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Biomedical subjects

G Medoff

Publications and source records attributed to G Medoff.

At least 91 records · Page 5Linked to original sources
PubMed1981

Potentiation of anticancer agents by amphotericin B.

Amphotericin B (AmB) has been shown to potentiate the cytotoxicity of several different anticancer agents in AKR mice. The extent of potentiation, as assessed quantitatively by a spleen colony assay, varied from a factor of approximately 3 for 1,3-bis(2-chlorethyl)-1-nitrosourea (BCNU) to over 100 for a number of alkylating agents and to over 1,000 for 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. Most phase-specific agents showed little potentiation of cytotoxicity by AmB. A dose-response effect was noted with both BCNU and adriamycin, with increased potentiation being observed with increasing doses of the anticancer agents. The effect on increase in life-span was also studied and for most of the combinations it correlated with the potentiating effects disclosed by the spleen colony assay. Such a correlation was not found for AmB combined with either BCNU or vincristine.

Amphotericin B↗
PubMed1980

Application of differential spectra in the ultraviolet-visible region to study the formation of amphotericin B-sterol complexes.

The extent of complex formation between the polyene antibiotic, amphotericin B, and cholesterol or ergosterol was investigated and a method for a quantitative measurement of the complex formation was developed. The effect of experimental conditions on the magnitude of the amphotericin B-sterol interaction and on the selectivity of this interaction showed that there was only a narrow range of solvent composition in which the differential selectivity of amphotericin B towards these two sterols could be observed.

Amphotericin B↗
PubMed1980

Comparison of the ribonucleic acid polymerases from both phases of Histoplasma capsulatum.

The three ribonucleic acid (RNA) polymerases (ribonucleoside triphosphate RNA nucleotidyltransferases, EC 2.7.7.6) of the two phases (yeast and mycelial) of the dimorphic fungus Histoplasma capsulatum have been purified and characterized. The corresponding enzymes from the two phases differ in sensitivity to alpha-amanitin, ion and salt requirements, temperature sensitivity, and subunit structure. This is the first case in which such qualitative differences in RNA polymerases have been demonstrated in two growth states of the same organism.

Amanitins↗
PubMed1980

Effect of exogenous lipids and lipoproteins on the primary immune response in vitro.

Cholesterol and certain lipoproteins have regulatory effects on the primary immune responses of murine spleen cells in vitro. The plaque-forming cell (PFC) responses to sheep red blood cells of trinitrophenylated Brucella abortus were studied in complete, lipid-depleted or lipoprotein-reconstituted media. The requirement for exogenous low density lipoprotein (LDL) and its cholesterol moiety was established by comparison of the yield of PFC in cell cultures deprived of lipoproteins with that in cultures to which specific classes of lipoproteins were added. The spleen cells in complete medium yielded about 10-fold greater PFC responses than cells in lipoprotein-deficient medium. In lipoprotein-deficient media, human LDL completely reversed the decreased immune response, LDL lipids and free cholesterol partially reversed the deficit, the human high density lipoproteins and an apo B phospholipid complex were ineffective. In complete media, cholesterol at higher concentrations (100--200 microgram/ml) and LDL lipids partially inhibited the primary immune response. Exogenous cholesterol was required for the in vitro response to both thymus-dependent and thymus-independent antigens.

Animals↗
PubMed1980

Permeabilizing and hemolytic action of large and small polyene antibiotics on human erythrocytes.

The effects of large polyenes (heptaenes and the "degenerate heptaene" nystatin) on human erythrocytes were found to occur in three separate stages. Stage I was a reversible increase in cell membrane permeability to monovalent cations and occurred at low antibiotic concentrations. At intermediate antibiotic concentrations, an irreversible increase in cell membrane permeability to cations (stage II) occurred, which then led to swelling of cells and hemolysis (stage III). Hemolysis could be prevented by sucrose, mannitol, or melezitose, but stages I and II still occurred under these conditions. The effects of the small polyenes (pentaenes and a tetraene) occurred in only one stage. Changes in cell membrane permeability (stages I and II) were not noted before hemolysis (stage III) even in the presence of carbohydrate. Carbohydrates gave only weak, transient protection from the hemolytic action of small polyenes, probably because the membrane damage induced by these antibiotics was more extensive than that induced by the large polyenes. In the presence of sucrose, large polyenes were able to inhibit the hemolytic action of small polyenes, implying that both antibiotics have the same binding sites.

Anti-Bacterial Agents↗
PubMed1980

Influence of extracellular K+ or Mg2+ on the stages of the antifungal effects of amphotericin B and filipin.

The macrolide heptaene amphotericin B (AmB) induced concentration-dependent effects on Saccharomyces cerevisiae which were separable into two distinct stages. At low concentrations the drug inhibited the growth of the yeast and reversible changed cell permeability to Na+ and K+. At high levels it was lethal. The intracellular K+ concentration of cells with reversible damage (stage I) could be increased by addition of K+ to the medium, but cells irreversibly damaged (stage II) were not able to retain K+. The addition of K+ to the medium did not influence the growth-inhibitory or killing action of AmB. Addition of Mg2+ to cultures increased S. cerevisiae resistance to the killing effects of AmB. At low concentrations of AmB, growth inhibition was also decreased by extracellular Mg2+, but at higher concentration of AmB, growth inhibition was increased, probably because the prevention by Mg2+ of the lethal effect allowed expression of the inhibitory effect in a greater range. Simultaneous addition of K+ and Mg2+ markedly decreased both the inhibitory and lethal action of AmB at all concentrations. Filipin, a pentaene macrolide, had only lethal effects, which were unaffected when K+ was added to the medium but were diminished when medium was supplemented with Mg2+.

Amphotericin B↗
PubMed1980

Balanced growth and morphogenesis of Histoplasma capsulatum in a defined synthetic medium.

We have characterized balanced growth of yeast and hyphal cells of Histoplasma capsulatum and cells during transition from yeast to hyphae in a newly developed synthetic medium, R3B3. Homogeneous populations of yeast at 37 degrees C and hyphae at 25 degrees C grew in this medium with generation times of 10h and 19h, respectively. The growth rates were exponential, as demonstrated by the kinetics of net increase in dry weight. Identical rates of net increase were observed for ribonucleic acid (RNA) and protein, indicating conditions which approached steady state growth. In addition, this defined medium facilitated incorporation of radioactive precursors into RNA and protein and thus will allow for future detailed studies of macromolecular synthesis. When the incubation temperature of growing yeast cells was switched from 37 degrees C to 25 degrees C, the growth rate decreased as indicated in the generation time (19 h). Although the kinetic rates of RNA and protein synthesis also decreased, these rates were slightly faster relative to that observed for the increase in dry weight. During the later stage(s) of the yeast to hyphae transition a marked increase and subsequent decrease was observed for both RNA and protein. After this period of time, the synthesis of RNA and protein proceeded at the steady state rates usually observed in hyphal cultures.

Cell Count↗
PubMed1979

A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis.

We compared amphotericin B therapy for cryptococcal meningitis with a newer regimen containing both amphotericin B and flucytosine. In 50 patients with 51 courses of therapy adherent to the protocol, 27 courses were with amphotericin B and 24 with the combination. Even though the combination regimen was given for only six weeks and amphotericin B for 10 weeks, the combination cured or improved more patients (16 vs 11), produced fewer failures or relapses (three vs. 11), more rapid sterilization of the cerebrospinal fluid (P less than 0.001) and less nephrotoxicity (P less than 0.05) than did amphotericin B alone. The number of deaths was the same (five) with each regimen. Adverse reactions to flucytosine occurred in 11 of 34 patients but were not life threatening. We conclude that combined flucytosine-amphoericin B therapy is the regimen of choice in cryptococcal meningitis.

Adolescent↗
PubMed1979

Demonstration of antigenemia by radioimmunoassay in rabbits experimentally infected with Aspergillus.

Antigens were detected in the blood of rabbits infected with Aspergillus fumigatus by a solid-phase (tube) radioimmunoassay (RIA). The radiolabel for the assay was a polysaccharide-rich alkali extract (APAE) from the mycelia of A. fumigatus. Before this extract could be suitable labeled with 125I, it had to be conjugated with tyramine. Rabbits immunized with heat-killed mycelia had titers of antibody in serum of as high as 1:38,000 against this radiolabeled antigen. With unlabeled and unconjugated APAE as the standard antigen, the sensitivity of the RIA was 12 ng per test, or 500 ng/ml. Antigenemia was detectable by RIA three days after infection of rabbits with A. fumigatus. Blood cultures taken concomitantly were uniformly negative. These results indicate that antigenemia occurs in invasive aspergillus infection and in such cases can be detected by RIA. These observations may be important in the diagnosis of invasive aspergillus infections in humans.

Animals↗
PubMed1979

In vitro activity of HR 756, a new cephalosporin, against Neisseria gonorrhoeae.

The in vitro activity of HR 756 was compared with penicillin, cefamandole, cefoxitin, and tetracycline against Neisseria gonorrhoeae. A total of 192 randomly selected isolates (of which 23 had minimal inhibitory concentrations of >/=0.5 mug/ml for penicillin) and three beta-lactamase-producing isolates were tested. HR 756 was the most active antibiotic tested, with more than 90% of the isolates inhibited by 0.008 mug/ml and all inhibited by 0.25 mug/ml.

Cephalosporinase↗
PubMed1979

Classification of polyene antibiotics according to chemical structure and biological effects.

Fourteen polyene antibiotics and six of their semisynthetic derivatives were compared for their effects on potassium (K(+)) leakage and lethality or hemolysis of either Saccharomyces cerevisiae or mouse erythrocytes. These polyene antibiotics fell into two groups. Group I antibiotics caused K(+) leakage and cell death or hemolysis at the same concentrations of added polyene. In this group fungistatic and fungicidal levels were indistinguishable. Group I drugs included one triene (trienin); tetraenes (pimaricin and etruscomycin); pentaenes (filipin and chainin); one hexaene (dermostatin); and one polyene antibiotic with unknown chemical structure (lymphosarcin). Group II antibiotics caused considerable K(+) leakage at low concentrations and cell death or hemolysis at high concentrations. The fungistatic levels were clearly separable from fungicidal. This group included the heptaenes (amphotericin B, candicidin, aureofungin A and B, hamycin A and B), and five of their semisynthetic derivatives (amphotericin B methyl ester, N-acetyl-amphotericin B, hamycin A and B methyl esters, and N-acetyl-candicidin). Nystatin, classified as a tetraene, and its derivative, N-acetyl nystatin, also were in this group.

Animals↗
PubMed1979

Potentiation of anticancer agent cytotoxicity against sensitive and resistant AKR leukemia by amphotericin B1.

Amphotericin B was able to enhance the effects of actinomycin D (Act-D), adriamycin, and vincristine against AKR leukemia. AKR leukemia lines of increasing resistance to Act-D were obtained by passage in syngeneic mice treated with Act-D. The cells selected for Act-D resistance also eventually became cross-resistant to vincristine and Adriamycin, but resistance to these agents developed at a slower rate. Amphotericin B enhanced the effects of all these agents against the resistant cells, although the degree of enhancement varied among these antitumor agents and decreased as drug resistance increased in the late-passage leukemia lines.

Amphotericin B↗
PubMed1978

Comparison of the in vitro activities of HR756 with cephalothin, cefoxitin, and cefamandole.

The in vitro activity of HR756, a new semisynthetic cephalosporin, was compared with the activities of cephalothin, cefoxitin, and cefamandole against 1,535 isolates of gram-positive and gram-negative bacteria. HR756 was less active than cephalothin and cefamandole and twofold more active than cefoxitin against Staphylococcus. All four of the antibiotics were inactive against the enterococcus group of Streptococcus; however, HR756 was the most active antibiotic against the other isolates of Streptococcus. HR756 was also more active against isolates of Enterobacteriaceae, including 84 to 95% of the isolates resistant to one or more of the other three antibiotics. HR756, at a concentration of 12.5 mug/ml, inhibited 86, 75, and 100% of the isolates of Pseudomonas aeruginosa, other Pseudomonas species, and Acinetobacter, respectively. The minimal inhibitory concentrations and minimal bactericidal concentrations of HR756 were within one twofold dilution for 11 of 21 gram-positive cocci and 119 of 125 gram-negative bacilli tested.

Bacteria↗
PubMed1978

Cystine reductase in the dimorphic fungus Histoplasma capsulatum.

Organo-sulfur compounds favor the transition of mycelia of Histoplasma capsulatum to the yeast form (6, 8). Investigation of the role of cystine in the transition revealed that the two phases concentrated this amino acid at comparable rates and that mutants defective in the uptake of cystine were still able to undergo the transition normally. Uptake of cystine is therefore probably not a requirement for transition to or maintenance of the yeast phase. Both phases contained a reduced nicotinamide adenine dinucleotide phosphate-dependent glutathione reductase; but a reduced nicotinamide adenine dinucleotide-dependent cystine reductase was detectable only in the yeast phase. The cystine reductase appeared early in the transition of mycelium to yeast. Treatment of mycelia with p-chloromercuriphenylsulfonic acid, which prevented the transition to yeast, had no effect on cystine uptake but strongly inhibited the cystine reductase. These results suggest that cystine reductase may provide reduced sulfhydryl groups involved in the transition of mycelium to yeast.

4-Chloromercuribenzenesulfonate↗