PubMed · 5313904
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J C Gingell. 1971-05-01. Bacteriuria again.. https://doi.org/10.1136/bmj.2.5756.278-c
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AIM: If appropriately accounted for in a pharmacokinetic (PK)-pharmacodynamic (PD) model, time-varying covariates can provide additional information to that obtained from time-constant covariates. The aim was to present and apply two models applicable to time-varying covariates that capture such additional information. METHODS: The first model estimates different covariate-parameter relationships for within- and between-individual variation in covariate values, by splitting the standard covariate model into a baseline covariate (BCOV) effect and a difference from baseline covariate (DCOV) effect. The second model allows the magnitude of the covariate effect to vary between individuals, by inclusion of interindividual variability in the covariate effect. The models were applied to four previously analysed data sets. RESULTS: The models were applied to 10 covariate-parameter relationships and for three of these the first extended model resulted in a significant improvement of the fit. Even when this model did not improve the fit significantly, it provided useful information because the standard covariate model, which assumes within- and between-patient covariate relationships of the same magnitude, was only supported by the data in four cases. The inclusion of BCOV was not supported in two cases and DCOV was unnecessary in three cases. In one case, significantly different, nonzero, relationships were found for DCOV and BCOV. The second extended model was found to be significant for four of the 10 covariate-parameter relationships. CONCLUSIONS: On the basis of the examples presented, traditionally made simplifications of covariate-parameter relationships are often inadequate. Extensions to the covariate-parameter relationships that include time-varying covariates have been developed, and their appropriateness and benefits have been described.
Gentamicin is a 4,6-disubstituted aminocyclitol antibiotic complex synthesised by some members of the actinomycete genus Micromonospora. In a search for the gentamicin biosynthetic gene cluster we identified, using a cosmid library approach, a region of the M. echinospora ATCC15835 chromosome that encodes homologues of aminoglycoside biosynthesis genes including gntB-a close homologue of the 2-deoxy-scyllo-inosose synthase gene (btrC) from butirosin-producing Bacillus circulans. Insertional inactivation was achieved by homologous recombination with an internal gntB fragment-containing suicide plasmid, delivered by conjugal transfer from Escherichia coli. gntB disruptants were gentamicin nonproducing mutants as assayed by an ELISA antibiotic detection system, proving the association of gntB (or a downstream region) with gentamicin biosynthesis. The function of some open reading frames within the cluster, predicted by nucleotide database homology searching, is discussed with regards to their potential roles in gentamicin biosynthesis. The discovery of this genetic region represents the first report of a gene cluster involved in the biosynthesis of a 4,6-disubstituted aminocyclitol antibiotic.
Carrier systems for local gentamicin (GS) treatment based on collagen sponges and polymethylmethacrylate beads show pharmacokinetic disadvantages in their GS-release profiles. Therefore, poly(lactic-co-glycolic acid) (PLGA) microparticles were devised. None of the five poly(alpha-hydroxy acid)s tested resulted in the desired antibiotic release over approximately one week. However, preparing microparticles from a 50/50 blend of Resomer RG 502H, an uncapped variety, and Resomer RG 503, an endcapped polymer, yielded the targeted liberation profile. The mechanism of GS release was investigated by analyzing water uptake and polymer molecular weight. Release of GS from RG 502H particles occurred instantaneously and coincided with substantial water penetration. Particles prepared from RG 503 started out at a higher molecular weight and since the endcapped polymer takes up less water, the decrease in molecular weight was delayed. The threshold of collapse was reached after two weeks, which coincided with water penetration and GS release. For the 50/50 RG 502H/RG 503 blend, this process was delayed for two to three days. Hydrolysis occurred at the same rate as for RG 502H due to the high water content as a consequence of the uncapped polymer fraction and renders GS release over one week with release limited to 30% in the first two days due to the endcapped polymer fraction of higher molecular weight. Thus, the mixture of endcapped and uncapped Resome exhibits a new quality for adjusting drug release from poly(alpha-hydroxy acid)s.