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Biomedical subjects

R A Fromtling

Publications and source records attributed to R A Fromtling.

At least 37 records · Page 2Linked to original sources
PubMed1989

L-658,310, a new injectable cephalosporin. III. Experimental chemotherapeutics and pharmacokinetics in laboratory animals.

The therapeutic activity of L-658,310 was demonstrated in experimental bacteremias in normal, diabetic and neutropenic mice. Especially potent activity was shown against the usually difficult to control pathogens, Enterobacter cloacae and Pseudomonas aeruginosa, that were resistant to ceftazidime and/or gentamicin. Pharmacokinetic studies in mice showed a linear dose response in serum after the 20 and 50 mg/kg subcutaneous dose and urinary recoveries of administered dose of about 60% in 6 hours. Excretion was mainly by glomerular filtration. In a crossover design in rhesus monkeys, the pharmacokinetics of L-658,310 were similar to those of ceftazidime and suggest a moderately long half-life in serum of humans.

Animals↗
PubMed1989

Lack of cross-resistance between efrotomycin and antibacterial agents used in the therapy of human and animal infections.

Efrotomycin is an N-methylhydroxypyridone glycoside antibiotic with activity primarily against Gram-positive bacteria. It is intended for use as a feed additive for swine. Although efrotomycin is unrelated to any antibacterial drug used in human or veterinary medicine, the possibility of cross-resistance with other antibacterials is of concern. The minimum inhibitory concentrations (MICs) of efrotomycin were determined for a broad panel of bacterial isolates. In addition, the susceptibility of each isolate to 12-15 antibacterials was determined using a standardized disk susceptibility test. No evidence of cross-resistance between efrotomycin and any of the 12-15 antibacterial compounds was observed. When the MIC of efrotomycin for nine selected isolates was increased from 16- to greater than 100-fold by serial passage in subinhibitory concentrations of efrotomycin, no increased resistance to the 15 antibacterials was noted. Subinhibitory concentrations of efrotomycin had no effect on the conjugative transfer of antibacterial-resistance plasmids between K-12 strains of Escherichia coli. The data from this study suggest that if resistance to efrotomycin should occur, it is unlikely to result in the appearance of multiply-resistant bacterial populations.

Animals↗
PubMed1988

Cryptococcus neoformans: a central nervous system isolate from an AIDS patient that is rhinotropic in a normal mouse model.

A strain of Cryptococcus neoformans that was isolated from the cerebrospinal fluid of a human diagnosed as having acquired immunodeficiency syndrome (AIDS), and that produced cutaneous lesions in experimentally infected, normal mice is described. Although no unusual cutaneous manifestations were noted in the patient's records, this isolate of C. neoformans proved to be dermotropic when injected intravenously into CD-1 mice. The LD50 at 28 days post infection ranged from 3.6-7.5 X 10(5) cells per mouse, and in vitro growth rate studies demonstrated that this isolate grew well at 35 degrees C and at 37 degrees C, but did not grow at 40 degrees C and higher. This isolate was rhinotropic producing large granulomatous lesions in the nasal tissues. Other cutaneous tissues affected were the periocular tissues, ears, feet and tail, although the granulomas were nodular in structure and less necrotic than the nasal lesions. The brain, lungs, liver, kidneys and spleen also were culture positive for C. neoformans. Histopathologically, each affected tissue examined had large densities of yeast cells and a chronic, granulomatous host response. Animals surviving the infection appeared to develop a commensal-type relationship with the infective yeast. This is the first report of an isolate of C. neoformans from an AIDS patient that has caused cutaneous manifestations in an animal model. The model described in this report may be useful for elucidating pathogenic mechanisms of cryptococcosis, particularly cutaneous manifestations of the disease.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Renal pathology and spleen cell chemiluminescence of mice infected with a wild-type and a low-virulence mutant of Candida albicans.

Pathogenicity and virulence factors were studied for a wild-type strain of Candida albicans (MY 1044) and an auxotrophic, temperature-sensitive mutant strain (MY 1049) that was derived by ultraviolet irradiation. The mutant was a temperature-sensitive, serine auxotroph. Renal pathology and chemiluminescence of spleen cells from infected mice were assessed in an attempt to identify virulence factors. Renal damage was evident following intravenous infection with either strain, although the mutant appeared to be less invasive; MY 1044 produced characteristic miliary, subcapsular lesions, while the mutant (MY 1049) produced large granulomas. Spleen cells from each infected group were stimulated in vitro with either phytohemagglutinin, concanavalin A or opsonized yeast cells to measure the respiratory burst using a luminol-dependent chemiluminescence assay. The highest chemiluminescence responses correlated with severe renal damage (uremia) and not with yeast virulence. No differences in chemiluminescence were observed among spleen cells from mice infected with either strain when renal pathology was minimal.

Animals↗
PubMed1988

Overview of medically important antifungal azole derivatives.

Fungal infections are a major burden to the health and welfare of modern humans. They range from simply cosmetic, non-life-threatening skin infections to severe, systemic infections that may lead to significant debilitation or death. The selection of chemotherapeutic agents useful for the treatment of fungal infections is small. In this overview, a major chemical group with antifungal activity, the azole derivatives, is examined. Included are historical and state of the art information on the in vitro activity, experimental in vivo activity, mode of action, pharmacokinetics, clinical studies, and uses and adverse reactions of imidazoles currently marketed (clotrimazole, miconazole, econazole, ketoconazole, bifonazole, butoconazole, croconazole, fenticonazole, isoconazole, oxiconazole, sulconazole, and tioconazole) and under development (aliconazole and omoconazole), as well as triazoles currently marketed (terconazole) and under development (fluconazole, itraconazole, vibunazole, alteconazole, and ICI 195,739).

Animals↗
PubMed1988

L-656,575 (OCP-9-176): a novel oxacephem. In vitro activity against aerobic and anaerobic clinical bacterial isolates.

L-656,575 (OCP-9-176) is a novel oxacephem superior to ceftazidime in in vitro activity against clinical isolates of Enterobacter species, methicillin-susceptible Staphylococcus aureus and Staphylococcus epidermidis, and multiply-resistant Pseudomonas aeruginosa. Our results suggest that L-656,575 has a high affinity for penicillin binding proteins of Pseudomonas and may bind preferentially to PBP-3 in this organism. L-656,575 is active against beta-lactamase derepressed Enterobacteriaceae and ceftazidime-resistant P. aeruginosa.

Animals↗
PubMed1988

L-656,575 (OCP-9-176): a novel oxacephem. Pharmacokinetics and experimental chemotherapy.

L-656,575 is a new oxacephem that, based on studies in rhesus monkeys, is expected to have a moderately long half-life in humans. After administration of a 10-mg/kg dose by the intramuscular route to rhesus monkeys, peak serum concentrations of 32-54 micrograms/ml were seen at about 30 minutes, and the half-life was estimated to be 63 minutes. Urinary recovery of administered dose was greater than 94% in 6 hours. In mice given a 20-mg/kg dose by the subcutaneous route, a peak serum concentration of 22.9 microgram/ml was observed at 15 minutes after dosing, and the half-life in serum was about 18 minutes. Urinary recovery of the dose was 59% in 6 hours. In another study in mice, administration of probenecid did not extend the half-life of L-656,575, suggesting that the antibiotic is excreted primarily by glomerular filtration in this species. Binding to human plasma proteins was 30% at drug concentrations from 25-100 micrograms/ml. L-656,575 also was shown to be efficacious in experimental bacteremias due to Gram-positive and Gram-negative pathogens in mice, thus confirming the broad spectrum of activity demonstrated for L-656,575 in vitro.

Animals↗
PubMed1987

Effects of bifonazole, fluconazole, itraconazole, and terbinafine on the chemiluminescence response of immune cells.

The luminol-enhanced chemiluminescence (CL) assay was used to examine the effects of antifungal agents tested at concentrations above and below therapeutically achievable levels on the CL response of mouse spleen cells. Reduction in the CL response of phagocytic cells may be indicative of an inhibition of the cellular immune response. Concomitantly, an increase in the CL response of phagocytic cells may indicate an enhancement of the immune capacity of these cells. The effects of four antifungal agents, bifonazole, fluconazole (UK-49,858), itraconazole, and terbinafine were studied. Changes in the CL response were assessed in terms of peak intensity, time to peak intensity, and area under the intensity-time curve compared with appropriate diluent controls for each drug. Both bifonazole and itraconazole caused significant reduction in peak CL intensity only at the highest level assayed (20 mg/l). Fluconazole had no significant effect on the CL response of mouse spleen cells at levels up to 20 mg/l, inclusive. Although terbinafine had no significant effect on peak CL intensity, it did cause a significant decrease in time to peak response at levels above 5 mg/l. This decrease in time to peak response may be indicative of an enhancement in the immune capacity of the mouse spleen cells; the clinical significance of this observation remains to be determined.

Animals↗
PubMed1987

Candida tropicalis infection in normal, diabetic, and neutropenic mice.

Opportunistic infections caused by Candida tropicalis have been noted with increasing frequency in compromised patients. The pathogenicity of three isolates of C. tropicalis was studied in normal CD-1 mice, streptozotocin-induced diabetic mice, and cyclophosphamide-induced neutropenic mice. Lethal dose 50% endpoints and quantitative distribution of yeast cells in spleen, liver, and kidneys of mice infected intravenously were determined. The virulence of one yeast isolate was greater than that of the other two. The order of susceptibility to mortality and degree of organ colonization was neutropenic greater than diabetic greater than normal. Renal lesions resembling those associated with infection by C. albicans appeared by day 5 postinfection in diabetic and neutropenic mice. Greater numbers of C. tropicalis yeast cells were isolated from homogenates of the affected kidneys, suggesting that the kidney is a target organ for this fungus. This study demonstrates the increased susceptibility of compromised mice to C. tropicalis as compared with normal mice and verifies the ability of these yeasts to cause opportunistic disease.

Agranulocytosis↗
PubMed1986

Cryptococcus neoformans: comparisons of in vitro antifungal susceptibilities of serotypes AD and BC.

Thirty-nine isolates of Cryptococcus neoformans, nineteen serotype AD and twenty serotype BC, were assayed for susceptibility to eight antifungal agents using an in vitro agar dilution assay. Media employed were Kimmig agar and yeast nitrogen base supplemented with 10% glucose. The antifungal agents used were ketoconazole, amphotericin B, 5-fluorocytosine, nystatin, miconazole, BAY N 7133, ICI 153,066, and itraconazole. No clinically significant differences in vitro minimum inhibitory concentrations were detected between serotypes AD and BC against any of the compounds tested. An adverse medium effect was observed in two of the assays, but the outcome of the AD/BC comparison was not affected. This is the first report in which the in vitro antifungal susceptibilities of Cryptococcus neoformans serotypes are analyzed.

Amphotericin B↗
PubMed1986

An overview of macrophage-fungal interactions.

A review of the literature (148 references) on the interactions of fungi with polymorphonuclear cells, monocytes and macrophages is presented. The interactions of Aspergillus species, Coccidioides immitis, Blastomyces dermatitidis, Histoplasma capsulatum, Cryptococcus neoformans, Candida albicans, and Candida species with human and experimental animal derived immune cells are examined in this overview. An effort has been made to present the reader with a comprehensive list of references with the intent of encouraging additional reading and research in this important area.

Animals↗
PubMed1986

Influence of six antifungal agents on the chemiluminescence response of mouse spleen cells.

The luminol-enhanced chemiluminescence (CL) assay is a measure of the early events of phagocytosis, leukocyte activation, and immune cell interactions. Reduction in the CL response of immune cells may be indicative of an inhibition of the immune response. This study was undertaken to examine the effects of antifungal agents tested at concentrations above and below therapeutically achievable levels on the CL response of mouse spleen cells. The effects of six antifungal agents--amphotericin B, ketoconazole, miconazole, 5-fluorocytosine, Bay-n-7133, and ICI 153,066--were studied. Changes in the CL response were assessed in terms of peak intensity and area under the intensity-time curve compared with appropriate diluent controls for each drug. Only amphotericin B and ketoconazole caused statistically significant lowering of the peak intensity at levels that are therapeutically attainable (mean peak plasma levels of 2 to 4 and 3.5 to 16 micrograms/ml, respectively). Although amphotericin B and ketoconazole caused reduction in the CL response, removal of the unbound drug in the preparation by centrifugation, washing, and suspension of cells in fresh drug-free medium resulted in a return of CL activity equivalent to the activity observed in cells not exposed to these agents. These results suggest that amphotericin B and ketoconazole at therapeutic concentrations may cause a reduction in immune cell antimicrobial activity; the clinical significance of these observations remains to be determined.

Amphotericin B↗
PubMed1986

Design and analysis considerations in evaluating the chemiluminescence response of mouse spleen cells.

Chemiluminescence is the result of the respiratory burst generated by phagocytic cells after stimulation by antigen. The measurement of chemiluminescence represents a sensitive means for detecting antigenic stimulation and immune cell function. Although the kinetics of chemiluminescence reactions have been described, appropriate statistical methods for the evaluation of data from chemiluminescence assays have not been reported. Based on examination of data from several studies in which the chemiluminescence response of spleen cells was investigated after stimulation with the particulate antigen zymosan, recommendations are made for the design and statistical evaluation of such studies. Three parameters were used in assessing the chemiluminescence response; peak intensity of the emitted light, time to peak, and the area under the intensity-time curve. The data indicated that peak intensity alone provides an adequate characterization of the chemiluminescence response. Since percent change in response upon treatment is of interest, analysis on the log scale is appropriate, and the statistical procedure of choice in evaluating data of this type is a trend analysis. The need for a balanced allocation of treatments to avoid potential bias is demonstrated. The methods proposed are illustrated with data from two studies in which the effect of preincubation with low concentrations of ketoconazole, an antifungal agent, on the chemiluminescence response of BALB/cBY spleen cells was examined.

Analysis of Variance↗
PubMed1986

Evaluation of lymphocytes' influence in luminol-dependent chemiluminescence emission of mouse spleen cells.

The focus of this study was to elucidate the influence of lymphocytes on phagocytic cell-dependent chemiluminescence (CL). CL was induced by in vitro addition of mitogens, particulate substances and Keyhole Limpet Hemocyanin (KLH)-antigen. CL was measured in spleen cells of immunologically naive mice and in mice immunized with KLH. Mice immunized with KLH and Freund's adjuvant incomplete (FA) showed a lower CL-response than mice injected with FA only. No influence on CL-activity by lymphocytes derived from immunologically naive mice could be found. Adoptive transfer of T cells from KLH-sensitized donor mice did not influence CL-activity elicited with Zymosan in spleen cells derived from KLH-unsensitized recipient mice. Preincubation of spleen cells with supernatants of T cell cultures or with T cell growth factor (TCGF) stimulated with KLH or Con A could not trigger CL-reactivity. Therefore, the lower CL-response of spleen cells derived from KLH-sensitized mice appears to be not a consequence of a suppressive cellular or lymphokine effect, but is due to direct influence of KLH on accessory cells themselves.

Animals↗