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Biomedical subjects

C E Swenson

Publications and source records attributed to C E Swenson.

At least 19 recordsLinked to original sources
PubMed2000

A pharmacokinetic study of amphotericin B lipid complex injection (Abelcet) in patients with definite or probable systemic fungal infections.

This study describes a pharmacokinetic evaluation of amphotericin B (AMB) lipid complex injection (ABLC or Abelcet) in 17 patients with systemic fungal infection administered 5 mg/kg of body weight/day by infusion for 10 to 17 days. The results showed that AMB exhibited multiexponential disposition with high clearance, large volume of distribution at steady state, and long apparent elimination half-life but no evidence of accumulation in the blood after multiple daily doses. The results confirm previous observations and further reinforce the suggestion that ABLC may exist as a depot in the tissues from which free AMB is slowly released to limit exposure.

Adult↗
PubMed1999

ABELCET treatment.

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Amphotericin B↗
PubMed1998

In vitro and in vivo antifungal activity of amphotericin B lipid complex: are phospholipases important?

Amphotericin B lipid complex for injection (ABLC) is a suspension of amphotericin B complexed with the lipids L-alpha-dimyristoylphosphatidylcholine (DMPC) and L-alpha-dimyristoylphosphatidylglycerol. ABLC is less toxic than amphotericin B deoxycholate (AmB-d), while it maintains the antifungal activity of AmB-d. Active amphotericin B can be released from ABLC by exogenously added (snake venom, bacteria, or Candida-derived) phospholipases or by phospholipases derived from activated mammalian vascular tissue (rat arteries). Such extracellular phospholipases are capable of hydrolyzing the major lipid in ABLC. Mutants of C. albicans that were resistant to ABLC but not AmB-d in vitro were deficient in extracellular phospholipase activity, as measured on egg yolk agar or as measured by their ability to hydrolyze DMPC in ABLC. ABLC was nevertheless effective in the treatment of experimental murine infections produced by these mutants. Isolates of Aspergillus species, apparently resistant to ABLC in vitro (but susceptible to AmB-d), were also susceptible to ABLC in vivo. We suggest that routine in vitro susceptibility tests with ABLC itself as the test material may not accurately predict the in vivo activity of ABLC and that the enhanced therapeutic index of ABLC relative to that of AmB-d in vivo may be due, in part, to the selective release of active amphotericin B from the complex at sites of fungal infection through the action of fungal or host cell-derived phospholipases.

Amphotericin B↗
PubMed1997

Pharmacokinetic profile of ABELCET (amphotericin B lipid complex injection): combined experience from phase I and phase II studies.

Amphotericin B (AmB) has been the most effective systemic antifungal agent, but its use is limited by the dose-limiting toxicity of the conventional micellar dispersion formulation (Fungizone). New formulations with better and improved safety profiles are being developed and include ABELCET (formerly ABLC), but their dispositions have not been well characterized; hence, the reason for their improved profiles remains unclear. This report details the pharmacokinetics of ABELCET examined in various pharmacokinetic and efficacy studies by using whole-blood measurements of AmB concentration performed by high-pressure liquid chromatography. The data indicated that the disposition of AmB after administration of ABELCET is different from that after administration of Fungizone, with a faster clearance and a larger volume of distribution. It exhibits complex and nonlinear pharmacokinetics with wide interindividual variability, extensive distribution, and low clearance. The pharmacokinetics were unusual. Clearance and volume of distribution were increased with dose, peak and trough concentrations after multiple dosings increased less than proportionately with dose, steady state appeared to have been attained in 2 to 3 days, despite an estimated half-life of up to 5 days, and there was no evidence of significant accumulation in the blood. The data are internally consistent, even though they were gathered under different conditions and circumstances. The pharmacokinetics of ABELCET suggest that lower concentrations in blood due to higher clearance and greater distribution may be responsible for its improved toxicity profile compared to those of conventional formulations.

Amphotericin B↗
PubMed1997

Behavior of amphotericin B lipid complex in plasma in vitro and in the circulation of rats.

Amphotericin B lipid complex (ABLC) shows reduced toxicity relative to that of amphotericin B deoxycholate (AmB-d) while maintaining antifungal activity. Rat blood or plasma was spiked with ABLC in vitro. Released amphotericin B was separated from the parent material by centrifugation. At early times (0 to 15 min) most (approximately 90%) of the amphotericin B was complexed. The amount of released amphotericin B increased gradually in a time- and temperature-dependent fashion. The released amphotericin B was associated with plasma lipoprotein and nonlipoprotein proteins. The area under the concentration-time curve from 0 to 24 h for total amphotericin B in whole blood of rats given a single intravenous bolus dose of 1 mg of ABLC per kg of body weight was fourfold lower than that in rats given 1 mg of AmB-d per kg. The complexed amphotericin B was rapidly removed from the circulation and was distributed to the tissues in these rats. Other rats were treated intravenously with ABLC (10 mg/kg/day) or AmB-d (0.5 mg/kg/day) daily for 15 days. Blood was collected at 15 and 180 min after administration of the last dose. The total levels of amphotericin B in the blood of the group given ABLC were about three to five times those in the group given AmB-d, and the concentration of released, protein-bound amphotericin B in the plasma of the group given ABLC was about one to two times that observed for the group given AmB-d, despite the 20-fold difference in dose. The relative protein distribution of amphotericin B in plasma was similar after ABLC or AmB-d administration under these steady-state conditions in vivo. The rapid uptake of complexed amphotericin B by tissues and the very low levels of circulating protein-bound amphotericin B in plasma after the administration of ABLC may explain, in part, the reduced toxicity and enhanced therapeutic index of this preparation.

Amphotericin B↗
PubMed1996

Use of an amphotericin B lipid complex for treatment of blastomycosis in dogs.

OBJECTIVE: To evaluate efficacy and nephrotoxicity of amphotericin B lipid complex used for treatment of dogs with naturally developing blastomycosis. DESIGN: Prospective clinical trial. ANIMALS: 11 dogs with blastomycosis. PROCEDURE: All dogs were treated with an amphotericin B lipid complex. Two dogs received a cumulative dose of 8 mg/kg of body weight, 1 received a cumulative dose of 10 mg/kg, and 8 received a cumulative dose of 12 mg/kg. RESULTS: The 2 dogs that received a cumulative dose of 8 mg/kg and 1 of the dogs that received a cumulative dose of 12 mg/kg had a relapse of blastomycosis within 30 days after treatment. Seven of the remaining 8 dogs were clinically free of blastomycosis 6 months after treatment. One dog died of an unrelated cause 5.5 months after treatment, but did not have clinical signs of blastomycosis at the time of death. There were not any adverse clinical effects attributable to drug administration in any of the dogs in this study, and none of the dogs developed clinical signs of renal disease or failure. CLINICAL IMPLICATIONS: Amphotericin B lipid complex was a safe and effective treatment for blastomycosis in these dogs.

Amphotericin B↗
PubMed1993

Liposome-encapsulated gentamicin treatment of Mycobacterium avium-Mycobacterium intracellulare complex bacteremia in AIDS patients.

TLC G-65, a liposome-encapsulated gentamicin, was given intravenously twice weekly for 4 weeks to AIDS patients with Mycobacterium avium-M. intracellulare complex (MAC) bacteremia at 1.7 mg of gentamicin per kg of body weight per infusion (4 patients), 3.4 mg/kg (10 patients), and 5.1 mg/kg (7 patients). MAC colony counts in blood fell by 75% or more in all three groups (P < 0.005). Drug resistance did not emerge during the study period. Transient renal insufficiency developed in one patient; no other adverse effects were detected. Liposome-encapsulated gentamicin is a potential therapy for MAC infections in AIDS patients.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Amphotericin B-phospholipid interactions responsible for reduced mammalian cell toxicity.

When interacting with phospholipid in an aqueous environment, amphotericin B forms unusual structures of markedly reduced toxicity (Janoff et al. (1988) Proc. Natl. Acad. Sci. USA 85, 6122-6126). These structures, which appear ribbon-like by freeze-fracture electron microscopy (EM), are found exclusively at amphotericin B to lipid mole ratios of 1:3 to 1:1. At lower mole ratios they occur in combination with liposomes. Circular dichroism (CD) spectra revealed two distinct modes of lipid-amphotericin B interaction, one for liposomes and one for the ribbon-like structures. In isolated liposomes, amphotericin B which comprised 3-4 mole percent of the bulk lipid was monomeric and exhibited a hemolytic activity comparable to amphotericin B suspended in deoxycholate. Above 3-4 mole percent amphotericin B, ribbon-like structures emerged and CD spectra indicated drug-lipid complexation. Minimal inhibitory concentrations for Candida albicans of liposomal and complexed amphotericin B were comparable and could be attributed to amphotericin a release as a result of lipid breakdown within the ribbon-like material by a heat labile extracellular yeast product (lipase). Negative stain EM of the ribbon-like structures indicated that the ribbon-like appearance seen by freeze-fracture EM arises as a consequence of the cross-fracturing of what are aggregated, collapsed single lamellar, presumably interdigitated, membranes. Studies examining complexation of amphotericin B with either DMPC or DMPG demonstrated that headgroup interactions played little role in the formation of the ribbon-like structures. With these results we propose that ribbon-like structures result from phase separation of amphotericin B-phospholipid complexes within the phospholipid matrix such that amphotericin B release, and thus acute toxicity, is curtailed. Formation of amphotericin B-lipid structures such as those described here indicates a possible new role for lipid as a stabilizing matrix for drug delivery of lipophilic substances, specifically where a highly ordered packing arrangement between lipid and compound can be achieved.

Amphotericin B↗
PubMed1992

TLC G-65 in combination with other agents in the therapy of Mycobacterium avium infection in beige mice.

The activity of TLC G-65 (a liposomal gentamicin preparation), alone and in combination with rifapentine, clarithromycin, clofazimine and ethambutol, was evaluated in the beige mouse (C57BL/6J--bgj/bgj) model of disseminated Mycobacterium avium infection. TLC G-65 was found to be more active than amikacin. The combination of rifapentine and TLC G-65 was more active than either agent alone. The activity of clarithromycin in combination with TLC G-65 was similar to that of either agent alone. Clofazimine improved the activity of TLC G-65 with respect to the spleen, while ethambutol improved the activity with respect to the liver. Clofazimine and ethambutol enhanced the activity of TLC G-65 against bacteria in the lungs. TLC G-65 in combination with rifapentine appears to be an attractive regimen for the treatment of infections caused by bacteria in the M. avium complex.

Amikacin↗
PubMed1990

Pharmacokinetics and in vivo activity of liposome-encapsulated gentamicin.

Gentamicin sulfate was encapsulated in liposomes composed solely of egg phosphatidylcholine and administered via intravenous injection to rats and mice. The total gentamicin activity (regardless of whether it was free or liposome associated) in serum and selected tissues was determined for 24 h (serum) or up to 15 weeks (tissues) by using a microbiological assay. The mean half-lives in serum of a single 20-mg/kg dose of free (nonencapsulated) gentamicin in mice and rats were estimated to be 1.0 and 0.6 h, respectively, whereas a similar dose of encapsulated drug had apparent mean half-lives of 3.8 h in mice and 4.0 h in rats. In both species, the apparent half-life in serum of the liposomal formulation increased as the dose increased. Liposome encapsulation resulted in higher and more prolonged activity in organs rich in reticuloendothelial cells (especially spleen and liver). In acute septicemia infections in mice, the liposomal formulation showed enhanced prophylactic activity (as determined by calculation of the 50% protective dose). In a model of murine salmonellosis, liposomal gentamicin greatly enhanced survival when given as a single dose (10 mg/kg) at 1 or 2 days after infection as well as up to 7 days before infection.

Animals↗
PubMed1990

Liposome-encapsulated-gentamicin therapy of Mycobacterium avium complex infection in beige mice.

The efficacy of liposome-encapsulated gentamicin and free gentamicin was evaluated with the beige (C57BL/6J-bgj/bgj) mouse model of disseminated Mycobacterium avium complex infection. Approximately 10(7) viable M. avium complex cells were given intravenously. Seven days later, treatment with either encapsulated or free gentamicin at 20 mg/kg of body weight was started. Treatment was given daily for 5 consecutive days or twice weekly for 3 weeks. The mice were sacrificed 5 days after the last dose. Spleens, livers, and lungs were homogenized, and viable cell counts were determined. An analysis of variance and subsequent Tukey honestly significant difference tests indicated that both encapsulated and free gentamicin reduced viable cell counts in each of the organs compared with no treatment. Encapsulated gentamicin significantly reduced viable cell counts in the spleen and liver compared with the free gentamicin. A dose-response experiment was performed with a daily dose of 0.2, 2, or 20 mg/kg. Dose-related reductions in viable cell counts were observed for spleens and livers, although none of the regimens resulted in sterilization of these organs. Liposome-encapsulated gentamicin should be considered for further evaluation in the treatment of M. avium complex infection in humans.

Animals↗
PubMed1989

Liposome-encapsulated-amikacin therapy of Mycobacterium avium complex infection in beige mice.

Efficacy of liposome-encapsulated amikacin and free amikacin against Mycobacterium avium complex was evaluated in the beige mouse (C57BL/6J-bgJ/bgJ) acute infection model. Approximately 10(7) viable M. avium complex serotype 1 cells for which the MIC of amikacin was 8 micrograms/ml were given intravenously. Treatment was started with encapsulated or free amikacin at approximately 110 or 40 mg/kg of body weight 7 or 14 days later. In the former experiment, treatment was given two or three times per week. In the latter experiment, treatment was given daily for 5 days. The animals were sacrificed 5 days after the last dose. Liver, spleen, and lung were homogenized, and viable cell counts were determined on 7H10 agar. An analysis of variance and subsequent Tukey HSD (honestly significant difference) tests indicated that both encapsulated and free amikacin significantly reduced viable cell counts in each of the organs compared with counts in the control group. Compared with free amikacin, encapsulated amikacin significantly reduced viable cell counts in the liver and spleen. Liposome encapsulation of an active agent appears to be a promising therapeutic approach to M. avium complex infection.

Amikacin↗
PubMed1989

Efficacy of various treatment regimens, using liposomal streptomycin in cows with brucellosis.

Thirty cows naturally infected with Brucella abortus were treated by various routes, using free or liposomal streptomycin or a combination of liposomal streptomycin and a long-acting oxytetracycline preparation. Of 21 cows treated with liposomal streptomycin alone, 3 (14%) were culture negative and 3 had 10 or fewer bacterial colonies isolated from tissues obtained at necropsy. Thirteen (62%) cows continued to shed organisms in udder secretions and were considered treatment failures. Of 9 cows that were given a combination of liposomal streptomycin and long-acting oxytetracycline, 5 (56%) were cured, 3 had 10 or fewer colonies on culture plates of tissue after necropsy and only 1 continued to shed B abortus in udder secretions after treatment. Eleven cows were given streptomycin liposomes by intramammary infusion with or without IM administration of long-acting oxytetracycline. The most effective regimen consisted of 2 intramammary infusions of streptomycin liposomes and 2 doses of oxytetracycline administered IM. Of 5 cows treated thusly, 2 were cured and all others had fewer than 10 B abortus colonies isolated from tissues obtained at necropsy.

Animals↗
PubMed1988

Preparation and use of liposomes in the treatment of microbial infections.

The potential application of liposomes to drug delivery has been apparent since 1965, when these phospholipid vesicles were first described by Bangham. Since then, experiments on animals have shown that liposome encapsulation can dramatically alter the distribution of drugs in the body and their rate of clearance. These pharmacokinetic differences, as well as other less well-understood effects, can result in reduced toxicity and enhanced efficacy of the encapsulated drug. The vast majority of studies on the therapeutic use of liposomes have involved the delivery of drugs used in cancer chemotherapy and metabolic storage diseases, but there is now more literature on the use of liposomes for the delivery of antimicrobial drugs and immunomodulating agents. This review briefly discusses the general properties of liposomes and the rationale for their use in antimicrobial drug delivery and immunomodulation, as well as the encapsulation of specific agents and the effect of encapsulation on the treatment of infectious diseases.

Anti-Infective Agents↗
PubMed1984

Ultrastructure of Chlamydia trachomatis infection of the mouse oviduct.

Chlamydial inclusions were found in the luminal epithelium of all segments of the oviducts (ostium, ampulla, and isthmus) of mice experimentally inoculated with the mouse pneumonitis (MoPn) biovar of Chlamydia trachomatis. Electron microscopy of infected oviducts revealed chlamydial inclusions in both ciliated and nonciliated cells of the oviduct epithelium. Inclusions contained typical elementary, intermediate and reticulate bodies as well as numerous "miniature reticulate bodies" and membrane ghosts. Small, vesicle-like structures were observed in infected cells near inclusions but were not seen in apparently uninfected cells nor in the oviducts of mice inoculated with the control (sterile tissue culture supernate) suspension. Chlamydia-like particles were seen in vacuoles of polymorphonuclear leukocytes. Intracellular Chlamydia-like particles were not seen in any other cell type in the mouse oviduct. Infection of the mouse oviduct with MoPn is a convenient model for the study of C. trachomatis morphology in vivo.

Animals↗
PubMed1983

Chlamydia trachomatis-induced salpingitis in mice.

Inoculation of the mouse pneumonitis biovar of Chlamydia trachomatis into the ovarian bursa of mice resulted in salpingitis. An acute inflammatory response in the bursa and contiguous oviduct peaked at six to nine days postinoculation. At day 14, most animals showed an acute and chronic infiltrate that occluded the oviductal lumen in some sections. Inflammatory exudate and debris accumulated in the periovarial space near the ostium of the oviduct. Inclusions were demonstrated in the lumenal epithelial cells of the oviduct and uterus. The mouse pneumonitis agent could be recovered from genital tissues for up to 21 days postinoculation but not from other organs. IgG antibodies to the mouse pneumonitis agent were detected at seven days postinoculation and reached peak titers by 21-30 days. By 25-30 days postinoculation, the inflammatory reaction declined and hydrosalpinx was observed. This model for salpingitis may be useful in understanding some aspects of the pathogenesis of C trachomatis genital infections.

Animals↗
PubMed1982

Specificity of sperm-zona interaction.

The specificity of early sperm-zona interactions in vitro was studied using gametes from the mouse, rabbit, pig, and human. Mouse epididymal spermatozoa, capacitated in vitro, bound to the zonae of intact mouse oocytes and zona fragments removed mechanically from oocytes. When viewed with the scanning electron microscope (SEM), spermatozoa were found adherent more frequently to the external (cumulus) surface of the zonae than the internal (oocyte) surface. Noncapacitated mouse spermatozoa or spermatozoa incubated with zonae in the absence of external calcium did not bind to homologous zonae. by contrast, fresh, epididymal mouse spermatozoa and mouse spermatozoa capacitated in vitro appeared to attach equally well to both surfaces of zonae and zona fragments from rabbit and pig oocytes. Rabbit spermatozoa "capacitated" in vivo as well as noncapacitated rabbit spermatozoa, attached rapidly to both inner and outer surfaces of zonae from rabbit, mouse, and pig oocytes. This reaction was not dependent on external calcium. Human spermatozoa did not display any tendency to adhere to zonae from the rabbit, mouse, or pig. The results of these studies suggest that spermatozoa can associate with zona in a nonspecific as well as a specific manner. The use of heterologous systems in addition to homologous systems in sperm binding assays may be useful in distinguishing these two types of interaction.

Animals↗