Direct lung delivery of para-aminosalicylic acid by aerosol particles

Tsapis, Nicolas; Bennett, Derrick; O'driscoll, K.; Shea, Katherine; Lipp, Mike; Fu, Karen K.; Clarke, Robert W.; Deaver, Daniel R.; Yamins, Daniel; Wright, Jim; Peloquin, Charles A.; Weitz, David A.; Edwards, David A.

doi:10.1016/j.tube.2003.08.016

Cited by 67 publications

(35 citation statements)

References 15 publications

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“…Particles for inhalation were manufactured from a capreomycin solution containing 80% capreomycin sulfate and 20% L-leucine in 50% ethanol, using a Niro Mobile Minor spray dryer (Columbia, MD) at a feed flow rate of 80 ml/min, with an inlet temperature of 189 to 192°C, as described elsewhere (10,34).…”

Section: Methodsmentioning

confidence: 99%

Inhaled Large Porous Particles of Capreomycin for Treatment of Tuberculosis in a Guinea Pig Model

García-Contreras

Fiegel

Telko

et al. 2007

Antimicrob Agents Chemother

131

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Capreomycin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB), but it is limited therapeutically by its severe side effects. The objectives of the present studies were (i) to design low-density porous capreomycin sulfate particles for efficient pulmonary delivery to improve local and systemic drug bioavailability and capacity to reduce the bacillary load in the lungs in a manner similar to that achieved with intramuscular injections; (ii) to determine pharmacokinetic parameters after pulmonary administration of these capreomycin particles; and (iii) to evaluate the efficacy of these particles in treating animals in a small-aerosol-inoculum guinea pig model of TB. Capreomycin particles were manufactured by spray drying and characterized in terms of size and drug content. Pharmacokinetic parameters were determined by noncompartmental methods with healthy guinea pigs after administration of capreomycin particles by insufflation. The efficacy of the particles was evaluated by histopathological analysis and in terms of wet organ weight and bacterial burden in TB-infected animals. Lungs of animals receiving a 14.5-mg/kg dose of capreomycin particles showed significantly lower wet weights and smaller bacterial burdens than those of animals receiving any other treatment. These results were supported by histopathological analysis. The feasibility of inhaling capreomycin in a novel powder form, with the ultimate objective of the treatment of MDR-TB, is demonstrated by pharmacokinetic and pharmacodynamic studies with guinea pigs. If applied to humans with MDR-TB, such a therapeutic approach might simplify drug delivery by eliminating injections and might reduce adverse effects through lowering the dose.Worldwide, there is an increase in multiple drug-resistant tuberculosis (MDR-TB), including reports of outbreaks of extensive MDR-TB in several countries (4, 36). Patients suffering from MDR-TB have infections which are resistant to at least two key drugs in the first-line regimen, namely, rifampin and isoniazid, in part as a consequence of poor compliance to the current first-line regimen (approximately 23% of active TB patients presently complete first-line treatment) (5). To treat MDR-TB, other, second-line antibiotics are needed and therapy lasts up to 2 years, typically requiring parenteral injection (2).Among the drugs injected is the polypeptide antibiotic capreomycin, the only second-line drug specifically indicated for MDR-TB. Capreomycin is a complex of four microbiologically active components that has been shown to be effective in combination with other appropriate anti-TB drugs in the treatment of pulmonary Mycobacterium tuberculosis infections when the primary agents (in particular isoniazid and rifampin) have become ineffective as a result of bacterial resistance or toxicity. The drug is painful to receive by injection and is associated with serious side effects, such as anorexia, thirst, anemia, and notably, nephrotoxicity and damage to the auditory and vestibular divisions of cranial nerv...

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Section: Methodsmentioning

confidence: 99%

Inhaled Large Porous Particles of Capreomycin for Treatment of Tuberculosis in a Guinea Pig Model

García-Contreras

Fiegel

Telko

et al. 2007

Antimicrob Agents Chemother

131

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“…A smaller dose combined with the absence of first pass metabolism and avoidance of gastrointestinal track is expected to lead reduced systemic side effects and enhanced tolerability. Various Anti-TB drugs have been formulated in dry microparticles for pulmonary delivery, including capreomycin [25,26] and para-aminosalicylic acid [27]. They provide promise in targeting TB sites, that can be directly administered to the lungs with reduced systemic side effects [28].…”

Section: Introductionmentioning

confidence: 99%

Present status of nanoparticle research for treatment of Tuberculosis

2011

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-Nanotechnology has offered enormous improvement in field of therapeutics by means of designing of drug delivery systems and opened the possibility of controlling infections at the molecular level. Nanocarriers can cross biological barriers and are able to target cellular reservoirs of Mycobacterium tuberculosis (M. tuberculosis). Nanoparticle-based systems have significant potential for treatment and prevention of tuberculosis (TB). A variety of nanocarriers have been widely evaluated as potential drug delivery systems for various administration routes. Targeting the drugs to certain physiological sites such as the lymph nodes has emerged as a promising strategy in treating TB with improved drug bioavailability and reduction of the dosing frequency. Nanotechnology based rational targeting may improve therapeutic success by limiting adverse drug effects and requiring less frequent administration regimes, ultimately resulting in more patients compliance and thus attain higher adherence levels. The development of nanoparticle based aerosol vaccine is undergoing which could serve as new platform for immunization. Present article compiles the general physiological aspects of the infection along with new research uptades on nanocarriers used in prevention of tuberculosis. _______________________________________________________________________________________

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“…The porous particle system, a dry powder formulation, is well suited for efficient delivery to the lungs (2). Use of this novel particulate aerosol has also been explored for the treatment of TB with the tuberculostatic agents para-aminosalicyclic acid (PAS) and capreomycin (3,4,23). PAS, delivered as a dry powder, was shown to achieve greater lung exposure in rats at a lower total body drug dose than the typical oral dose (23).…”

mentioning

confidence: 99%

“…Use of this novel particulate aerosol has also been explored for the treatment of TB with the tuberculostatic agents para-aminosalicyclic acid (PAS) and capreomycin (3,4,23). PAS, delivered as a dry powder, was shown to achieve greater lung exposure in rats at a lower total body drug dose than the typical oral dose (23). The pulmonary delivery of capreomycin gave promising efficacy results in a guinea pig model of TB, with lower wet organ weights and bacterial burdens in the lungs of animals given treatment by aerosol delivery than animals given intravenous (i.v.)…”

mentioning

confidence: 99%

Dry Powder Nitroimidazopyran Antibiotic PA-824 Aerosol for Inhalation

Sung

García-Contreras

VerBerkmoes

et al. 2009

Antimicrob Agents Chemother

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We formulated PA-824, a nitroimidazopyran with promise for the treatment of tuberculosis, for efficient aerosol delivery to the lungs in a dry powder porous particle form. The objectives of this study were to prepare and characterize a particulate form of PA-824, assess the stability of this aerosol formulation under different environmental conditions, and determine the pharmacokinetic parameters for the powder after pulmonary administration. The drug was spray dried into porous particles containing a high drug load and possessing desirable aerosol properties for efficient deposition in the lungs. The physical, aerodynamic, and chemical properties of the dry powder were stable at room temperature for 6 months and under refrigerated conditions for at least 1 year. Pharmacokinetic parameters were determined in guinea pigs after the pulmonary administration of the PA-824 powder formulation at three doses (20, 40, and 60 mg/kg of body weight) and compared to those after the intravenous (20 mg/kg) and oral (40 mg/kg) delivery of the drug. Oral and inhaled delivery of PA-824 achieved equivalent systemic delivery at the same body dose within the first 12 h of dosing. However, animals dosed by the pulmonary route showed drug loads that remained locally in the lungs for 32 h postexposure, whereas those given the drug orally cleared the drug more rapidly. Therefore, we expect from these pharmacokinetic data that pulmonary delivery may achieve the same efficacy as oral delivery at the same body dose, with a potential improvement in efficacy related to pulmonary infection. This may translate into the ability to deliver lower body doses of this drug for the treatment of tuberculosis by aerosol.The global epidemic caused by the infectious disease tuberculosis (TB) has recently garnered attention due to the growing concern over the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), which are caused by Mycobacterium tuberculosis strains that show resistance to multiple first-line drugs or that are virtually untreatable by existing anti-TB antibiotics (7). An investigational nitroimidazopyran, PA-824, is one of the most promising anti-TB drug candidates to have been discovered in 30 years. PA-824 appears to have bactericidal activity against both active replicating and persisting or latent M. tuberculosis strains and has the potential to be used for the treatment of MDR-TB (21). It has been proposed that this activity against static bacilli could help sterilize TB lesions faster (26). Therefore, reduced treatment times may be possible with drug regimens that include PA-824. Any advance in anti-TB therapy that addresses drug-resistant TB and that reduces the frequency of dosing, the dose required, and the duration of treatment has the potential to improve patient treatment.Preclinical evaluation with animal models of PA-824 alone and in combination with moxifloxacin, rifampin (rifampicin), isoniazid, and/or pyrazinamide indicated the potential of the use of PA-824 alone and in combination for...

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Direct lung delivery of para-aminosalicylic acid by aerosol particles

Cited by 67 publications

References 15 publications

Inhaled Large Porous Particles of Capreomycin for Treatment of Tuberculosis in a Guinea Pig Model

Inhaled Large Porous Particles of Capreomycin for Treatment of Tuberculosis in a Guinea Pig Model

Present status of nanoparticle research for treatment of Tuberculosis

Dry Powder Nitroimidazopyran Antibiotic PA-824 Aerosol for Inhalation

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