Pulmonary Delivery of Beclomethasone Liposome Aerosol in Volunteers

Waldrep, J. Clifford; Gilbert, Brian E.; Knight, Caroline; Black, Melanie; Scherer, Peter; Knight, Vernon; Eschenbacher, William L.

doi:10.1378/chest.111.2.316

Cited by 77 publications

(32 citation statements)

References 32 publications

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“…Liposomes have been widely used as carriers for inhaled drugs to prolong the retention of water-soluble drugs in the lung (Fielding and Abra, 1992), facilitate intracellular delivery, and reduce the toxicity of incorporated drugs (Schreier et al, 1993;Waldrep et al, 1997). There are several reports about the application of liposomes to incorporate dexamethasone (Dex), a potent GC, for lung inflammation by intratracheal (i.t.)…”

Section: Inhalation Of Lipopolysaccharide (Lps)mentioning

confidence: 99%

Enhanced Anti-Inflammation of Inhaled Dexamethasone Palmitate Using Mannosylated Liposomes in an Endotoxin-Induced Lung Inflammation Model

Wijagkanalan¹,

Higuchi²,

Kawakami³

et al. 2008

Mol Pharmacol

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Inhalation of bacterial endotoxin induces pulmonary inflammation by activation of nuclear factor B (NFB), production of cytokines and chemokines, and neutrophil activation. Although glucocorticoids are the drugs of choice, administration of free drugs results in adverse effects as a result of a lack of selectivity for the inflammatory effector cells. Because alveolar macrophages play a key role in the inflammatory response in the lung, selective targeting of glucocorticoids to alveolar macrophages offers efficacious pharmacological intervention with minimal side effects. We have demonstrated previously the selective targeting of mannosylated liposomes to alveolar macrophages via mannose receptor-mediated endocytosis after intratracheal administration. In this study, the anti-inflammatory effects of dexamethasone palmitate incorporated in mannosylated liposomes (DPML) at 0.5 mg/kg via intratracheal administration were investigated in lipopolysaccharide-induced lung inflammation in rats. DPML significantly inhibited tumor necrosis factor ␣, interleukin-1␤, and cytokine-induced neutrophil chemoattractant-1 levels, suppressed neutrophil infiltration and myeloperoxidase activity, and inhibited NFB and p38 mitogen-activated protein kinase activation in the lung. These results prove the value of inhaled mannosylated liposomes as powerful targeting systems for the delivery of anti-inflammatory drugs to alveolar macrophages to improve their efficacy against lung inflammation. Inhalation of lipopolysaccharide (LPS), which is a component of Gram-negative bacteria presenting as an environment pollutant, contributes to inflammation in the lung. The downstream signaling pathways after LPS stimulation include the activation of alveolar macrophages, which are key effector cells to release proinflammatory cytokines including tumor necrosis factor ␣ (TNF␣), interleukin-1␤ (IL-1␤) (Ulich et al., 1991), chemokines such as cytokine-induced neutrophil chemoattractant-1 (CINC-1) (Ulich et al., 1995), and activation of nuclear factor B (NFB) and p38 mitogen-activated protein kinase (p38MAPK). Thereafter, neutrophils are recruited into the lung and release protease enzymes, which trigger lung injury. Corresponding to these studies, depletion of alveolar macrophages by liposomal clodronate treatment completely suppressed the downstream signaling after LPS stimulation (Koay et al., 2002). These results indicate that alveolar macrophages play a key role in the inflammation to release proinflammatory cytokines and chemokines after LPS stimulation.Glucocorticoids (GCs) are the drugs of choice for treatment of lung inflammation via systemic or local administration. Although inhalation of free GC is a promising therapy with less systemic toxicity, the therapeutic efficacy has been ques-

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Section: Inhalation Of Lipopolysaccharide (Lps)mentioning

confidence: 99%

Enhanced Anti-Inflammation of Inhaled Dexamethasone Palmitate Using Mannosylated Liposomes in an Endotoxin-Induced Lung Inflammation Model

Wijagkanalan¹,

Higuchi²,

Kawakami³

et al. 2008

Mol Pharmacol

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“…The advantages of such a novel pulmonary drug delivery system compared to conventional approaches include direct delivery of the drug to the lung with high concentrations of the drug at the lung parenchyma (Waldrep et al, 1997), avoiding the first pass effect and systemic distribution, equal distribution of the drug within the entire lung (i.e. by replacing edematous fluid) (Hirschl et al, 1994;Lehmler, 2007;Lehmler et al, 1999), and controlled release of the drug which further reduces systemic toxicity (Keller, 1999).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, physicochemical properties and in vitro cytotoxicity of nicotinic acid ester prodrugs intended for pulmonary delivery using perfluorooctyl bromide as vehicle

Lehmler

Vyas

et al. 2008

International Journal of Pharmaceutics

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This study explores perfluorooctyl bromide (PFOB) as a potential vehicle for the pulmonary delivery of a series of prodrugs of nicotinic acid using cell culture studies. The prodrugs investigated have PFOB-water (log K p = 0.78 to > 2.2), perfluoromethylcyclohexane-toluene (log K p = −2.62 to 0.13) and octanol-water (log K p = 0.90 to 10.2) partition coefficients spanning several orders of magnitude. In confluent NCI-358 human lung cancer cells, the toxicity of prodrugs administered in culture medium or PFOB depends on the medium of administration, with EC20's above 8 mM and 2.5 mM for culture medium and PFOB, respectively. Short-chain nicotinates administered both in PFOB and medium increase cellular NAD/NADP levels at 1 mM nicotinate concentrations. Long-chain nicotinates, which could not be administered in medium due to their poor aqueous solubility, increased NAD/NADP levels if administered in PFOB at concentrations ≥ 10 mM. These findings suggest that even highly lipophilic prodrugs can partition out of the PFOB phase into cells, where nicotinic acid is released and converted to NAD. Thus, PFOB may be a novel and biocompatible vehicle for the delivery of lipophilic prodrugs of nicotinic acid and other drugs directly to the lung of laboratory animals and humans.

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“…The tolerability and safety of liposome aerosols has been previously tested in animals as well as in human volunteers; no untoward effects have been recognized. 14,15 As a drug delivery system, liposomes can significantly alter the pharmacokinetics and pharmacodynamics of entrapped drugs, for example by enhancing drug uptake, delaying rapid drug clearance, and reducing drug toxicity. [16][17][18] Liposomes are also known to sustain the release of the entrapped drug(s) and to decrease the mucociliary clearance of the drug(s) because of their surface viscosity.…”

Section: Introductionmentioning

confidence: 99%

A preliminary pharmacokinetic study of liposomal leuprolide dry powder inhaler: A technical note

Shahiwala

Misra

2005

AAPS PharmSciTech

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Pulmonary Delivery of Beclomethasone Liposome Aerosol in Volunteers

Cited by 77 publications

References 32 publications

Enhanced Anti-Inflammation of Inhaled Dexamethasone Palmitate Using Mannosylated Liposomes in an Endotoxin-Induced Lung Inflammation Model

Enhanced Anti-Inflammation of Inhaled Dexamethasone Palmitate Using Mannosylated Liposomes in an Endotoxin-Induced Lung Inflammation Model

Synthesis, physicochemical properties and in vitro cytotoxicity of nicotinic acid ester prodrugs intended for pulmonary delivery using perfluorooctyl bromide as vehicle

A preliminary pharmacokinetic study of liposomal leuprolide dry powder inhaler: A technical note

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