hour infusion. In IB regimen, 1mcg/kg/dose was administered every 4 hours.Maximum six blood samples were collected in 48 hours from each baby at prespecified time points for estimating serum fentanyl concentration. Secondary outcomes were pain scores (Neonatal Infant Pain Scale and Neonatal Pain, Agitation and Sedation Scale for acute and ongoing pain, respectively) and incidence of adverse effects of fentanyl.Results100 neonates were recruited, 53 in CI and 47 in IB group. In CI regimen, median (IQR) serum fentanyl concentration was 0.42 (0.35, 0.46) to 0.61 (0.47, 0.89) ng/mL throughout the infusion period. In IB regimen, median (IQR) peak concentration ranged from 2.21 (1.82, 3.55) to 3.61 (2.91, 4.51) ng/mL and trough concentration 0.41 (0.33, 0.48) to 0.97 (0.56, 1.25) ng/mL for various doses.Median (IQR) peak concentration (Cmax, 3.06 (1.09, 4.50) vs 0.78 (0.49, 1.73) ng/mL; p0–24, 19.6 (10.4, 33.5) vs 13.2 (10.8, 22.6) µg·hour/L; p=0.12) was higher (though not statistically significant) in IB than CI regimen. Pain scores and adverse effects were comparable between the two regimens.ConclusionCI regimen of fentanyl produces steady serum concentrations, whereas IB regimen produces wide fluctuations in serum concentration with high-peak concentrations. A serum fentanyl concentration of 0.4–0.6 ng/mL produces adequate analgesia and sedation in neonates.Trial registration numberCTRI/2014/11/005190.

Context: Kv7 potassium channels are expressed in several types of smooth muscles and could mediate physiological responses in the tissues expressed. Flupirtine is an analgesic that acts by opening Kv7 potassium channels. It has been shown to inhibit the contractility of several types of isolated smooth muscle. Aims: This study investigated the ability of flupirtine to inhibit the spontaneous contractility of isolated distal caprine (goat) ureter. Settings and Design: Spontaneous contractility of the isolated goat ureter was recorded using a physiograph. Materials and Methods: The ability of 1, 3, 10, 30, and 90 μM concentrations of flupirtine maleate to inhibit the spontaneous contractility of isolated distal goat ureter was investigated. The ability of the nonspecific potassium channel blocker 4-aminopyridine (4-AP; 1 mM) and the specific Kv7 channel blocker XE-991 (100 μM) to reverse the inhibitory effect of flupirtine on ureteric contractility was also investigated. Statistical Analysis Used: Both parametric and nonparametric statistical tests were used. Results: At 10, 30, and 90 μM concentrations, flupirtine significantly inhibited the spontaneous contractility of the isolated goat ureter. The EC50 of flupirtine for a contact period of 10 min was 17.7 μM. The inhibitory effect of flupirtine on ureteric contractility was significantly reversed by 4-AP and XE-991. Conclusions: Flupirtine inhibits the spontaneous contractility of the isolated goat ureter by opening Kv7 channels.