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Biomedical subjects

F A Andrews

Publications and source records attributed to F A Andrews.

At least 19 recordsLinked to original sources
PubMed1981

Liquid chromatographic assay of ketoconazole.

A reverse-phase, high-pressure liquid chromatographic method for the rapid and quantitative determination of ketoconazole has been developed. Drug levels from 0.5 to 10 microgram/ml can be determined in either yeast nitrogen base medium or human serum by using an octadecylsilane column. A retention time of 4.9 +/- 0.1 min resulted when the drug was eluted from a column with 75% methanol-25% 0.02 M (pH 7.5) phosphate buffer at a flow rate of 2 ml/min. Optimum sensitivity was obtained at a wavelength of 231 nm.

Antifungal Agents↗
PubMed1981

Combined action of amphotericin B and 5-fluorocytosine on pathogenic yeasts susceptible to either drug alone.

Amphotericin B (AMB)-5-fluorocytosine (5-FC) synergism has generally been observed in yeasts displaying 5-FC resistance. The present study was designed to assess activity of these drugs on yeasts showing susceptibility to 5-FC as well as AMB. Selected strains were incubated in a synthetic liquid medium with the test agents and viability or 14C-5-FC uptake was determined. Combinations of AMB and 5-FC continued to be inhibitory during the period that cultures treated with either drug alone were recovering from transient inhibition. In this sense, AMB + 5-FC exerted greater antifungal activity than either drug alone. However, combined activity did not involve AMB stimulation of 5-FC uptake by the organism. Results were indicative of sequential drug action.

Amphotericin B↗
PubMed1978

Synergistic action of amphotericin B and antioxidants against certain opportunistic yeast pathogens.

Results of earlier turbidimetric growth experiments showed that certain antioxidants prolonged the antifungal activity of amphotericin B (AB) against Candida albicans, presumably by retarding autoxidative destruction of the drug. Viability studies were designed to examine this in more detail. Subinhibitory concentrations of either butylated hydroxyanisole, n-propyl gallate, or nordihydroguaiaretic acid in combination with fungistatic levels of AB exerted synergistic fungicidal activity against two strains of C. albicans and one of C. parapsilosis. Although synergism was not seen in tests with a strain of Torulopsis glabrata, antioxidants prolonged the inhibitory action of AB against this organism. On the basis of these findings and other considerations that are discussed, it is suggested that stabilization of AB and the ability to act synergistically with AB represent two distinctly different effects of the antioxidants.

Amphotericin B↗
PubMed1977

Influence of antioxidants on the bioactivity of amphotericin B.

Four antioxidants, propyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, and d-alpha-tocopherol acid succinate were found to stabilize amphotericin B and to prolong its antifungal activity against Candida albicans. Although each of the antioxidants was effective in this respect, propyl gallate and butylated hydroxyanisole were better than butylated hydroxytoluene and d-alpha-tocopherol acid succinate. None of the antioxidants alone adversely affected normal cell growth. It is suggested that amphotericin B instability is due, at least in part, to lability of the carbon-carbon double bonds of the polyene moiety toward autoxidation. By protecting the drug molecule with an antioxidant, it is possible to significantly lower the quantity of AB necessary to obtain particular antifungal effects.

Amphotericin B↗
PubMed1976

Role of ionic strength in salt antagonism of aminoglycoside action on Escherichia coli and Pseudomonas aeruginosa.

Studies were designed to determine whether ionic strength (mu) is a significant factor in salt inhibition of aminoglycoside action against Escherichia coli and Pseudomonas aeruginosa. In both nutrient broth (a low mu medium) and Mueller-Hinton broth (a relatively high mu medium), protection of E. coli from dihydrostreptomycin or gentamicin action by MgCl2, NaCl, or Na2SO4 was attributed to ionic strength alone. The percentage of protection increased with ionic strength and was independent of the particular salt used. Antagonism of aminoglycoside action against P. aeruginosa appeared to involve both a specific, divalent caption-dependent mechanism, revealed in Mueller-Hinton broth, and a nonspecific, ionic strength effect, elicited by sodium salts in nutrient broth. With media of relatively low salt content, variation in ionic strength itself over a range of mu of 0.02-0.14 significantly influences the effectiveness of aminoglycoside antibiotics against E. coli and P. aeruginosa.

Aminoglycosides↗
PubMed1976

Inhibition of dihydrostreptomycin binding to Mycobacterium smegmatis by monovalent and divalent cation salts.

To better understand salt antagonism of dihydrostreptomycin (DSM) action on Mycobacterium smegmatis, the effects of monovalent and divalent cation salts on drug uptake were studied in relation to the lethal activity of DSM. In Sauton liquid medium NaCl, MgCl(2), and SrCl(2) inhibited the initial instantaneous binding of [(3)H]DSM to the organism and suppressed secondary uptake. These data correlated well with the capacity of each salt to prevent the lethal activity of DSM. It was concluded that monovalent and divalent cation salt antagonism of DSM action on M. smegmatis involves nonspecific interference with drug uptake.

Chlorides↗
PubMed1975

Inhibition of dihydrostreptomycin action on Mycobacterium smegmatis by monovalent and divalent cation salts.

We have examined and compared the effects of monovalent and divalent cation salts on dihydrostreptomycin (DSM) action against Mycobacterium smegmatis. The Sauton synthetic liquid medium used was supplemented with test salts on the basis of ionic strength (mu). Turbidimetric growth experiments showed that 0.02 M MgSO(4) (mu = 0.08) prevented growth inhibition by 0.1 mug of dihydrostreptomycin per ml, but 0.02 M NaCl (mu = 0.02) did not. However, at molarities equivalent to mu = 0.08, four monovalent cation salts, including NaCl, Na(2)SO(4), NH(4)Cl, and (NH(4))(2)SO(4), all prevented inhibition by dihydrostreptomycin. When magnesium and sodium salts were compared at mu = 0.02, 0.04, and 0.05, two distinct growth protective patterns were seen. These data were indicative of two different mechanisms of dihydrostreptomycin antagnosim by salts; the first being divalent cation and concentration dependent, and the second being nonspecific and ionic strength dependent. Viability studies supported the existence of two mechanisms.

Cations, Divalent↗
PubMed1974

Chemical characterization of ethambutol binding to Mycobacterium smegmatis.

Recent studies showed that critical binding of ethambutol to Mycobacterium smegmatis was both inhibited and reversed by ions. This apparent ion-susceptible characteristic suggested that ethambutol is held at critical sites by electrostatic bonds. Dissociation constant, pH, and ionic strength studies were designed to further characterize ethambutol binding. M. smegmatis was grown in Sauton synthetic liquid medium (pH 7.4) under aerated conditions at 37 C. The pH or ionic strength of the medium was modified to meet the needs of particular experiments. Titration data revealed that ethambutol dihydrochloride has two apparent dissociation constants (pKa(1) = 6.35, pKa(2) = 9.35). Uptake experiments, in which pH was varied, showed that dihydrochloride and free base ethambutol were bound to a greater extent than the monohydrochloride. However, dihydrochloride and free base binding were not related to biological activity. Ethambutol exerted its maximal growth inhibitory effect at pH values near neutrality, where it exists primarily as the monohydrochloride and showed minimal binding. The increased ethambutol binding observed at pH 7.4 in media of lowered ionic strength was consistent with growth studies showing a reduction in the minimal inhibitory growth concentration in such media. However, nonspecific as well as critical binding was enhanced at low ionic strength. We conclude that binding of ethambutol by M. smegmatis involves a heterogeneous group of drug binding sites, only one of which is directly related to biological activity. Although nothing is known about the ethambutol target site itself, critical binding of the drug seems to require the single positively charged monohydrochloride form. Both hydrogen bonds and ionic linkages are probably involved.

Carbon Radioisotopes↗
PubMed1973

Nonspecific ionic inhibition of ethambutol binding by Mycobacterium smegmatis.

Magnesium sulfate and spermidine were tested for their effects on binding of (14)C-ethambutol by Mycobacterium smegmatis. Concentrations were used that protected the organism from ethambutol inhibition. Sodium salts were examined as possible ethambutol antagonists to test the previously reported specificity of the divalent cation salt effect. Consistent with growth-protection experiments, 20 mM MgSO(4) or 2.0 mM spermidine prevented and reversed (14)C binding by cells shaken with 0.2 mug of (14)C-ethambutol per ml of Sauton medium at 37 C. Sodium salts were not effective ethambutol antagonists when tested at 20 mM, but at concentrations equivalent in ionic strength (mu) to that provided by 20 mM MgSO(4) they were effective. Thus, 20 mM MgSO(4), 80 mM NaCl, or 27 mM Na(2)SO(4) (mu = 0.08) all gave similar results in growth protection and binding experiments, suggesting that MgSO(4) antagonism is a nonspecific ionic effect. Because spermidine (mu </= 0.012) antagonized ethambutol at an ionic strength substantially less than that required for the metal salts, its effect may hinge on structural similarity to ethambutol rather than its cationic character. Drug and polyamine may compete for one site or a heterogeneous group of binding sites involving adsorption, transport, and intracellular target reactions. Until we know at which of these levels spermidine antagonizes ethambutol binding, the relationship between polyamines and ethambutol action will remain obscure. However, these studies have weakened the earlier argument for a divalent cation-requiring system as a specific ethambutol target site.

Carbon Radioisotopes↗