Exhaled NO is increased in patients with asthma and may reflect disease severity. We examined whether the level of exhaled NO is related to the degree of airway obstruction induced by direct and indirect stimuli in asthma. Therefore, we measured exhaled NO levels before and during recovery from histamine and hypertonic saline (HS) challenge (Protocol 1) or histamine, adenosine 5'-monophosphate (AMP), and isotonic saline (IS) challenge (Protocol 2) in 11 and in nine patients with mild to moderate asthma, respectively. The challenges were randomized with a 2-d interval. Exhaled NO and FEV1 were measured before and at 4, 10, 20, and 30 min after each challenge. NO was measured during a slow VC maneuver with a constant expiratory flow of (0.05 x FVC)/s against a resistance of 1 to 2 cm H2O. Baseline exhaled NO levels were not significantly different between study days in Protocol 1 (mean +/- SD: 4.8 +/- 1.8 ppb [histamine] versus 5.4 +/- 2.1 ppb [HS], p = 0.4) or in Protocol 2 (7.9 +/- 4.7 ppb [histamine], 8.3 +/- 5.2 ppb [AMP], and 7.2 +/- 3.7 ppb [IS], p = 0.7). A significant reduction in exhaled NO was observed directly after HS (mean +/- SEM: 39.2 +/- 3.9 %fall) and AMP challenge (32.3 +/- 7.3 %fall) (MANOVA, p < 0.001), respectively, whereas exhaled NO levels tended to decrease after histamine challenge. Isotonic saline challenge did not induce changes in exhaled NO (p = 0.7). There was a positive correlation between %fall in FEV1 and the %fall in exhaled NO after histamine, HS, and AMP challenge as indicated by the mean slope of the within-subject regression lines (p <= 0.04). We conclude that acute bronchoconstriction, as induced by direct and indirect stimuli, is associated with a reduction in exhaled NO levels in asthmatic subjects. This suggests that airway caliber should be taken into account when monitoring exhaled NO in asthma.

Aims Intravenous formulations of busulfan have recently become available. Although busulfan is used frequently in children as part of a myeloablative regimen prior to bone marrow transplantation, pharmacokinetic data on intravenous busulfan in children are scarce. The aim was to investigate intravenous busulfan pharmacokinetics in children and to suggest a limited sampling strategy in order to determine busulfan systemic exposure with the minimum of inconvenience and risk for the patient. Methods Plasma pharmacokinetics after the first administration was investigated in six children using nonlinear mixed effect modelling. Results Pharmacokinetics showed little variability and were described adequately with a one-compartment model (population estimates CL,av=0.29 l h x1 kg x1 ;V,av=0.84 l kg x1; t 1/2 =1.7-2.8 h). Combined with limited sampling and a Bayesian fitting procedure, the model can adequately estimate the systemic exposure to intravenous busulfan, which in children appears to be at the lower end of the adult range. Conclusions Busulfan systemic exposure in children during intravenous administration can be estimated adequately with limited sampling and a Bayesian fitting procedure from a one-compartment model. Intravenous busulfan pharmacokinetics in children should be the subject of more research.

Nitrogen-containing bisphosphonates (N-PCP) are bisphosphonates with an increased antiresorptive potency. Aminobisphosphonates, N-PCPs with an amino group, can cause nonspecific gastrointestinal complaints. It is not known whether these side effects are specific for these bisphosphonates or for the whole class of N-PCPs. In this study, we investigated the effects of two aminobisphosphonates (pamidronate and alendronate) and a structurally similar N-PCP (olpadronate) and their three respective calcium complexes on the viability and the intracellular calcium concentration ([Ca 2+ ] i ) of cultured Caco-2 cells a model for intestinal epithelium. These cells were also examined for apoptosis or necrosis. In the presence of calcium, pamidronate and alendronate were toxic to the cells, with pamidronate being more toxic than alendronate. Olpadronate induced toxicity only at concentrations more than ten times higher than the toxic concentrations of pamidronate. In the absence of calcium definite signs of toxicity were observed only with pamidronate at clinically relevant concentrations. The complexes of pamidronate and alendronate with calcium were considerably less soluble than the olpadronate calcium complex. There were no signs of apoptosis. [Ca 2+ ] i was transiently raised after treatment with the N-PCPs. Doses at which responses were seen were, respectively, 0.02 mM (pamidronate), 0.3 mM (alendronate), and 2 mM (olpadronate). The peak of response was slightly greater after pamidronate treatment than after alendronate or olpadronate, respectively. In conclusion pamidronate, either as an ion or as a calcium complex, is the most toxic of the bisphosphonates tested for Caco-2 cells. Alendronate was less toxic while olpadronate was the least toxic in presence of calcium. The solubility of the bisphosphonate complexes with calcium may account for these differences in toxicity. (J Bone Miner Res 1999;14:784-791)

No abstract

No abstract