Biomedical subjects
Publications and source records attributed to J S Millership.
The sorption of the antifungal drug miconazole onto the plastics of infusion bags and intravenous administration sets has been investigated. HPLC methodology was applied for the determination of miconazole concentrations. The results obtained indicate that the sorption of miconazole is low and is unlikely to result in significant loss of clinical efficacy.
Two methods for the determination of aqueous glutaraldehyde, a gas chromatographic method and an ultraviolet spectrophotometric difference method, were compared. The two methods gave similar results for glutaraldehyde concentration determination when investigating undegraded samples. However, the ultraviolet method gave lower values than the gas chromatographic method when degraded samples were studied. A possible source of these discrepancies is discussed.
Measurement of K+ ions in extracellular fluids was used to provide evidence of direct membrane damage induced by miconazole and clotrimazole in Trichophyton mentagrophytes mycelium. K+ release from mycelium treated with high concentrations of drug was extensive, although leakage occurred more rapidly and to a greater extent with miconazole than with clotrimazole. Cells treated with fungicidal concentrations of drug were completely necrotic. The effect of miconazole was concentration dependent. A reduction in ergosterol levels was evident after 5 h treatment with miconazole. Further reduction in ergosterol concentration was demonstrated after 24 h with fungistatic concentrations of drug and was a concentration dependent effect. Fungistatic concentrations of miconazole also induced ultrastructural changes in mycelium, which were apparent within 5 h of treatment and became more pronounced after 24 h. Clotrimazole also reduced ergosterol levels and affected ultrastructure of mycelium. The plasma membrane in particular was affected by both these drugs.
Several congeneric series of antimicrobial agents previously studied by Hansch analysis have been investigated using molecular connectivity as the descriptor of molecular structure. In all cases connectivity gave comparable or improved correlations compared with log P, particularly where the pattern of molecular substitution was more complex. It was concluded that the use of computer-generated connectivity terms had advantages over calculated log P values in its ease of application and should be considered at least for initial screening of structure-activity data.
Kier & Hall (1976) demonstrated that a relationship existed between molecular connectivity and Log P (the Log of the octanol/water partition coefficient) for several classes of compounds and also for the combined classes. This work utilized a number of Log P values calculated using Pi values. We have reinvestigated this relationship using experimentally determined Log P values. The results confirm Kier & Hall's findings although different connectivity indices are brought into the equations.
The relation between gas chromatographic retention parameters and molecular connectivity has been investigated for several series of compounds including hydrocarbons, compounds containing oxygen functional groups (esters, aldehydes, ketones, alcohols and ethers) and drug molecules., With the oxygenated compounds good correlation was observed with the first order valence connectivity index, whilst for the other groups multiparameter equations were required for satisfactory correlation. The effect of column to column variation within a series was also investigated.
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The recently developed topological index, molecular connectivity (chi), has been correlated using multiple regression analysis with gas chromatographic retention time (Rt) for various series of compounds. For saturated and unsaturated aliphatic hydrocarbons, and aliphatic aldehydes, good correlation with log Rt was achieved by one-parameter linear equations in terms of the first-order conncectivity index. (1chi). The equation for aliphatic alcohols required an additional parameter, the valence connectivity (vchi) for satisfactory correlation. One-parameter equations using 1chi also good correlation with log Rt for three series of drug molecules, amphetamines, barbiturates and phenothiazines. In all cases the equations generated gave good agreement between calculated and observed log Rt values.
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The metabolism of an oral dose of S-carboxymethyl-L-cysteine (SCMC) in man has been studied; the quantitative determination of SCMC, S-methyl-L-cysteine (SMC) and their sulphoxide metabolites (SCMCO and SMCO), in urine, was carried out using high performance liquid chromatography (HPLC) with electrochemical detection (ECD); the possibility of stereospecific sulphoxidation was investigated.
The metabolism of the antiepileptic drug ethosuximide (3-ethyl-3-methylpyrollidine-2,5-dione) (I) in animals and humans is reviewed. Chiral aspects of the metabolism of ethosuximide are discussed. Clarification of the precise nature of the hydroxymetabolites of ethosuximide is presented.