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Biomedical subjects

A M Sugar

Publications and source records attributed to A M Sugar.

At least 91 records · Page 5Linked to original sources
PubMed1985

Characteristics of the pulmonary cellular immune response to two strains of Blastomyces dermatitidis in the mouse.

In order to assess the cellular responses in the lung in murine pulmonary blastomycosis, serial lung lavages were performed in normal BALB/cByJ mice that had received an intranasal inoculation with 1 of 2 strains of Blastomyces dermatitidis of opposite virulence. The virulent strain, ATCC 26199, induced an increasing number of neutrophils recovered from the lung lavages. An early peak of incoming neutrophils was seen at 1 to 2 days, followed by a more rapid accumulation of intraalveolar neutrophils, until by the ninth day after infection, 80% of the cells recovered from the mice were neutrophils. In contrast, the avirulent strain, ATCC 26197, induced the same degree (20%) of neutrophil influx on Days 1 and 2. Thereafter, the percentage of neutrophils consistently declined, so that by Day 6 after inoculation, the differential counts were normal. The total number of cells recovered from the mice challenged with the virulent strain did not increase significantly until Day 4; then the total number of cells consistently increased until the experiment was terminated on Day 14. The total number of cells obtained from the mice challenged with the avirulent organism never exceeded the normal range. To assess the effects of nonviable inert particles, mice were given Sephadex G-25 beads by the intranasal route, and the total number of cells recovered from the lung lavage fluid and the differential counts were determined. The peak neutrophil influx occurred 6 h after aspiration of the beads, compared with 24 to 48 h with the fungi.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Ketoconazole-induced increase in estradiol-testosterone ratio. Probable explanation for gynecomastia.

Ketoconazole, an antifungal drug, causes gynecomastia in some patients. It also inhibits androgen and glucocorticoid synthesis. In four volunteer male subjects, 600-mg doses of ketoconazole depressed serum testosterone concentrations markedly, but serum estradiol to a much lesser degree. The bound and free percentages of both hormones were not significantly altered. The net result was a significant elevation of the estradiol-testosterone ratio, expressed as either total circulating hormone or free hormone. In five male patients receiving long-term high-dose ketoconazole therapy, the testosterone concentrations fell, but the effect on estradiol was variable. In these patients the estradiol-testosterone ratio was persistently increased. Since gynecomastia appears to be the result of an elevated estradiol-testosterone ratio, the selective hormonal effect demonstrated may explain the side effect of gynecomastia after ketoconazole therapy.

Estradiol↗
PubMed1984

Immunological activation of polymorphonuclear neutrophils for fungal killing: studies with murine cells and blastomyces dermatitidis in vitro.

The interaction of elicited murine polymorphonuclear neutrophils (PMN) and the thermally dimorphic fungal pathogen Blastomyces dermatitidis in vitro was studied. The PMN elicited intraperitoneally with thioglycollate, in normal mice or mice immune to B dermatitidis, failed to reduce colony forming units (CFU) of B dermatitidis in the inoculum in a 4-hr in vitro assay, even in the presence of 10% fresh immune serum. In contrast, PMN elicited intraperitoneally in immune mice by injection of nonviable B dermatitidis cells significantly reduced inoculum CFU (60 +/- 5%) under the same conditions. Furthermore, nonviable B dermatitidis intraperitoneally (i.p.) in normal mice or nonviable Candida albicans i.p. in immune mice failed to elicit peritoneal exudate cells that reduced inoculum CFU in this system. These results support the concept that PMN, elicited in a site by means of an immunological reaction, acquired enhanced microbicidal activity. The fungicidal activity of immunologically elicited PMN was shown to be most effective at high effector to target cell ratios (1,000:1), maximal within 2 hr of coculture, and significantly enhanced in the presence of fresh immune serum compared to heat-inactivated immune serum, normal mouse serum, or fetal bovine serum. Such PMN also had significantly enhanced fungicidal activity against C albicans compared to normal PMN. Fungicidal activity was abrogated in the presence of catalase, implicating hydrogen peroxide generation as the killing mechanism in the activated cells.

Animals↗
PubMed1984

The iron-hydrogen peroxide-iodide system is fungicidal: activity against the yeast phase of Blastomyces dermatitidis.

A series of experiments show the potency of a newly described microbicidal system, involving iron, H2O2, and halide, in killing a fungus (Blastomyces dermatitidis). B dermatitidis has previously been shown susceptible to the myeloperoxidase-H2O2-halide system. The present studies show killing of either of two strains in 1 hour if Fe++ at 5 X 10(-5)M, H2O2 at 5 X 10(-5)M and Kl at 5 X 10(-4)M are all present (P less than 0.001). EDTA, a Fe++ chelator, abrogates killing. The mechanism presumably utilizes hydroxyl radical, since an inhibitor, ethanol, also neutralizes the system. The bactericidal and fungicidal system is of great potential importance in vivo.

Antifungal Agents↗
PubMed1984

Toxic effect of products of oxidative metabolism on the yeast form of Paracoccidioides brasiliensis.

The effectiveness of toxic oxygen metabolites in killing the yeast form of Paracoccidioides brasiliensis (the form that occurs in host tissues) was studied with a fluorescence method in vitro. The two isolates studied were similar in susceptibility and H2O2 alone was lethal with an LD50 of 15-25 mM. The addition of halide (5 X 10(-4) M) augmented the lethality of H2O2 and in that setting H2O2 was c.90% lethal at 5 X 10(-5) M. Killing was most effective in the presence of peroxidase, when only 5 X 10(-6) M H2O2 (a concentration attainable in vivo by phagocytes) was required for a 95% kill. Kinetic studies revealed that toxic concentrations of H2O2 alone or of the H2O2-halide-peroxidase (PPH) system produced significant killing in 1 min; killing was maximal in 15 min. The PPH system was the more rapid in action. The dependence of the PPH killing system on H2O2 was demonstrated by an absence of killing in the presence of catalase. The susceptibility of P. brasiliensis to H2O2 and the PPH system appeared different in some respects from that noted for other dimorphic fungal pathogens. These studies suggest that toxic oxygen metabolites are important in host defence against P. brasiliensis.

Catalase↗
PubMed1984

Paracoccidioidomycosis in the immunosuppressed host: report of a case and review of the literature.

A case of reactivated paracoccidioidomycosis in an immunosuppressed host is described, the first association of this disease with renal transplantation. His presentation and clinical course was similar to the general experience with this mycosis. his response to ketoconazole was delayed when compared with that in non-immunosuppressed patients. Ketoconazole produced a dramatic resolution of all symptoms within 7 months. Serial determinations of paracoccidioides complement fixing antibodies showed falling titers, accurately reflecting his clinical status. Comparisons are made with other endemic mycoses in immunosuppressed patients. More cases of paracoccidioidomycosis in immunosuppressed patients can be expected to occur as immunosuppressive therapy becomes more common in areas endemic for Paracoccidioides brasiliensis, and with current trends in migration and travel.

Complement Fixation Tests↗
PubMed1983

Experience with ketoconazole in three major manifestations of progressive coccidioidomycosis.

Forty-seven courses of oral ketoconazole therapy administered to 46 patients with progressive coccidioidomycosis were evaluated. Responses, of varying degrees evaluated by a point system, occurred in 81, 94, and 91 percent of courses evaluated for skeletal, chronic pulmonary, and cutaneous disease, respectively. Presumed side effects occurred in 26 percent of courses and were generally minor and reversible. Relapse occurred in 33, 33, and 11 percent of evaluable responding patients with skeletal, chronic pulmonary and cutaneous disease, respectively. From this experience, ketoconazole appears to be an important advance in the therapy of chronic coccidioidomycosis. Whether cure is possible will require further study and follow-up.

Adult↗
PubMed1983

A cephalosporin active in vivo against Nocardia: efficacy of cefotaxime in murine model of acute pulmonary nocardiosis.

Cefotaxime, a cephalosporin drug, has been shown to be active in vitro against nocardiae, a finding confirmed in this study. Pharmacokinetic studies were performed in mice to define regimens which provided peak serum levels comparable to that achieved in man with currently used doses. These regimens were shown to be effective with only short courses of therapy of rapidly progressive and highly lethal N. asteroides infection, produced by pulmonary challenge of mice. This suggests the possible utility of this drug in human nocardiosis.

Acute Disease↗
PubMed1983

Activation of peritoneal macrophages by concanavalin A or Mycobacterium bovis BCG for fungicidal activity against Blastomyces dermatitidis and effect of specific antibody and complement.

With a new short-term assay, where the reduction of CFUs in the inoculum could be measured, we investigated the killing of the dimorphic fungal pathogen Blastomyces dermatitidis in its yeast phase by murine peritoneal macrophages. Peritoneal macrophages from concanavalin A- or Mycobacterium bovis BCG-treated mice, but not resident or thioglycolate-elicited macrophages, significantly reduced the CFUs of B. dermatitidis in the inoculum. The activation of peritoneal macrophages for fungicidal activity by concanavalin A treatment was shown to be dose dependent and transient, i.e., absent after 72 h. These results indicate that it is possible for murine peritoneal macrophages to kill B. dermatitidis in vitro. The addition of specific antibody or complement or both did not enhance the killing of B. dermatitidis by these nonspecifically activated macrophages.

Animals↗
PubMed1983

Susceptibility of Blastomyces dermatitidis strains to products of oxidative metabolism.

Three strains of Blastomyces dermatitidis which differ in their virulence for mice were exposed in their yeast form to various components of the peroxidase-hydrogen peroxide-halide system. Susceptibility to H2O2 alone correlated with virulence, with the most virulent strain (ATCC 26199) least susceptible (50% lethal dose, greater than 50 mM) and an avirulent strain (ATCC 26197) most susceptible (50% lethal dose less than 3.3 mM). A strain of intermediate virulence (ATCC 26198) was of intermediate susceptibility (50% lethal dose, 11.5 mM). The addition of a nontoxic concentration of KI (5 X 10(-4) M) did not increase H2O2 toxicity. However, the addition of either myeloperoxidase or horseradish peroxidase and KI markedly decreased the amount of H2O2 required to kill the organisms, with 100 +/- 0% of all strains killed at 5 X 10(-5) M H2O2 and 97 +/- 4, 100 +/- 0, and 94 +/- 8% of ATCC 26199, ATCC 26198, and ATCC 26197 killed, respectively, at 5 X 10(-6) M H2O2. Kinetic studies with H2O2 alone revealed a delayed onset of killing, but virtually 100% of organisms were killed by 120 min of exposure in all strains. By comparison, the peroxidase-hydrogen peroxide-halide system was 100% lethal for all strains at 1 min. The relatively high concentrations of H2O2 required to kill the yeast phase of B. dermatitidis suggest that H2O2 alone does not account for host resistance to the organism. However, the rapidly lethal effect of the peroxidase-hydrogen peroxide-halide system at physiologically relevant concentrations suggests that this may be one mechanism of host defense to B. dermatitidis.

Animals↗
PubMed1983

Murine pulmonary macrophages: evaluation of lung lavage fluids, miniaturized monolayers, and candidacidal activity.

Optimal yields of pulmonary macrophages (PuM) from lavage of normal murine lungs have been obtained by the study of several different lung lavage fluids. Approximately 1 X 10(6) PuM can be consistently recovered from mice weighing 20 to 30 g, using 15 ml of phosphate buffered saline with 0.1% EDTA, with or without 10% fetal calf serum at 37 degrees C. Use of Terasaki tray wells for monolayer formation has allowed a relatively small number of cells (75,000) to be used to prepare multiple replicate wells from each mouse. Simultaneous functional comparisons with other cell types, e.g., peritoneal macrophages (PeM) were performed using this practical and economical system. Data on the phagocytosis and killing of Candida albicans by PuM and PeM are presented as evidence of the utility of this miniaturized system.

Animals↗
PubMed1980

Possible thiabendazole-induced theophylline toxicity.

Strongyloidiasis in immunosuppressed patients often requires prolonged administration of the antihelminthic, thiabendazole. The case described herein represents the first report of theophylline toxicity induced by concurrent administration of thiabendazole. Preliminary studies suggest that interference with theophylline clearance by thiabendazole may be the mechanism involved in this drug interaction.

Aged↗
PubMed1979

New rapid assay for nafcillin in serum by spectrofluorometry.

A new, rapid method for measuring serum levels of nafcillin by spectrofluorometry is described. The method involves extraction of 2 ml of acidified serum with n-butyl chloride, subjecting the organic solvent layer to excitation at 340 nm, and measuring the relative intensity of emission fluorescence at 380 nm. An excellent linear correlation exists between serum levels of nafcillin and the relative intensity in a drug concentration range of 0.25 to 150 mug/ml. The results obtained by this spectrofluorometric technique are in complete accord with those obtained by the conventional microbiological assay using Staphylococcus aureus ATCC 6538P. The method is not interfered with by elevated levels of endogenous metabolic products or the presence of other drugs, including a number of antimicrobial agents. The assay is interfered with, however, by the presence of salicylates, for which appropriate correction can easily be made. A salicylate assay employing a spectrofluorometric technique is also described.

Biological Assay↗
PubMed1979

Rapid assay for determination of trimethoprim and sulfamethoxazole levels in serum by spectrofluorometry.

A rapid spectrofluorometric method for determining the levels of both trimethoprim and sulfamethoxazole from the same specimen of serum is described. The method involves stepwise extraction of the specimen first with chloroform at an alkaline pH (pH 9.0) for trimethoprim followed by n-butyl chloride at an acidic pH (pH 2.0) for sulfamethoxazole. To quantitate trimethoprim, the chloroform layer was subjected to fluorometry by exciting the specimen at 295 nm and measuring the relative intensity at 330 nm. To determine sulfamethoxazole levels, the n-butyl chloride layer was subjected to fluorometry by exciting the specimen at 285 nm and measuring the relative intensity at 330 nm. Relative intensities were linear (r greater than 0.99) over the concentration ranges of 0.5 to 40 microgram/ml for trimethoprim and 1 to 400 microgram/ml for sulfamethoxazole. Values obtained by this spectrofluorometric procedure were in excellent agreement with those obtained by a conventional fluorometric assay for trimethoprim and a colorimetric assay for sulfamethoxazole. Elevated levels of endogenous metabolic products and numerous other drugs, including a number of antimicrobial agents, did not interfere with the method. Although salicylates interfere with the determination of sulfamethoxazole, an appropriate correction can be made. This method can also be used to determine the drug levels in cerebrospinal fluid.

Humans↗