Fine-mapping of genes determining extrafusal fiber properties in murine soleus muscle.

Muscle fiber cross-sectional area (CSA) and proportion of different fiber types are important determinants of muscle function and overall metabolism. Genetic variation plays a substantial role in phenotypic variation of these traits; however, the underlying genes remain poorly understood. This study aimed to map quantitative trait loci (QTL) affecting differences in soleus muscle fiber traits between the LG/J and SM/J mouse strains. Fiber number, CSA, and proportion of oxidative type I fibers were assessed in the soleus of 334 genotyped female and male mice of the F34 generation of advanced intercross lines (AIL) derived from the LG/J and SM/J strains. To increase the QTL detection power, these data were combined with 94 soleus samples from the F2 intercross of the same strains. Transcriptome of the soleus muscle of LG/J and SM/J females was analyzed by microarray. Genome-wide association analysis mapped four QTL (genome-wide P < 0.05) affecting the properties of muscle fibers to chromosome 2, 3, 4, and 11. A 1.5-LOD QTL support interval ranged between 2.36 and 4.67 Mb. On the basis of the genomic sequence information and functional and transcriptome data, we identified candidate genes for each of these QTL. The combination of analyses in F2 and F34 AIL populations with transcriptome and genomic sequence data in the parental strains is an effective strategy for refining QTL and nomination of the candidate genes.

[The relative bioavailability of paracetamol in suppositories in comparison to tablets]. / Untersuchungen zur relativen Bioverfügbarkeit von Paracetamol in Suppositorien im Vergleich zu Tabletten.

Relative Bioavailability Studies on Paracetamol in Suppositories as Compared to Tablets. Relative bioavailabilities of 250 mg paracetamol (CAS 103-90-2) in ben-u-ron 125 mg and ben-u-ron 250 mg suppositories were determined in comparison with that of cut-in-half Benuron tablets 500 mg in an open intraindividual 3-period-changeover-study in 18 healthy volunteers. Plasma concentrations of paracetamol were analyzed by means of a specific and sensitive HPLC-method with UV-detection. For the assessment of the bioavailability AUC, Cmax, tmax and HVD (half value duration) were used as pharmacokinetic characteristics. Relative bioavailability of paracetamol was 102% for 125 mg and 93% for 250 mg suppositories, compared with that of cut-in-half 500 mg tablets. Mean maximum paracetamol plasma concentrations (Cmax) were determined as 2.1 micrograms/ml (CV = 31%; (CV = Coefficient of Variation), 2.0 micrograms/ml (CV = 27%) and 3.5 micrograms/ml (CV = 27%) after administration of 125 mg and 250 mg suppositories and 500 mg cut-in-half tablets, respectively. These maximum concentrations were achieved 2.2 +/- 0.7, 1.8 +/- 0.7 and 0.6 +/- 0.3 h (tmax) after administration of the respective preparations. The corresponding HVD-values were 3.8 +/- 1.0, 3.5 +/- 0.9 and 1.8 +/- 0.8 h, respectively. Extent of bioavailability of paracetamol (dose: 250 mg) following administration of 125 mg as well as 250 mg suppositories in comparison with 500 mg tablets was shown to be equivalent. The results obtained in this study confirm the adequate bioavailability of both suppositories compared with tablets. On the other hand both suppository preparations were assessed as being bioequivalent concerning AUC and Cmax.

[Relative bioavailability of paracetamol in suppositories preparations in comparison to tablets]. / Relative Bioverfügbarkeit von Paracetamol in Suppositorien-Zubereitungen im Vergleich zu Tabletten.

Relative Bioavailability of Paracetamol as Suppositories Compared to Tablets. The relative bioavailability of paracetamol (CAS 103-90-2) in ben-u-ron 500 mg and ben-u-ron 1000 mg suppositories (test formulations) was compared with that of Benuron tablets 500 mg (reference product) in an open, intraindividual, 3-period-changeover-study in 18 healthy subjects. Plasma concentrations of paracetamol were determined using a specific and sensitive HPLC method with UV detection. For the assessment of bioavailability AUC, Cmax, tmax and HVD were used as pharmacokinetic characteristics. Bioequivalence of the rectal formulations was tested by calculating 90% confidence intervals using the Two-one-sided-t-tests-procedure and log-transformed data of AUC and Cmax. For AUC the confidence intervals were required to be in the 80 and 125% range, for Cmax between 70 and 143% (inclusion rule). Data from 17 subjects could be evaluated. Bioavailability of paracetamol was 89 and 90% for the 500 and 1000 mg suppositories, respectively compared with that of the 500 mg reference tablets. Mean maximum paracetamol plasma concentrations (Cmax) were 3.55 and 6.02 or 7.16 mg/l after administration of the 500 and 1000 mg suppositories or the 500 mg tablets, respectively. These maximum concentrations were achieved 2.0, 2.7 and 0.6 h (tmax) after administration of the respective preparations. The corresponding HVD values were 4.3, 5.2 and 2.0 h, respectively. After dose adjustment of the results for the 1000 mg suppositories relative bioavailabilities of paracetamol from both rectal formulations exceeded 80% of that from the tablets.(ABSTRACT TRUNCATED AT 250 WORDS)