Establishment of tolerance to commensal bacteria requires a complex microbiota and is accompanied by decreased intestinal chemokine expression.

Intricate regulation of tolerance to the intestinal commensal microbiota acquired at birth is critical. We hypothesized that epithelial cell tolerance toward early gram-positive and gram-negative colonizing bacteria is established immediately after birth, as has previously been shown for endotoxin. Gene expression in the intestine of mouse pups born to dams that were either colonized with a conventional microbiota or monocolonized (Lactobacillus acidophilus or Eschericia coli) or germ free was examined on day 1 and day 6 after birth. Intestinal epithelial cells from all groups of pups were stimulated ex vivo with L. acidophilus and E. coli to assess tolerance establishment. Intestine from pups exposed to a conventional microbiota displayed lower expression of Ccl2, Ccl3, Cxcl1, Cxcl2, and Tslp than germ-free mice, whereas genes encoding proteins in Toll-like receptor signaling pathways and cytokines were upregulated. When comparing pups on day 1 and day 6 after birth, a specific change in gene expression pattern was evident in all groups of mice. Tolerance to ex vivo stimulation with E. coli was only established in conventional animals. Colonization of the intestine was reflected in the spleen displaying downregulation of Cxcl2 compared with germ-free animals on day 1 after birth. Colonization reduced the expression of genes involved in antigen presentation in the intestine-draining mesenteric lymph nodes, but not in the popliteal lymph nodes, as evidenced by gene expression on day 23 after birth. We propose that microbial detection systems in the intestine are upregulated by colonization with a diverse microbiota, whereas expression of proinflammatory chemokines is reduced to avoid excess recruitment of immune cells to the maturing intestine.

Combined intervention programme reduces inappropriate prescribing in elderly patients exposed to polypharmacy in primary care.

PURPOSE: To evaluate the effect of a combined or a single educational intervention on the prescribing behaviour of general practitioners (GPs). The primary endpoint was effect on inappropriate prescribing according to the Medication Appropriateness Index (MAI). METHODS: General practitioners were randomised to either (1) a combined intervention consisting of an interactive educational meeting plus feedback on participating patients' medication, (2) a single intervention with an interactive educational meeting or (3) a control group (no intervention). Elderly (>65 years) patients exposed to polypharmacy (>or=5 medications) were identified and approached for inclusion. Data on medications prescribed over a 3-month period were collected, and the GPs provided detailed information on their patients before and after the intervention. A pre- and post-MAI were scored for all medications. RESULTS: Of the 277 GPs invited to participate; 41 (14.8%) volunteered. Data were obtained from 166 patients before and after the intervention. Medication appropriateness improved in the combined intervention group but not in the single intervention group. The mean change in MAI and number of medications was -5 [95% confidence interval (CI) -7.3 to -2.6] and -1.03 (95% CI -1.7 to -0.30) in the combined intervention group compared with the group with the educational meeting only and the no intervention group. CONCLUSIONS: A combined intervention consisting of an interactive educational meeting plus recommendations given by clinical pharmacologists/pharmacists concerning specific patients can improve the appropriateness of prescribing among elderly patients exposed to polypharmacy. This study adds to the limited number of well-controlled, randomised studies on overall medication appropriateness among elderly patients in primary care. Important limitations to the study include variability in data provided by participating GPs and a low number of GPs volunteering for the study.

Absorption spectra of photoactive yellow protein chromophores in vacuum.

The absorption spectra of two photoactive yellow protein model chromophores have been measured in vacuum using an electrostatic ion storage ring. The absorption spectrum of the isolated chromophore is an important reference for deducing the influence of the protein environment on the electronic energy levels of the chromophore and separating the intrinsic properties of the chromophore from properties induced by the protein environment. In vacuum the deprotonated trans-thiophenyl-p-coumarate model chromophore has an absorption maximum at 460 nm, whereas the photoactive yellow protein absorbs maximally at 446 nm. The protein environment thus only slightly blue-shifts the absorption. In contrast, the absorption of the model chromophore in aqueous solution is significantly blue-shifted (lambda(max) = 395 nm). A deprotonated trans-p-coumaric acid has also been studied to elucidate the effect of thioester formation and phenol deprotonation. The sum of these two changes on the chromophore induces a red shift both in vacuum and in aqueous solution.

Kinetics of propylthiouracil in the elderly.

The pharmakokinetics of propylthiouracil was evaluated in 9 elderly patients and compared to previous results from 6 younger subjects. By giving the drug both by the intravenous and oral route of administration it was possible to estimate the rate and extent of bioavailability. The various kinetic parameters were calculated according to a two-compartment model by use of two different methods: a graphical hand drawn one and by a special developed computer program based on a least squares minimalisation. While no significant differences could be demonstrated between the two age groups concerning volumes of distribution, clearance and extent of absorption, a large difference was found with regard to the absorption rate constant ka, which was about 3 times higher in the younger than in the elderly subjects, presumably due a reduced gastric emptying time. Considering the comparison between the two methods of calculations all the kinetics parameters were similar except ka and the slow disposition rate constant betw which were underestimated by the graphical method. It is concluded that no-age dependent changes exist concerning the kinetics of propylthiouracil except for a decreased rate of absorption. Graphical methods in pharmacokinetics are useful in obtaining distribution and elimination data but seem often biased for the evaluation of absorption rate constants.

The influence of disulfiram on the half life and metabolic clearance rate of diphenylhydantoin and tolbtamide in man.

Diphenylhydantoin (DPH) and tolbutamide serum levels were studied in ten volunteers before and after 4 days of disulfiram treatment. The mean DPH half life increased significantly from 11.0 +/- a.2 h to 19.0 +/- 3.3 h, and the mean DPH metabolic clearance rate decreased significantly from 51.2 +/- 17.2 ml/min to 33.9 +/- 12.0 ml/min during medication. No significant changes in the half life or metabolic clearance rate of tolbutamide was observed.

Drug interactions and clinical pharmacokinetics.

Some drugs influence the gastro-intestinal absorption, distribution , metabolism or renal excretion of other drugs, i.e., processes involved in pharmacokinetic interactions. The clinical consequences of pharmacokinetic drug-drug interactions will be either an increase or a decrease in known therapeutic or toxic effects of the interacting drug. In order to evaluate the importance of drug interaction affecting gastro-intestinal absorption, it is necessary to distinguish between interactions which alter the rate of absorption of another drug and those which alter the amount of drug absorbed. Many drugs displace other drugs from their protein binding sites in vitro. This may cause an increase in the pharmacological effect of the displaced drug. However, much discrepancy exists between in vitro findings. In some cases, the enhanced effect only seems to be a temporary phenomenon. The degree of protein binding and the size of apparent volume of distribution (Vd) must also be taken into consideration. Perhaps the importance of interaction involving protein binding has been overemphasized. Barbiturates, glutethimide, rifampicin and phenytoin increase the rate of drug metabolism in man. The most important interactions reported are between oral anti-coagulants and barbiturates. After withdrawal of these hepatic microsomal enzyme inducing drugs, it takes 2 to 3 weeks before the rate of drug metabolism reaches the pretreatment level. In this period, risk of haemorrhage exists. Induction seems to be dose-dependent, but not all persons are inducible. Many drugs compete for the drug metabolising enzyme system in the liver and consequently some drugs inhibit the biotransformation of other drugs. The time course of these interactions depends on the pharmacokinetic properties of the drug involved, and these interactions also seem to be dose-dependent. The most important of such interactions, clinically involved the oral sulphonylurea hypoglycaemic drugs and the antiepilepic drug phenytoin. Drugs are eliminated by urinary excretion through three mechanisms: glomerular filtration, tubular reabsorption, and active tubular secretion. The most important interactions seem to be those involving competition for tubular secretion.