Double-blind food challenges in children in general paediatric practice: useful and safe, but not without pitfalls.

OBJECTIVE: To describe results of double-blind placebo-controlled food challenges (DBPCFC) with cow's milk, hen's egg, soy, peanut and hazelnut in general paediatric practice. METHODS: Food challenges were performed between January 2006 and June 2011, in children 0-18 years of age, on two half-day hospital admissions with a one-week interval. Tests were performed in a double-blind fashion following a standardised protocol with validated recipes. RESULTS: Overall, 234 food challenges were performed in 209 children: 160 with cow's milk, 35 with peanut, 21 with hen's egg, 11 with hazelnuts, and 7 with soy. In two thirds of the cases, the DBPCFC was negative (cow's milk: 57.5%; peanut: 40.0%; hen's egg: 66.7%, hazelnut: 90.9%, soy: 100%). The only patient characteristic significantly associated with a positive DBPCFC was the presence of symptoms from three different organ systems (p=0.007). Serious systemic allergic reactions with wheeze or anaphylaxis occurred in only two children (0.9%). Symptoms were recorded on 29.3% of placebo days. In 30/137 children with a negative test (22%), symptoms returned when reintroducing the allergen into the diet, mostly (66.7%) transient. Of the 85 tests regarded as positive by the attending physician, 19 (22.4%) did not meet predefined criteria for a positive test. This was particularly common with non-specific symptoms. CONCLUSION: A DBPCFC can be safely performed in a general hospital for a range of food allergens. The test result is negative in most cases except for peanut. Non-specific symptoms may hamper the interpretation of the DBPCFC, increasing the risk of a false-positive result.

Theoretical study of mixed LiLnX4 (Ln = La, Dy; X = F, Cl, Br, I) rare earth/alkali halide complexes.

The structure, bonding and vibrational properties of the mixed LiLnX4 (Ln = La, Dy; X = F, Cl, Br, I) rare earth/alkali halide complexes were studied using various quantum chemical methods (HF, MP2 and the Becke3-Lee-Yang-Parr exchange-correlation density functional) in conjunction with polarized triple-zeta valence basis sets and quasi-relativistic effective core potentials for the heavy atoms. Our comparative study indicated the superiority of MP2 theory while the HF and B3-LYP methods as well as less sophisticated basis sets failed for the correct energetic relations. In particular, f polarization functions on Li and X proved to be important for the Li...X interaction in the complexes. From the three characteristic structures of such complexes, possessing 1-(C3v), 2-(C2v), or 3-fold coordination (C3v) between the alkali metal and the bridging halide atoms, the bi- and tridentate forms are located considerably lower on the potential energy surface then the monodentate isomer. Therefore only the bi- and tridentate isomers have chemical relevance. The monodentate isomer is only a high-lying local minimum in the case of X = F. For X = Cl, Br, and I this structure is found to be a second-order saddle point. The bidentate structure was found to be the global minimum for the systems with X = F, Cl, and Br. However, the relative stability with respect to the tridentate structure is very small (1-5 kJ/mol) for the heavier halide derivatives and the relative order is reversed in the case of the iodides. The energy difference between the three structures and the dissociation energy decrease in the row F to I. The ionic bonding in the complexes was characterized by natural charges and a topological analysis of the electron density distribution according to Bader's theorem. Variation of the geometrical and bonding characteristics between the lanthanum and dysprosium complexes reflects the effect of "lanthanide contraction". The calculated vibrational data indicate that infrared spectroscopy may be an effective tool for experimental investigation and characterization of LiLnX4 molecules.

Bioavailability of carbamazepine from four different products and the occurrence of side effects.

The relative bioavailability of four different carbamazepine products, showing large differences in in vitro dissolution profiles, was studied in healthy volunteers to correlate the occurrence of side effects with a measure of the rate of absorption in vivo for bioequivalence testing. Two of the three generic products investigated showed bioequivalence with respect to the extent of absorption with Tegretol. In vivo, the differences found in absorption rate were reflected in the occurrence of side effects, especially dizziness. As a measure for the rate of absorption, the partial AUC did not seem to be a good characteristic to test bioequivalence, as the variability is very high and dependent on the AUC taken. The Cmax/AUCpart seems more promising, especially the partial AUC directly after completion of the absorption process. The variability is low in the case of carbamazepine after a single dose. However, as long as no consensus on the use of other metrics and the objective (clinical or quality control aspects) of bioequivalence testing is reached, and no other pharmacokinetic characteristic is validated, Cmax should be the characteristic of choice for the rate of absorption in single-dose studies with carbamazepine products.

Determination of drug protein-binding by high-performance liquid chromatography using a chemically bonded bovine albumin stationary phase.

A liquid chromatographic method for the determination of the degree of protein-binding of drugs has been established, using a stationary phase to which bovine serum albumin has been bonded chemically. In a structurally heterogeneous group of compounds, results of the method correlate well with protein-binding data obtained by equilibrium dialysis (r = 0.89, n = 23, p less than 0.001). Within a series of analogous piperazines a good correlation is found (r = 0.981, n = 11, p less than 0.001). The chromatographic method allows automation of the measurement of protein-binding of large series of compounds with protein-binding ranging between 10 and 99%. The method is not expensive and is less time consuming than equilibrium dialysis. Only 1 mg of technical-grade material is required to determine the protein-binding, and radioactive labelling of the material is not necessary.

Rapid determination of indomethacin and salicylic acid in serum by means of reversed-phase liquid chromatography.

A method for the quantitative analysis of indomethacin and salicylic acid in blood serum and urine by high-performance liquid chromatography is described. A C18-bonded silica was used as the stationary phase and mixtures of ethanol, n-butanol and aqueous buffer as the mobile phase. Before injection the serum is deproteinized and extracted in one step. The recovery of the extraction was found to be 88% and 77% for indomethacin and salicylic acid, respectively. The relative standard deviations of the analysis for 0.5 micrograms indomethacin and 5 micrograms salicyclic acid per ml serum were 3.6% and 3.2%, respectively. The detection limits for indomethacin and salicylic acid were 2 ng. This corresponds for both substances to 0.1 micrograms/ml serum for an injection volume of 100 microliters. The method enables simultaneous determination of possibly formed metabolites. A number of concurrently administered drugs do not interfere with the analysis. The interactive effects of co-medication of indomethacin and salicylic acid on the serum concentration of indomethacin is demonstrated by measuring the pharmacokinetic curves.

Rapid direct determination of trace amounts of salicylic acid in deproteinized serum by means of high-pressure liquid--liquid chromatography.

A simple method for the quantitative analysis of salicylic acid in blood serum is described. A liquid--liquid chromatographic system, consisting of a long-chain aliphatic amine as the stationary phase and dilute aqueous perchloric acid as the mobile phase, enables the direct injection of deproteinized serum into the system. No change in the chromatographic properties of the system was noticed after 2000 injections of deproteinized serum. Quantitative analysis is possible using peak area or peak height measurements. The method has a high precision: relative standard deviations of 0.4% and 5% are found for samples containing 10 micrograms and 10 ng injected salicylic acid respectively. The detection limit is found to be about 1 ng slicylic acid, corresponding to 40 ppb salicylic acid in serum. Simultaneously administered drugs such as indomethacin, acetylsalicylic acid, caffeine and phenacetin, and metabolites of salicylic acid do not interfere with the analysis. The time course of the concentration of salicylic acid in serum is demonstrated after oral administration of 1 g sodium-salicylate. The phase system was also found to be suitable for the analysis of salicylic acid in urine.