AimThe rising prevalence of bronchial asthma has led to world-wide efforts to understand and stem this development. Cross-sectional studies appear to show that early childhood use of antibiotics may be an important contributory factor, with paracetamol as an additional suspected cause. However, mounting evidence, which is reviewed here, points to various confounding factors as the major reasons for these reported associations.MethodsPubMed and EMBASE were systematically searched for studies on associations between antibiotics and/or paracetamol with asthma and/or wheezing, published up to November 2012. A total of 64 pertinent studies were identified, 35 focusing on antibiotics, 19 on paracetamol, and ten addressing both antibiotics and paracetamol, bringing the number of relevant datasets to 74.ResultsNumerous studies were cross-sectional and made no adjustment for the indication of antibiotics or paracetamol; consequently, they were unable to dismiss possible confounding by indication. Where such adjustments could be performed (mostly in longitudinal studies), they substantially weakened or entirely eliminated the association with asthma or asthma surrogates present in the unadjusted data.ConclusionThe weight of evidence of the collected studies in our review strongly suggests that the association of antibiotics with childhood asthma reflects various forms of bias, the most prominent of which is confounding by indication. Recent studies and meta-analyses support the same conclusion for paracetamol. Truly indicated antibiotics should not be withheld from infants or young children for fears they might develop asthma. Likewise, there is no sound reason to replace paracetamol as the preferred pain relief and fever medication in this age group.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-012-1463-7) contains supplementary material, which is available to authorized users.

Electrogenic, cAMP-mediated Cl secretion across rabbit descending colon in vitro is independent of the rate or presence of active Na absorption. Yet, several observations indicate that this process is Na dependent: a) Cl secretion requires the presence of Na in the serosal solution alone, b) the kinetics of Cl transport as a function of external Na concentration are virtually identical to the Cl concentration dependence, and c) exchange of cell Cl with isotopic Cl added to the serosal solution is inhibited by Na-free media and by addition of furosemide to the serosal solution; the diuretic also inhibits Cl secretion. These findings suggest that Cl entry into the secretory cells across the basolateral membrane is mediated by NaCl cotransport. Addition of ouabain to, or removal of K from, the serosal solution inhibits Cl secretion so that Na entering the secretory cell across the basolateral membrane may be returned to the serosal solution by the Na-K pump. Finally, increasing the K concentration of the serosal solution inhibits Cl secretion under short-circuit conditions. This appears to result from K-induced depolarization of the electrical potential difference across the apical membrane so that diffusional Cl exit from cell to mucosal solution is reduced.

Gallbladder fluid and electrolyte transport was investigated in vitro. In guinea pig gallbladder, equimolar substitution of acetate, propionate, butyrate or valerate for HCO3 was increasingly effective in stimulating fluid absorption. The stimulatory potency of these compounds was a function of their chloroform water partition coefficients. The stimulatory effects of the isomers isobutyrate and isovalerate were less than predicted from their partition coefficients. Acidification of the gallbladder lumen, however, was strictly dependent on the partition coefficients for all of the above fatty acids. Unidirectional 22Na fluxes were measured in rabbit and guinea pig gallbladders under short-circuit conditions. In the presence of butyrate stimulation of net Na flux was due entirely to an increase in the mucosal-to-serosal Na flux. Stimulation by butyrate was abolished by its omission from the mucosal bathing solution. The transepithelial electrical potential difference in both rabbit and guinea pig gallbladder became more lumen positive following mucosal but not serosal addition of butyrate. Net 14C-butyrate fluxes were too small to account for stimulation of Na absorption in either species. Butyrate stimulation of Na absorption by guinea pig gallbladder was abolished by increasing the bathing pH from 7.4 to 8.1. Tris buffer (25 mM) partially inhibited butyrate-dependent gallbladder fluid absorption by rabbit and guinea pig at pH 6.4 and 7.0, respectively, and completely at pH 8.4. These results reveal a marked similarity between butyrate and HCO stimulation of gallbladder NaCl and fluid absorption. The results are best explained by a double ion-exchange model, in which butyrate (HCO3) in the mucosal solution acts to maintain the intracellular supply of H+ and butyrate (HCO3) for countertransport of Na and Cl, respectively.

The total clearance was 517 ml.min-1, and the absolute bioavailability was 91% for the 30-mg and 81% for the 15-mg enteric-coated formulation. The elimination half-life was about 1 h. No correlation of the plasma levels to the sparteine metabolic ratio was found, and no correlation to the mephenytoin type could be established, since all volunteers of the mephenytoin type were extensive metabolizers. Although considerable variation, inter- and intraindividually, was observed, the increase in Cmax and AUC did not deviate from dose proportionality. The present galenic formulation ensures a high bioavailability after a single dose.

Fluid transport and net fluxes of Na, K, Cl and HCO3 by guinea pig gallbladder were investigated in vitro. A perfused gallbladder preparation was devised to simultaneously study unidirectional fluxes of 22Na and 36Cl. The net Cl flux exceeded the net Na flux during fluid absorption in the presence of HCO3. This Cl excess was counterbalanced by a net HCO3 secretion: a HCO3-Cl exchange. PGE1 reversed the direction of fluid transport and abolished the net Cl flux. The magnitude of the HCO3 secretion remained unchanged, but shifted from a HCO3-Cl exchange to a net secretion of NaHCO3 and KHCO3. Furosemide inhibited both the HCO3-Cl exchange and HCO3 secretion after PGE1 without influencing fluid absorption. Ouabain inhibited the HCO3-Cl exchange as well as fluid absorption; only the effect on the HCO3 secretion was entirely reversible. Secreted HCO3 appeared not to be derived from metabolic sources since HCO3 secretion was abolished in a HCO3-free bathing medium. HCO3 secretion was also dependent on the Na concentration of the bathing fluid. Three lines of evidence are presented in favor of an active HCO3 secretion in guinea pig gallbladder. HCO3 is secreted against: (i) a chemical gradient, (ii) an electrical gradient and (iii) the direction of fluid movement under control conditions.