PubMed · 6097666
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W A Colburn, D M Gibson. 1984. Composite pharmacokinetic profiling.. https://doi.org/10.1002/jps.2600731152
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Radiation sterilisation is a promising method to sterilise pharmaceutical products. However, this process is accompanied by a modification of odour due to volatile compounds formation. The origin of malodorous compounds produced during solid cefotaxime radiosterilisation has been investigated and several mechanisms are proposed to explain their appearance. Moreover, some quantitative data are given. Analysis of the degradation products was performed using a GC-ITD system with an injection by the static headspace technique. It appeared that some of the radio-induced compounds (such as carbon oxide sulfide and carbon disulfide) came from the degradation of the drug itself, whereas the formation of others required the presence of residual solvents which are volatile impurities already present before irradiation. Acetaldehyde directly came from impurities but the appearance of esters and acetaldehyde O-methyloxime was due to the presence of both cefotaxime and residual solvents together. Thus, the residual solvents play a key role in the radiolysis compounds formation (six of eight require the presence of them) and consequently in the modification of odour as well.
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For a number of years a major limitation in genetic analysis of protein function has been the inability to introduce multiple substitutions at distant sites that would enable the selection of clusters of mutations required for improved or novel biological functions. In order to achieve this, we have recently developed a novel mutagenesis procedure in which the triphosphate derivatives of a pyrimidine (6-(2-deoxy-beta-d-ribofuranosyl)-3, 4-dihydro-8H-pyrimido-[4,5-c][1,2]oxazin-7-one; dP) and a purine (8-oxo-2'-deoxyguanosine; 8-oxodG) nucleoside analogue are employed in DNA synthesis reactions in vitro. The procedure allows control of the mutational load and can yield frequencies of amino acid residue substitutions at least one order of magnitude greater than those previously achieved. Here we report the results of an experiment in which we have hypermutated the bacterial enzyme TEM-1 beta-lactamase and selected small pools (<1.5x10(5)) of clones for enzymatic activity against the beta-lactam antibiotic cefotaxime. The experiment resulted in the isolation of a number of TEM-1 mutants with greatly improved activity against cefotaxime. Among these, clone 3D.5 (E104K:M182T:G238S) exhibited a minimum inhibitory concentration for cefotaxime 20,000-fold higher than wild-type TEM-1 and a catalytic efficiency (kcat/Km) 2383 times higher than the wild-type enzyme. Thus, small pools of hypermutated sequences enabled the selection of one of the most active extended beta-lactamases described so far. These results argue against the accepted view that multiple rounds of low-rate mutagenesis and stepwise selection are essential for in vitro protein evolution and extend the scope of directed molecular evolution to proteins for which no genetic selection is available.