Biomedical subjects
Publications and source records attributed to I Haller.
Difficulties in the in vitro testing of azole antimycotics are described. The value of minimal inhibitory concentration results are discussed and contrasted to those obtained with polyene antimycotics.
The experimentally induced aspergillosis of mice is discussed as a useful parameter for the screening of new antimycotics. There are important differences between this test model and aspergillus infections in humans. Mice must be infected intravenously with more than 10(6) spores of Aspergillus fumigatus to provoke multiple abscess formation in the kidneys which induces an acute, lethal course of infection. Intratracheal administration of 2 x 10(6) spores did not evoke any symptoms. The therapeutic efficacy of several antimycotics was examined; amphotericin B, 5-fluorocytosine and BAY h 4364--as the only imidazole-derivative--proved to be effective.
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The test procedure described in this paper aims at assessing the effectiveness of antimycotics against yeasts. The inhibitory effect on Candida albicans growth is determined in the presence of kidney homogenate, an in vitro test medium offering fungal growth conditions similar to physiological conditions. The inoculum consists of kidney material from Candida-infected mice. By dilution with kidney material from uninfected mice the initial number of viable particles is standardised. Specimens withdrawn from this inoculum are mixed with different concentrations of the test substance and incubated for 24 hours. The inhibition of fungal growth is assessed on the basis of the number of colony-forming units in comparison with controls to which no test substance was added. The growth phase of C. albicans during incubation in vitro resembles that observed in the kidney in vivo, i.e. besides yeast cells, the fungus produces a great number of pseudomycelia and mycelia. The results of the tests conducted with the top-ranking antimycotics give good evidence of their therapeutic efficacy. The testing of further active substances revealed advantages of the new test model over existing test methods.
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The in vitro antimicrobial activity of the antieczematic Bay f 4797 was studied. This combination drug contains the three active components acidamfenicol, clotrimazole and dexamethasone (prospective trade name: Baycuten). Various bacterial and fungal species of importance in dermatology served as test organisms. All the bacterial strains examined were found to be moderately susceptible to acidamfenicol; clotrimazole showed good inhibitory values agaisnt all the fungal species and the gram-positive bacterial strains. Additionally it was checked whether a synergistic or antagonistic interaction occurs with respect to the antimicrobial activity. An interference which could lead to impairment of the therapeutic activity was not observed.
The problem of side effects of radiotherapy in genital carcinomas on a concomitant vaginal yeast infection was investigated by subjecting candida albicans cells in vitro to the effects of gamma radiation. Agar plates with a defined number of candida albicans cells were irradiated with the conventional gynaecological sources of radium applicators and tele-cobalt. The experimental incubation of the agar plates showed that the number and growth of the yeast colonies were either completely inhibited or stunted by the effect of the radiation. There were also mutations in the cell morphology, animal pathogenecity and sensitivity to antimycotic drugs. The clinical implications of these results are discussed.
Formation of microlenses, a reduction in thickness, and a change in mechanical properties have been observed when Ca2+ or other multivalent ions are added to bathing solutions of Mueller-Rudin membranes of acidic phospholipids. The observations are interpreted as an extrusion of residual solvent from the hydrocarbon core of the bilayer due to changes in packing imposed by the reduction of electrostatic repulsion of the head groups.
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Ghosts from Escherichia coli have been oxidized with CuSO4-o-phenanthroline or ferricyanide-ferrocene. Upon oxidation they became resistant to boiling dodecyl sulfate. The resulting rod-shaped "oxidation containers" apparently held together by disulfide bridges, are practically pure protein. They are soluble in dodecyl sulfate when reduced and they contain a set of about 30 different polypeptide chains. The four major ghost membrane proteins are not represented among the "oxidation proteins." Comparison of data obtained from digestion of ghosts with trypsin or particle-bound trypsin showed that most of the "oxidation proteins" appear to be located at the outer surface of the ghost membrane which is derived from the outer cell envelope membrane. One of the major ghost membrane proteins, II, is partially digested by trypsin, and it is shown that its trypsin sensitive part is also exposed only at the outer surface of the ghost membrane. Native cells could be oxidized only with low yields of "oxidation containers." However, cell envelopes prepared without detergents or chelating agents, as well as cells depleted of phospholipid or treated with sucrose-Triton X-100, are completely accessible to oxidation. In each case, the same set of proteins as that present in "oxidation containers" from ghosts was found to be covalently linked. Treatment of cells with trypsin caused the loss of about five "oxidation proteins" and a complete loss of oxidizability of the ghosts derived from these cells. It therefore appears that arrangement and localization of the "oxidation proteins" are not greatly different in cells and in ghosts, i.e., that these proteins are also situated asymmetrically at the outer cell envelope membrane.
E. coli cells treated with the bifunctional crosslinking reagents dimethyl malonimidate, succinimidate, adipimidate, suberimidate, and sebacinimidate served for the isolation of rod-shaped "ghosts." These ghosts proved to be crosslinked over their entire surface; i.e., a macromolecule (resistant to boiling 1% Na dodecyl sulfate) the size of the cell had been created. Also, ghosts could similarly be crosslinked. In both cases, the final "sacs" contained about 60-70% protein, and very little or no lipopolysaccharide. When ghosts from which phospholipid had been removed were crosslinked, the covalently closed ghosts were almost pure protein; 80-90% of their dry mass was accounted for by protein. Ammonolysis of the crosslinked material (whether stemming from crosslinked cells or ghosts) showed that the same four proteins (Na dodecyl sulfate gel bands) had been crosslinked that are found in normally prepared ghosts. These observations practically exclude the hypothesis that a fluid mosaic model of membrane structure can be applied to the outer membrane of the E. coli cell envelope; rather, extensive protein-protein interactions must exist over the whole surface of this membrane. These findings are consistent with the possibility that the ghost polypeptide chains are involved in the determination of cellular shape.
Studies were carried out with the current leading antimycotic agents, using identical test methods, to compare their activity in vitro and in animal in vivo experiments. In the broth dilution test, the minimum inhibitory concentrations against approximately 50 strains of the most important species of yeasts, dermatophytes and moulds were determined using different culture media. Efficacy against yeasts was examined in experimentally-induced candidosis in mice treated orally, and against dermatophytes in experimentally-induced trichophytia in guinea pigs receiving topical treatment. The results showed that the imidazole derivatives studied can be regarded as true broad-spectrum antimycotics, and clotrimazole, in particular, had a well-balanced overall effect. The significance of the experimental data with respect to therapeutic efficacy in man in various indications is discussed.