Preliminary pharmacokinetic study of ibuprofen enantiomers after administration of a new oral formulation (ibuprofen arginine) to healthy male volunteers

The pharmacokinetics of ibuprofen enantiomers were investigated in a crossover study in which seven healthy male volunteers received single oral doses of 800 mg racemic ibuprofen as a soluble granular formulation (sachet) containing L-arginine (designated trade name: Spedifen®), 400 mg (-)R-ibuprofen arginine or 400 mg (+)S-ibuprofen arginine. Plasma levels of both enantiomers were monitored up to 480 minutes after drug intake using an enantioselective analytical method (HPLC with ultraviolet detection) with a quantitation limit of 0.25 mg/l. Substantial inter-subject variability in the evaluated pharmacokinetic parameters was observed in the present study. After (+)S-ibuprofen arginine, the following mean pharmacokinetic parameters ±SD were calculated for (+)S-ibuprofen: t_max 28.6 ± 28.4 min; C_max 36.2 ± 7.7 mg/l; AUC 86.4 ± 14.9 mg · h/l; t½ 105.2 ± 20.4 min. After (-)R-ibuprofen arginine, the following mean pharmacokinetic parameters were calculated for (+)S-ibuprofen and (-)R-ibuprofen, respectively: t_max 90.0 ± 17.3 and 50.5 ± 20.5 min; C_max 9.7 ± 3.0 and 35.3 ± 5.0 mg/l; AUC 47.0 ± 17.2 and 104.7 ± 27.7 mg · h/l; t_½ 148.1 ± 63.6 and 97.7 ± 23.3 min. After racemic ibuprofen arginine, the following mean pharmacokinetic parameters were calculated for (+)S- and (-)R-ibuprofen, respectively: t_max 30.7 ± 29.1 and 22.9 ± 29.8 min.; C_max 29.9 ± 5.6 and 25.6 ± 4.4 mg/l; AUC 105.1 ± 23.0 and 65.3 ± 15.0 mg · h/l; t_½ 136.6 ± 20.7 and 128.6 ± 45.0 min. T_max values of S(+)- and (-)R-ibuprofen after a single dose of 400 mg of each enantiomer did not differ significantly from the corresponding parameters obtained after a single dose of 800 mg of racemic ibuprofen arginine, indicating that the absorption rate of (-)R- and (+)S-ibuprofen is not different when the two enantiomers are administered alone or as a racemic compound. An average of 49.3 ± 9.0% of a dose of the (-)R-ibuprofen arginine was bioinverted into its antipode during the study period (480 minutes post-dosing). The percent bioinversion during the first 30 minutes after (-)R-ibuprofen arginine intake averaged 8.1 ± 3.9%. The mean AUC of (+)S-ibuprofen calculated after 800 mg racemic ibuprofen arginine (105.1 ± 23.0 mg · h/l) was lower than the mean AUC value obtained by summing the AUCs of (+)S-ibuprofen after administration of 400 mg (+)S-ibuprofen arginine and 400 mg (-)R-ibuprofen arginine (133.4 ± 26.6 mg · h/l). In conclusion, the administration of Spedifen® resulted in very rapid absorption of the (+)S-isomer (eutomer) with t_max values much lower than those observed for this isomer when conventional oral solid formulations such as capsules or tablets of racemic ibuprofen are administered. This characteristic is particularly favourable in those conditions in which a very rapid analgesic effect is required. Chirality 9:297–302, 1997. © 1997 Wiley-Liss, Inc.     

Sucrose uptake and metabolism in a double layer system for micropropagation ofRosa multiflora

Uptake and metabolism of sucrose in micropropagatedRosa multiflora using the double layer technique was investigated. In the multiplication as well as the root induction stage, hydrolysis of sucrose in the culture medium was observed. A mathematical model was developed to quantify sucrose hydrolysis and the uptake of sucrose, glucose and fructose, based on the time series for the different sugars in the culture medium. These data were linked to a study of the sugar metabolism in the microshoots. After 48 h of incubation on¹⁴C-[U]-glucose containing medium, the incorporated label was mainly detected in the ethanol soluble fraction; within this fraction sucrose was the most important compound. This indicates a significant re-synthesis of sucrose in the plant material after the uptake of hexose. To assess the extent that different enzymes of sucrose metabolism (invertases, sucrose synthase and sucrose-P-synthase) were involved, their activity in different plant parts (of final stage III microshoots) were assayed. A decreasing gradient for sucrose metabolising enzymes from the roots toward the leaves gave a good indication of how the different tissues depend on sucrose absorbed from the medium.     

Time-dependent AluI action on human chromosomes

We have analyzed the pattern of AluI digestion over time on human chromosomes in order to monitor the evolution of the in situ enzyme action. Short treatments followed by Giemsa staining produce a G-like banding effect, whereas longer treatments produce a C-like banding pattern. However, when Propidium iodide staining is used, it reveals a uniform bright fluorescence after short AluI digestions and C bands when longer treatments are developed. We propose that C banding is the result of a uniform DNA removal in non centromeric regions taking place after a critical time point, the initial G like banding being produced by changes in the DNA-proteins interactions.     

Microbiology: a dangerous profession?

The history of science contains many cases of researchers who have died because of their professional activity. In the field of microbiology, some have died or have come close to death from infection by agents that were the subject of their research (Table 1). Infections that had a lethal outcome were usually accidental. Sometimes, however, researchers inoculated themselves with the pathogen or did not take preventive measures against the potential pathogen because they wanted to prove their hypotheses--or disprove someone else's--regarding the origin of the infection. Here is an overview of several episodes in the history of microbiology since the mid nineteenth century involving researchers or workers in fields related to microbiology who have become infected. They are considered here in their historical context to provide insights into some of the pillars of modern microbiology--The giants on whose shoulders several generations of microbiologists have stood to see further.     

Genetic architecture of NaCl tolerance in Arabidopsis

The little success of breeding approaches toward the improvement of salt tolerance in crop species is thought to be attributable to the quantitative nature of most, if not all the processes implicated. Hence, the identification of some of the quantitative trait loci (QTL) that contribute to natural variation in salt tolerance should be instrumental in eventually manipulating the perception of salinity and the corresponding responses. A good choice to reach this goal is the plant model system Arabidopsis, whose complete genome sequence is now available. Aiming to analyze natural variability in salt tolerance, we have compared the ability of 102 wild-type races (named ecotypes or accessions) of Arabidopsis to germinate on 250 mM NaCl, finding a wide range of variation among them. Accessions displaying extremely different responses to NaCl were intercrossed, and the phenotypes found in their F(2) progenies suggested that natural variation in NaCl tolerance during germination was under polygenic controls. Genetic distances calculated on the basis of variations in repeat number at 22 microsatellites, were analyzed in a group of either extremely salt-tolerant or extremely salt-sensitive accessions. We found that most but not all accessions with similar responses to NaCl are phylogenetically related. NaCl tolerance was also studied in 100 recombinant inbred lines derived from a cross between the Columbia-4 and Landsberg erecta accessions. We detected 11 QTL harboring naturally occurring alleles that contribute to natural variation in NaCl tolerance in Arabidopsis, six at the germination and five at the vegetative growth stages, respectively. At least five of these QTL are likely to represent loci not yet described by their relationship with salt stress.