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Biomedical subjects

A J Hickey

Publications and source records attributed to A J Hickey.

At least 19 recordsLinked to original sources
PubMed2006

Evaluation of dosing regimen of respirable rifampicin biodegradable microspheres in the treatment of tuberculosis in the guinea pig.

OBJECTIVES: The efficacy of rifampicin-loaded polymeric microspheres (RPLGA) delivered to guinea pigs infected with Mycobacterium tuberculosis (H37Rv) was compared with a daily dose of nebulized rifampicin suspension. METHODS: Aerosol-infected animals were subjected to multiple dose or single dose treatment with RPLGA, PLGA microspheres or micronized rifampicin suspension aerosols. For comparison with treatment with suspensions of microspheres, additional groups received daily doses of rifampicin-only suspensions for 20 (20-RIF) and 10 (10-RIF) days. RESULTS: Drug and polymer treated multiple dose groups exhibited significantly lower wet lung weights than untreated animals. Spleen wet weights and viable bacterial counts (VBCs) were much lower for drug microsphere treated animals than for all other groups. In multiple dose studies with rifampicin-only suspensions, wet lung weights for 10-RIF and 20-RIF treated animals were much smaller than controls. Likewise, wet spleen weights of 10-RIF and 20-RIF treated animals were much smaller than controls, consistent with reduced inflammation. Spleen VBC of 20-RIF treated animals was much smaller than controls. No statistical differences were observed in the lung VBC among single dose groups. However, a trend similar to that of the wet weights was observed. CONCLUSIONS: Aerosolized RPLGA reduced most measures of tuberculosis (TB) infection. These studies are further evidence for the potential of inhaled aerosol therapy for the treatment of TB. However, additional studies are required to elucidate underlying mechanisms of action and optimize this route of drug delivery.

Administration, Inhalation↗
PubMed2006

Spray pattern analysis for metered dose inhalers I: Orifice size, particle size, and droplet motion correlations.

Factors that influence spray pattern measurements of pressurized, metered-dose inhalers have been evaluated. Spray patterns were correlated with changes in actuator orifice diameter, particle size profiles, and calculated estimates of particle-size dynamics of plumes during a spray. Spray patterns, regardless of actuator orifice size, were ellipsoid in the vertical direction. Measures of elliptical ratio, major axis, and minor axis were significantly influenced by orifice size in a non-linear fashion over the range of orifice sizes investigated. Spray patterns also correlated with particle size profile and spray geometry measurements. Spray distribution asymmetry may be related to droplet evaporation and sedimentation processes. However, the spray patterns did not appear sensitive to changes in gravitational force acting on the plume. Instead, it is postulated that elliptical spray patterns may have dependence on fluid dynamic processes within the inhaler actuator. Developing an understanding of these processes may provide a basis for developing spray pattern tests with relevance to product performance.

Aerosol Propellants↗
PubMed2003

Preparation of disodium fluorescein powders in association with lauric and capric acids.

In previous studies micronized disodium fluorescein (DF) powders were coated with lauric or capric acid. This was a precursor to evaluating the effects of the fatty acids on the hygroscopic growth of the DF aerosols. Studies of the association of fatty acids with DF reflected a limited interpretation of the data obtained. The present study examines more closely the phenomena involved in coating the DF. It is concluded that lateral interactions due to the hydrophobic aliphatic tails of the fatty acids give rise to adsorption, aggregation, and flocculation, all of which cause inflections in the association isotherm rendering it nonlinear.

Chromatography, Gas↗
PubMed2002

Aerosol transport and deposition in a triple bifurcation bronchial airway model with local tumors.

Airflow characteristics and particle deposition have been numerically simulated in a triple bifurcation lung airway model (from generation 3-6 airways) with local tumors protruded from the sidewalls of generation 5 airways. The effects of tumors in terms of size and location on airflow, particle transport, and deposition patterns were analyzed for constant inspiratory flow rates with inlet Reynolds (Re(match) = 463 and 1882) and Stokes number (St(match) = 0.02-0.12) combinations that match different cyclic inhalation waveforms. The size of tumors was varied to induce an obstruction of airway lumen by 16-74%. Extreme conditions, 2 and 100% obstruction, were also examined. The results show that enhanced deposition occurs in the carina region at each bifurcation, and deposition increases with increasing Stokes and Reynolds number as expected from earlier studies. In addition, deposition increases at the tumor site until the tumor blocks about half of the airway lumen and then decreases with a further obstruction. In other words, there exists a maximum particle deposition fraction (DF) for a protruding tumor that occludes the lumen. The maximum DF at the tumor was 10.2% within the test conditions used. Deposition occurs mainly on the frontal surface of the tumors, but spreads out to the opposite wall, or upstream sections, or sister branches of the tumor at high flow rates and Stokes number. The present results (1) help in the understanding of the complex toxic or therapeutic aerosol dynamics in the lung with local airways obstruction, and (2) provide quantitative information on critical tumor size and particle deposition to health care specialists.

Administration, Inhalation↗
PubMed2001

Evaluation of preseparator performance for the 8-stage nonviable andersen impactor.

The preseparator of an Andersen impactor with different coating treatments for a range of particle-size distributions was evaluated. Limited theoretical simulations constrained by simplifying assumptions of the airflow fields in the preseparator and upper stages of an 8-stage Andersen impactor were used to reveal low-velocity and high-pressure regions for potential deposition. These regions were then sampled in subsequent particle deposition experiments. Disodium fluorescein aerosols were sampled with different coating treatments of the preseparator floor. Particles collected at impactor stages determined particle size distributions. Stage deposition was compared between different preseparator treatments (buffer and silicon oil). Collection efficiency in the preseparator followed the pattern buffer > silicon oil > untreated. Statistical differences (P < 0.05) were noted in collection efficiency of large particles (45 micro m-75 microm) in the preseparator. The mass median aerodynamic diameters and geometric standard deviations showed some statistical differences when different preseparator treatments for large particles were used; therefore, preseparator coating was shown to influence performance and thereby estimates of particle size by inertial impaction.

Aerosols↗
PubMed2001

Ontogenetic changes in enzyme activities associated with energy production in the spiny lobster, Jasus edwardsii.

The larval life of the spiny lobster Jasus edwardsii is one of the longest and most complex of any marine organism and is poorly understood due to the difficulty of studying cryptic, pelagic organisms. Hence, the capacity for active swimming in the phyllosoma, puerulus and juvenile stages and the use of possible metabolic fuel reserves was inferred from a number of enzyme activities, including citrate synthase, lactate dehydrogenase, and HOAD. High activities of CS and LDH in abdominal tissues of Stage 11 phyllosoma and pueruli are consistent with a capacity to commence active on-shore movement. The activities of LDH and HOAD showed positive allometry while CS was independent of body mass. The body mass dependence of LDH activity may reflect the developing ability of the lobster to initiate brief escape manoeuvres, and the scaling of HOAD reflects an increased use of lipid fuel reserves. Aerobic enzyme activities were higher in abdominal tissues than in cephalic tissues of pelagic pueruli, but high activities appear in the cephalic tissues of juveniles. These changes mirror a developmental shift in activity from pelagic oceanic swimming to a benthic existence on the seabed of the near shore. The low LDH activity in pueruli confirmed previous findings that they have limited feeding capacity, with carbohydrate contributing little towards the major energy reserves. The highest LDH activities occur in the abdominal muscles of juveniles and correlate with rapid tail-flicking escape behaviour. The activities of HOAD increased throughout development, and in the abdominal tissues of juveniles, may reflect lipid transformation and accumulation as an energy reserve. Enzyme activities, therefore, provide useful information concerning migratory behaviour that is presently unavailable from ecological studies.

Animals↗
PubMed2001

Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: screening in an infectious disease model.

PURPOSE: Targeted delivery of rifampicin loaded microspheres to the alveolar macrophage, the host cell for Mycobacterium tuberculosis (MTB), may be an effective targeted approach to pulmonary tuberculosis therapy. A guinea pig infection model has been adopted as a post-treatment screening method for antimicrobial effect. Insufflation and nebulization methods of drug delivery were evaluated. METHODS: Rifampicin alone (RIF, 1.03-1.72 mg/kg), within poly(lactide-co-glycolide) microspheres (R-PLGA, equivalent to 1.03-1.72 mg/kg) or polymer microparticles alone (PLGA) were administered by insufflation or nebulization, 24 h before bacterial aerosol exposure. Animals were infected with an aerosol containing a small number (2 x 10(5) cfu/mL) of virulent H37Rv strain of MTB. Lung and spleen tissue samples were collected 28 days after infection for quantitative bacteriology and histopathological analysis. RESULTS: There was a dose-effect relationship between insufflated R-PLGA and burden of bacteria in the lungs. In addition, guinea pigs treated with R-PLGA had a significantly smaller number of viable bacteria (P < 0.05), reduced inflammation and lung damage than lactose or saline control, PLGA or RIF treated animals. CONCLUSIONS: These studies indicate the potential of R-PLGA, delivered by insufflation or nebulization directly to the lungs, to affect the early development of pulmonary TB.

Administration, Inhalation↗
PubMed2001

Facilitation of pulmonary insulin absorption by H-MAP: pharmacokinetics and pharmacodynamics in rats.

PURPOSE: Several low molecular weight amino acids have previously been reported to enable the oral delivery of proteins. In the present studies, the effect of H-MAP (hydroxy methyl amino propionic acid) on the pharmacokinetics (PK) and pharmacodynamics (PD) of porcine insulin delivered to the lungs of rats by spray-instillation (SI) has been determined. METHODS: Aliquots (100 microl) of increasing doses of porcine insulin alone (0.26, 1.3, 2.6, 13, and 26 U/kg) or combined with increasing doses of H-MAP (5, 10, 16, and 25 mg/kg), at pH 7.2-7.6 were administered intratracheally to fasted anesthetized rats using a micro spray-instillator. Blood samples were collected from the jugular vein at specified intervals and the plasma concentrations of insulin and glucose were determined. The PK and PD of porcine insulin alone following subcutaneous (SC) administration of increasing doses were also determined. RESULTS: The PK of insulin administered either by SI to the lungs or SC injection were absorption rate dependent, resulting in post-peak half-lives 10 to 25-fold greater than the reported intravenous elimination half-life (3 min). The relative bioavailability (F') of insulin administered alone by SI varied from 23.8 to 80% for the lowest and highest insulin dose, respectively. Co-administration of H-MAP and insulin to the lungs significantly changed the PK and PD of insulin in a dose dependent fashion. Maximum PK and PD responses were obtained at an H-MAP dose of 16 mg/kg and an insulin dose of 1.3 U/kg. At this combination, the relative bioavailability of insulin was increased more than 2.5 fold, maximum concentration (Cmax) increased 2-fold and the minimum plasma glucose concentration (%MPGC) was reduced more than 2-fold with respect to same dose of insulin alone. A greater total reduction in plasma glucose (%TRPG0-->t) was achieved for H-MAP/insulin combination (66+/-5%) compared to insulin alone (47+/-10 %). CONCLUSION: H-MAP has potential for increasing the pulmonary bioavailability of insulin administered through the lungs.

Absorption↗
PubMed2001

Prosthetic treatments for patients with ectodermal dysplasia.

This article defines and describes the nature of ectodermal dysplasias, highlighting the dental complications associated with this congenital/developmental condition. A treatment protocol for meeting patients' functional and esthetic needs as they grow into adulthood is presented.

Adolescent↗
PubMed2001

The influence of suspension nebulization or instillation on particle uptake by guinea pig alveolar macrophages.

Phagocytosis represents a crucial event in the host defense against pathogens. Experimental methods are required that allow a range of particle doses to be delivered. However, it is not clear that these methods result in the same sites of deposition or mechanisms of clearance. The effect of particle administration by nebulization or instillation on the uptake by guinea pig alveolar macrophages (AMs) has been studied. Suspensions of escalating quantities of 1-microm fluorescent polystyrene latex microspheres were delivered by 15 min of nebulization (1.4 x 10(7)-11.1 x 10(7) particles) or instillation (19 x 10(7)-152 x 10(7) particles) into the lungs of guinea pigs. These doses were selected to maximize delivery using each of these methods. Macrophages were collected by alveolar lavage 6 h postadministration. The total number of cells recovered was 3 x 10(6) and the cell viability was >97%, which was measured by trypan blue exclusion. Differential cell counts of lavaged cell suspensions were conducted and results showed no difference for the two methods of administration with various concentrations of latex particles and control samples. The uptake of particles was measured using epifluorescence, confocal microscopy, and flow cytometry. AMs showed a dose-dependent increase in associated particles measured by microscopy and flow cytometry. There was a direct correlation (R(2) =.99) in the phagocytic indices (PIs) measured by flow cytometry and fluorescence microscopy. The PI was 15 times higher after instillation than that obtained after particle nebulization. The percentage of AMs involved in phagocytosis observed after instillation was 55% and after nebulization 23%. The uptake of aerosolized particles by AMs and the number of cells involved in phagocytosis were dependent on the particle dose and the efficiency of aerosol delivery to the lungs.

Administration, Inhalation↗
PubMed2001

Airways delivery of rifampicin microparticles for the treatment of tuberculosis.

A Mycobacterium tuberculosis (H37Rv)-infected guinea pig model was used to screen for targeted delivery to the lungs by insufflation (with lactose excipient) or nebulization, of either rifampicin alone, rifampicin within poly(lactide-co-glycolide) microspheres (R-PLGA) or polymer microparticles alone (PLGA). Animals treated with single and double doses of R-PLGA microspheres exhibited significantly reduced numbers of viable bacteria, inflammation and lung damage compared with lactose-, PLGA- or rifampicin-treated animals 28 days post-infection (P < 0.05). Two doses of R-PLGA resulted in reduced splenic enlargement. These studies support the potential of R-PLGA delivered to the lung to treat pulmonary tuberculosis.

Animals↗
PubMed2001

Immunological and toxicological implications of short-term studies in animals of pharmaceutical aerosol delivery to the lungs: relevance to humans.

The effects of xenobiotics on the lungs have been studied for many years. In the past 50 years, delivery of drugs to the lungs has been adopted to achieve local effects, specifically for the treatment of asthma. Recently, due to the proximity of the circulating blood supply and to their large surface area, the lungs have been proposed as the port of entry for drugs to obtain systemic effects, particularly for macromolecular compounds of biological origin. Numerous studies regarding drug formulation, delivery systems, and related pharmacokinetics have been reported; however, the concurrent effects of pulmonary delivery of drugs on the physiology of the lung has not been evaluated early in the development process. The prospect of using the lungs for the delivery of biological molecules such as proteins, peptides, and nucleic acids raises the question of the local toxicity of these compounds. Therefore, criteria must be established to study the initial impact of pulmonary drug delivery on the physiology of the lungs. This relates particularly to subtle local and systemic implications of those effects on the transport phenomena that may be contrasted with conventional toxicity studies focused on gross effects.

Administration, Inhalation↗
PubMed2000

Identification of genes in the genome of the archaeon Methanosarcina mazeii that code for homologs of nuclear eukaryotic molecules involved in RNA processing.

A 2.6kb fragment of chromosomal DNA from the archaeon Methanosarcina mazeii was sequenced and analyzed, and it was found to contain coding regions for three proteins that were 321, 234, and 193 amino acids (aa) in length. Homologs of the 321-aa protein were found in all archaeal genomes examined, but not in eukaryotic or bacterial genomes, with one exception in the latter. The protein with 234aa (named PrpM) was most similar to the putative protein Prp31p from Methanobacterium thermoautotrophicum, while the 193-aa protein (named FibM) was identified as an archaeal fibrillarin homolog. Prp and fibrillarin proteins are involved in RNA processing in eukaryotes, but their functions in archaea are not yet understood. The M. mazeii PrpM was also similar to three proteins from Saccharomyces cerevisiae: Prp31p, Nop56p, and Nop58p. Prp31p is a pre-mRNA processing protein, while Nop56p and Nop58p are involved in rRNA processing and interact with fibrillarin. No homologs of either protein were found in bacteria. The archaeal fibrillarin was shorter than its eukaryotic counterpart because it lacked the N-terminal glycine-arginine-rich (GAR) domain, present in most eukaryal homologs. The archaeal prp and fibrillarin gene homologs were found adjacent to each other, whereas in eukarya these genes are on separate chromosomes. Sequence signatures typical of the eukaryal molecules were identified in the M. mazeii and the other archaeal molecules studied. The close proximity of the prp and fib genes raises the possibility of a Prp-fibrillarin interaction in archaea.

Amino Acid Sequence↗
PubMed2000

Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: manufacture and characterization.

PURPOSE: Particles with aerodynamic diameters of 1-5 microm deposit in the periphery of the lungs and are phagocytized by alveolar macrophages, the primary site of Mycobacterium tuberculosis infection. Aerosols of biodegradable polymeric microspheres containing antitubercular agents may be delivered to the lungs to improve the treatment of tuberculosis. METHODS: Poly(lactide-co-glycolide) (PLGA) microspheres containing rifampicin were prepared using solvent evaporation and spray drying methods. The solvent evaporation process was optimized using factorial experimental design and surface response methodology. The morphology, particle size, drug loading, and dissolution of microspheres was evaluated. RESULTS: The spray dried rifampicin loaded PLGA microparticles were shriveled, unlike the spherical particles produced by solvent evaporation. Drug loadings of 20% and 30% were achieved for solvent evaporation and spray dried products, respectively. The particles prepared by solvent evaporation and spray drying had 3.45 microm and 2.76 microm median diameters by volume, respectively. CONCLUSIONS: Respirable rifampicin loaded PLGA microspheres were produced by both solvent evaporation and spray drying methods. These particles are being evaluated in an animal model of tuberculosis.

Antibiotics, Antitubercular↗
PubMed2000

Lecithin inverse microemulsions for the pulmonary delivery of polar compounds utilizing dimethylether and propane as propellants.

Lecithin inverse microemulsions were investigated as a means of pulmonary drug delivery, utilizing dimethylethyleneglycol (DMEG) and hexane as models for dimethyl ether (DME) and propane, respectively. Addition of lecithin to the model propellant mixtures increased the solubility of water in a nonlinear, solvent-dependent manner. The concentration of water necessary to fully hydrate cobalt(II) decreased as the solvent composition was varied from DMEG to hexane. Water proton chemical shift increased in the presence of lecithin, with the largest increases in high hexane content samples. Equilibrium dialysis and component diffusion rate determination (by pulsed-field gradient [PFG]-NMR) indicated the quantity of water associated with the dispersed phase. Collectively, these methods demonstrated that a greater fraction of water was associated with the microemulsion-dispersed phase as the solvent was varied from DMEG to hexane. Iodine solubilization indicated microemulsion formation (operational critical micelle concentration [cmc], 10 moles water per mole lecithin) at approximately 10(-4)-10(-5) molal lecithin. NMR data (trimethylammonium proton chemical shift, water, and lecithin T1) were consistent with microemulsion formation. Water-soluble compounds dissolved in lecithin inverse microemulsions in a lecithin- and water-dependent manner. Experiments with DME/lecithin demonstrated microemulsion characteristics similar to those in the model propellant. DME/lecithin metered-dose inhalers (MDIs) produced a particle size and a fine particle fraction (36% by twin impinger method) suitable for pulmonary drug delivery.

Aerosol Propellants↗
PubMed2000

Aerosol delivery of muramyl dipeptide to rodent lungs.

Tuberculosis is the single most serious infectious disease worldwide. The respiratory tract is the primary site of infection by Mycobacterium tuberculosis(MTB). A number of immunogenic components of the cell wall of MTB, if delivered to the lungs as aerosols, can be used to study the local immune response. The site of deposition of these aerosols can be employed to control their residence time in the lungs. Muramyl dipeptide (MDP) aerosols were delivered to alveolar macrophages in the lungs of rodents. Guinea pig macrophages harvested by bronchoalveolar lavage were examined by differential interference contrast microscopy for morphological changes indicative of activation. Bronchoalveolar lavage fluid was analyzed for the presence of alkaline phosphatase, lactate dehydrogenase, N-acetyl-glucosaminidase (NAG), and total protein content. Rat alveolar macrophages were studied for the production of nitric oxide, by induction of nitric oxide synthase. Twenty-four hours following exposure to an aerosol of MDP, alveolar macrophages exhibited morphological characteristics (spreading and pseudopodia), enzyme activity (NAG 50% above control), and production of the reactive intermediate nitric oxide. Rat macrophages subjected to aerosol exposure to MDP when challenged with a second dose of MDP or lipopolysaccharide exhibited a linear dose response as measured by nitric oxide production. These studies indicate that the topical delivery of an MTB bacterial cell wall component, muramyl dipeptide, results in activation of alveolar macrophages. This approach may be useful in elucidating elements of the immune response to MTB.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2000

Effect of chloroquine on phagolysosomal fusion in cultured guinea pig alveolar macrophages: implications in drug delivery.

The aim of this study was to evaluate the effects of chloroquine on phagolysosomal fusion (PLF) in cultured guinea pig alveolar macrophages (AMs). This technique may be of significance for antitubercular drugs, because.the survival of Mycobacterium tuberculosis is linked to evasion of PLF. Guinea pig AMs were obtained from anesthetized animals after exsanguination. The AMs were cultured at a density of 1 x 10(6) cell/mL in 24-well plates after attachment to 13-mm coverslips. Culture conditions were at 37 degrees C, with 95% air/5% CO2 in Roswell Park Memorial Institute (RPMI) 1640 medium with 10% heat-inactivated fetal bovine serum. Rhodamine-dextran (70 kd) was incubated with the cells at 0.25 mg/mL for 24 hours to label the lysosomes. Chloroquine treatment where indicated was performed at 10-20 microg/mL for 1 hour. Fluorescent BioParticles were then added, and PLF was monitored by formation of an orange-yellow fluorescence on fusion of green fluorescent BioParticles with rhodamine-labeled lysosomes. PLF endpoints were measured by scoring for the percentage of orange-yellow cells in the field of view. Image analysis to measure the intensity of the orange-yellow color was performed by obtaining a, b values for 5 x 5 pixel areas using the PhotoAdobe program 4.0.1. The results indicated that the rate of PLF was enhanced by chloroquine. Thus, chloroquine may be used to potentiate the effects of rifampicin. This may be confirmed by studies involving similar dual fluorophore labeling techniques of fluorescein-labeled formulation in macrophages infected with M.tuberculosis. Preliminary studies with the rhodamine-labeled formulation confirmed cellular uptake and persistence for up to 7 days in culture.

Animals↗