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Pharmacy World & Science | 1995

Liposomes as delivery systems in the prevention and treatment of infectious diseases

Joep J. Bergers; Timo L.M. ten Hagen; Els W. M. van Etten; Irma A. J. M. Bakker-Woudenberg

Research on the potential application of liposomes in the prevention and treatment of infectious diseases has focussed on improvement of the therapeutic index of antimicrobial drugs and immunomodulators and on stimulation of the immune response to otherwise weak antigens in vaccines composed of purified micro-organism subunits. In this review current approaches in this field are outlined. The improved therapeutic index of antimicrobial drugs after encapsulation in liposomes is a result of enhanced drug delivery to infected tissue or infected cells and/or a reduction of drug toxicity of potentially toxic antibiotics. Liposomal encapsulation of immunomodulators that activate macrophages aims at reducing the toxicity of these agents and targeting them to the cells of the mononuclear phagocyte system in order to increase the nonspecific resistance of the host against infections. Studies on the immunogenicity of liposomal antigens have demonstrated that liposomes can potentiate the humoral and cell mediated immunity to a variety of antigens.


Journal of Controlled Release | 1995

Sterically stabilized amphotericin B-liposomes: Toxicity and biodistribution in mice

Els W. M. van Etten; Wim van Vianen; Ronald H.G. Tijhuis; Gert Storm; Irma A. J. M. Bakker-Woudenberg

In this study it was investigated whether long-circulating amphotericin B (AMB) containing liposomes could be prepared by incorporation of polyethylene glycol (1900) derivatized distearoylphosphatidylethanolamine (PEG-DSPE), and whether the incorporation of PEG-DSPE affected toxicity and biodistribution of the preparation in mice. Toxicity of two formulations of liposomes containing both PEG-DSPE and AMB (PEG-AMB-LIP, types 1 and 2) was compared with that of AMB-liposomes without PEG-DSPE (AMB-LIP) as well as that of MB-deoxycholate (AMB-DOC). The maximum tolerated dosage (MTD) of AMB-DOC, expressed in terms of death during treatment for 5 consecutive days or significant increases in the parameters used to monitor renal and hepatic functions, was 0.8 mg/kg per day. AMB-LIP were the least toxic, the MTD being 11 mg/kg per day. The formulation with AMB complexed to DSPG (PEG-AMB-LIP type 1) was as toxic as AMB-DOC. This PEG-AMB-LIP formulation was omitted from further studies on biodistribution. With AMB complexed to PEG-DSPE (PEG-AMB-LIP type 2) toxicity was substantially reduced, resulting in a MTD of 9 mg/kg per day. Biodistribution of radiolabeled PEG-AMB-LIP type 2 was compared with that of AMB-LIP. Blood residence time of PEG-AMB-LIP type 2 was prolonged as compared to AMB-LIP; For PEG-AMB-LIP type 2 at 24 h after administration 30% of the injected dosage of AMB in intact liposomes was circulating versus 6% for AMB-LIP.


Antimicrobial Agents and Chemotherapy | 2000

Efficacy of Liposomal Amphotericin B with Prolonged Circulation in Blood in Treatment of Severe Pulmonary Aspergillosis in Leukopenic Rats

Els W. M. van Etten; Lorna E. T. Stearne-Cullen; Marian T. ten Kate; Irma A. J. M. Bakker-Woudenberg

ABSTRACT The therapeutic efficacy of long-circulating polyethylene glycol-coated liposomal amphotericin B (AMB) (PEG-AMB-LIP) was compared with that of AMB desoxycholate (Fungizone) in a model of severe invasive pulmonary aspergillosis in persistently leukopenic rats as well as in temporarily leukopenic rats. PEG-AMB-LIP treatment (intravenous administration) consisted of a single, or double (every 72 h), or triple (every 72 h) dose of 10 mg of AMB/kg of body weight, a double dose (every 72 h) of 14 mg of AMB/kg, or a 5-day treatment (every 24 h) with 6 mg/kg/dose. AMB desoxycholate was administered for 10 consecutive days at 1 mg of AMB/kg/dose. Treatment was started 30 h after fungal inoculation, at which time mycelial growth was firmly established. Both persistently and temporarily leukopenic rats died between 4 and 9 days after Aspergillus fumigatus inoculation when they were left untreated or after treatment with a placebo. In persistently leukopenic rats, a single dose of PEG-AMB-LIP (10 mg/kg) was as effective as the 10-day treatment with AMB desoxycholate (at 1 mg/kg/dose) in significantly prolonging the survival of rats infected with A. fumigatus and in reducing the dissemination of A. fumigatus to the liver. Prolongation of PEG-AMB-LIP treatment (double or triple dose or 5-day treatment) did not further improve efficacy. For temporarily leukopenic rats no major advances in efficacy were achieved compared to those for persistently leukopenic rats, probably because the leukocyte numbers in blood were restored too late in the course of infection.


Antimicrobial Agents and Chemotherapy | 2006

Nebulized Amphotericin B Combined with Intravenous Amphotericin B in Rats with Severe Invasive Pulmonary Aspergillosis

Elisabeth J. Ruijgrok; Marcel H. A. M. Fens; Irma A. J. M. Bakker-Woudenberg; Els W. M. van Etten; Arnold G. Vulto

ABSTRACT Nebulized amphotericin B (AMB) combined with intravenous AMB was studied in persistently leukopenic rats with invasive pulmonary aspergillosis. Pulmonary concentrations of AMB after aerosol treatment were substantially higher than after intravenous liposomal AMB. Nebulized liposomal AMB in addition to intravenous AMB resulted in significantly prolonged survival compared to controls.


Journal of Liposome Research | 1999

Sterically Stabilized Liposomes Containing Gentamicin: Limitations to Gentamicin Encapsulation

Elisabeth J. Ruijgrok; Arnold G. Vulto; Els W. M. van Etten

AbstractAs sterically stabilized liposomes (SSL) containing the aminoglycoside gentamicin prepared by the method of passive loading are characterized by a low drug to lipid ratio, we attempted to prepare gentamicin containing SSL with a more efficient encapsulation. Passive loading of a dried lipid film (PEG-DSPE:PHEPC: cholesterol = 0.15:1.85:1.0) with a solution containing 125 mg gentamicin per 250 μmole lipid yielded liposomes with an encapsulation efficiency of 4.0 ± 0.4% and a gentamicin loading of 28.0 ± 0.7 μg gentamicin/μmole lipid. Encapsulation efficiency was calculated as the percentage of gentamicin incorporated into liposomes relative to the initial total amount of gentamicin in solution and gentamicin loading was calculated as the amount of gentamicin incorporated in liposomes relative to the content of total lipid.Active loading of gentamicin into preformed liposomes which exhibit a transmembrane pH gradient resulted in a lower encapsulation efficiency and gentamicin loading (0.4 ± 0.1% and...


Medical Applications of Liposomes | 1998

CHAPTER 3.2 – Long-circulating liposomes containing antibacterial and antifungal agents

Irma A. J. M. Bakker-Woudenberg; Els W. M. van Etten

This chapter describes antibacterial and antifungal agents in long circulating liposomes. In clinical practice, infectious complications caused by bacteria, fungi, viruses, and parasites frequently occur. The incidence of severe infections is related to developments in clinical medicine, such as new therapeutic modalities, an increased use of prosthetic and other medical devices, frequent diagnostic and therapeutic intervention, and an increasing number of immunocompromized patients. As a consequence, a growing number of patients are prone to severe (nosocomial) infections that are often difficult to treat. Failure of antibiotic treatment occurs despite the availability of potent antibiotics. Intensification of antibiotic treatment is needed and should meet various requirements as: Antibiotic treatment failure may be related to insufficient availability of antibiotic because of extremely low half-life in blood. In those cases, liposomes as carriers of antibiotics may be used as micro reservoir of antibiotic during circulation; relatively long circulating liposomes are needed for this purpose. Antibacterial agents in long circulating liposomes are: sterically stabilized liposomes containing gentamicin or ceftazidime and MiKasome, amikacin-containing liposomes. Antifungal agents in long circulating liposomes are: AmBisome, amphotericin B-containing liposomes and sterically stabilized liposomes containing amphotericin B. This chapter also focuses on the potential use of liposomal antimicrobial therapy for the future.


Journal of Antimicrobial Chemotherapy | 1995

Biodistribution of liposomal amphotericin B (AmBisome) and amphotericin B-desoxycholate (Fungizone) in uninfected immunocompetent mice and leucopenic mice infected with Candida albicans

Els W. M. van Etten; Marièe Otte-Lambillion; Wim van Vianen; Marian T. ten Kate; Irma A. J. M. Bakker-Woudenberg


Journal of Antimicrobial Chemotherapy | 1993

Efficacies of amphotericin B-desoxycholate (Fungizone), liposomal amphotericin B (AmBisome) and fluconazole in the treatment of systemic candidosis in immunocompetent and leucopenic mice

Els W. M. van Etten; Cora van den Heuvel-de Groot; Irma A. J. M. Bakker-Woudenberg


Journal of Antimicrobial Chemotherapy | 2001

Efficacy of aerosolized amphotericin B desoxycholate and liposomal amphotericin B in the treatment of invasive pulmonary aspergillosis in severely immunocompromised rats

Elisabeth J. Ruijgrok; Arnold G. Vulto; Els W. M. van Etten


Antimicrobial Agents and Chemotherapy | 1998

Administration of Liposomal Agents and Blood Clearance Capacity of the Mononuclear Phagocyte System

Els W. M. van Etten; Marian T. ten Kate; Susan V. Snijders; Irma A. J. M. Bakker-Woudenberg

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Wim van Vianen

Erasmus University Rotterdam

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Arnold G. Vulto

Erasmus University Rotterdam

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Marian T. ten Kate

Erasmus University Rotterdam

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Susan V. Snijders

Erasmus University Rotterdam

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Joep J. Bergers

Erasmus University Rotterdam

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Lorna E. T. Stearne-Cullen

Erasmus University Medical Center

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Marcel H. A. M. Fens

Erasmus University Medical Center

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