Monitoring salivary lamotrigine concentrations

Lamotrigine concentrations were measured simultaneously (as far as was feasible) in stimulated and unstimulated saliva samples, and in plasma, from seven adult volunteers over a 32 h period following a single 50 mg dose of the drug, and in 20 children and adolescents during the course of routine antiepileptic therapy. In individuals there was a close correlation between the measurements at least 2 It after ingestion of the drug. Concentrations in stimulated and unstimulated saliva were similar; the stimulation produced little change in the saliva secretion rate. The saliva-to-plasma concentration ratio increased linearly by 0.78% for each 1 mg/L plasma lamotrigine concentration, with a mean value of 48.8% at a plasma lamotrigine concentration of 10 mg/L. With appropriate precautions as to the timing of saliva collections, and a single plasma lamotrigine concentration measurement to calibrate the salivary values in the individual, salivary lamotrigine concentration measurement appears to be a practicable approach to therapeutic drug monitoring. This has significant implications for the elucidation of the pharmacokinetics of lamotrigine in the paediatric population.

Antibacterial dosing in intensive care: Pharmacokinetics, degree of disease and pharmacodynamics of sepsis

Treatment of sepsis remains a significant challenge with persisting high mortality and morbidity. Early and appropriate antibacterial therapy remains an important intervention for such patients. To optimise antibacterial therapy, the clinician must possess knowledge of the pharmacokinetic and pharmacodynamic properties of commonly used antibacterials and how these parameters may be affected by the constellation of pathophysiological changes occurring during sepsis. Sepsis, and the treatment thereof, increases renal preload and, via capillary permeability, leads to 'third-spacing', both resulting in higher antibacterial clearances. Alternatively, sepsis can induce multiple organ dysfunction, including renal and/or hepatic dysfunction, causing a decrease in antibacterial clearance. Aminoglycosides are concentration-dependent antibacterials and they display an increased volume of distribution (V-d) in sepsis, resulting in decreased peak serum concentrations. Reduced clearance from renal dysfunction would increase the likelihood of toxicity. Individualised dosing using extended interval dosing, which maximises the peak serum drug concentration (C-max)/minimum inhibitory concentration ratio is recommended. beta-Lactams and carbapenems are time-dependent antibacterials. An increase in Vd and renal clearance will require increased dosing or administration by continuous infusion. If renal impairment occurs a corresponding dose reduction may be required. Vancomycin displays predominantly time-dependent pharmacodynamic properties and probably requires higher than conventionally recommended doses because of an increased V-d and clearance during sepsis without organ dysfunction. However, optimal dosing regimens remain unresolved. The poor penetration of vancomycin into solid organs may require alternative therapies when sepsis involves solid organs (e.g. lung). Ciprofloxacin displays largely concentration-dependent kill characteristics, but also exerts some time-dependent effects. The V-d of ciprofloxacin is not altered with fluid shifts or over time, and thus no alterations of standard doses are required unless renal dysfunction occurs. In order to optimise antibacterial regimens in patients with sepsis, the pathophysiological effects of systemic inflammatory response syndrome need consideration, in conjunction with knowledge of the different kill characteristics of the various antibacterial classes. In conclusion, certain antibacterials can have a very high V-d, therefore leading to a low C-max and if a high peak is needed, then this would lead to underdosing. The Vd of certain antibacterials, namely aminoglycosides and vancomycin, changes over time, which means dosing may need to be altered over time. Some patients with serum creatinine values within the normal range can have very high drug clearances, thereby producing low serum drug levels and again leading to underdosing. Copyright © 2010 Elsevier Inc. All rights reserved.

The influence of dietary sodium chloride, Arginine : Lysine ratio, and methionine source on apparent ileal digestibility of arginine and lysine in acutely heat-stressed broilers

The present study was carried out to determine the ileal digestibility of Arg and Lys in acutely heatstressed broilers using diets varying in Arg:Lys ratio, NaCl concentration, and Met Source. Male broilers were maintained at 22degreesC from 21 to 33 d of age and then at 32degreesC from 33 to 38 d of age. From 28 to 38 d of age, birds were fed a diet with an Arg:Lys ratio of 1.05 and 3 g of supplemental NaCl/kg of diet with or without L-arg free base to increase the Arg:Lys to 1.35, and with or without 3 g/kg of additional NaCl. Methionine was supplied as equimolar amounts of DL-Met or 2-hydroxy-4-(methylthio)-butanoic acid in a 2 x 2 x 2 design. At 38 d of age, digesta were collected from the terminal ileum, and amino acid analyses were conducted on feed and digesta samples and compared with acid-insoluble ash (dietary celite) to calculate the apparent ileal digestibilities of Lys and Arg. Increasing the NaCl concentration and the presence of HMB significantly decreased the digestibility of both Arg and Lys, whereas increasing the Arg:Lys ratio increased the digestibility of only Arg but did increase BW gain (P = 0.08). An interaction between dietary NaCl and Arg:Lys ratio as well as the 3-way interaction suggested that dietary NaCl could affect the apparent ileal digestibility of Arg and Lys at certain Arg:Lys ratios and the response may be influenced by the Met source.