LC Plus Research Articles

AN IN VITRO COMPARISON OF THE IMPACT OF JET NEBULIZER DESIGN ON THE AEROSOL CHARACTERISTICS OF ALBUTEROL, IPRATROPIUM BROMIDE, AND BUDESONIDE

PURPOSE: Jet nebulizers are typically classified as conventional (e.g. Salter 8900®), active venturi (e.g. Sidestream®), or breath-enhanced (e.g. Pari LC Plus®) depending on air flow characteristics through the device. The in vitro aerosol characteristics of drugs like albuterol, ipratropium bromide and budesonide are likely to be affected by differences in nebulizer design.

Lung deposition of aerosolized anticancer drugs with a novel inhalation system: AKITA

12037 Background: Inhalation of anticancer drugs might be a helpful route of delivery in cancer therapy, particularly for lung tumors and metastasis in the lungs. In this experimental setup 12 different drugs (including antineoplastic drugs and immunotherapeutics) were nebulized with two different jet nebulizer systems. Aerosol particle size (MMD) and mass output were characterized. Methods: MMD was measured using a laser diffraction system (Sympatec, Clausthal-Zellerfeld, Germany). Mass output measurements were performed after CEN Standard using a Flow/volume simulator with radiolabelled (99m Tc) solution/suspension. The amount of radioactivity on the filters was detected with a scintillation counter. For aerosolization two nebulizer systems were used: Pari LC Plus with Pari compressor (PARI) and Pari LC Star with AKITA compressor (AKITA). To determine lung deposition a lung deposition model (International Commission of Radiological Protection, ICRP66, 1994) was used, taking into account: mass output, particle size and breathing pattern of patients. The AKITA guides the patient with a positive pressure through the inhalation maneuver, it is breath activated and delivers the medication only during inspiration. The PARI nebulizes continuously and the patient inhales with different individual breathing pattern. Results: MMD with PARI was found to be 4.2 ± 0.4 μm compared to 3.40 ± 0.3 μm for AKITA. After filling 2.5 ml into the nebulizers we found 1.4 ml residual volume with PARI and 1.0 ml for AKITA. The output rate was 0.15 ± 0.02 ml/min for PARI and 0.29 ± 0.03 ml/min for AKITA. Lung deposition relative to the emitted dose was determined to be 28 ± 10% for PARI and 85 ± 4% for AKITA. This is because the AKITA nebulizes only during inspiration and guides the patient through the inhalation maneuver, where as the PARI is running continuously and patients inhale with different breathing pattern. The result is that from 2.5 ml filled into the nebulizer, on average 0.3 ml will be deposited in the lungs with the PARI and 1.3 ml with the AKITA. To deposit 1 ml in the lungs with AKITA it will take 7 min, with PARI about 24 min. Conclusions: By use of modern inhalation devices with controlled inhalation lung deposition for cancer therapy can be optimized. [Table: see text]

Inhaled Azithromycin Therapy

The treatment of pulmonary infectious diseases with pharmaceutical aerosols is an attractive option considering the accessibility of the lungs for topical drug delivery. Aerosols have been targeted to the lungs for the treatment of asthma with great success. Current therapies for other diseases, including Pseudomonas aeruginosa, Pneumocystis jirovecii (formerly Pneumocystis carinii), and mycobacterial infections, remain suboptimal due to the efficacy/safety profile. This may be improved by aerosol targeted pulmonary drug delivery. Azithromycin is a broad spectrum antibiotic that acts by inhibiting protein synthesis. It is associated with side effects that might be avoided by aerosol delivery to the lungs. In the present study three concentrations of azithromycin (10, 50, and 100 mg/mL) were delivered from three nebulizers (Acorn II, Updraft, and LC Plus) operated at 8 L/min. Particles size analyses were conducted by inertial impaction and laser diffraction. In addition, emitted doses were determined. A linear proportionality existed across the concentration range between nominal dose and both fine particle dose/fraction and emitted dose, with R2 > 0.999 in all cases. The mass median aerodynamic diameter increased from 1.4 to 1.9 microm between 10 and 100 mg/mL of azithromycin solution concentration for the Acorn II. The particle size distributions were not all log-normally distributed. The median particle size delivered from the devices was largest for the Updraft (2.8 microm) and smallest for the Acorn II (1.9 microm) for 100 mg/mL azithromycin solution concentrations. The efficiencies of small particle delivery (%<4.7 microm) were as follows, LC Plus = Acorn II (85%) > UpDraft (75%). However, the emitted dose from the LC Plus (55 mg/min) was higher than the Acorn II (31 mg/min) to maximize lung exposure to the aerosol, small median diameters and broad particle size distributions would be most effective. This study demonstrates that the dose delivered to the lungs will be maximized, under the current operating conditions by adopting the LC Plus, and high (100 mg/mL) azithromycin concentrations.

Effect of High-Frequency Chest Wall Oscillation on the Central and Peripheral Distribution of Aerosolized Diethylene Triamine Penta-acetic Acid as Compared to Standard Chest Physiotherapy in Cystic Fibrosis

High-frequency chest wall oscillation (HFCWO) has been shown to be as effective as standard chest physiotherapy (SCPT) for removal of pulmonary secretions as well as increasing FEV(1) in cystic fibrosis (CF) patients. Patients using HFCWO often administer aerosolized medications simultaneously, reducing time required for daily care. While peripheral pulmonary distribution of tracer in normal subjects has been shown to be unaffected by HFCWO, this has not been studied in CF patients. We evaluated distribution of aerosolized (99m)Tc diethylene triamine penta-acetic acid (DTPA) administered simultaneously with HFCWO and compared this with DTPA aerosolized after SCPT. Ten CF patients, ages 22 to 38 years, with moderate-to-severe obstructive disease were studied in a crossover design after documentation of stable lung function. (133)Xe was administered to delineate total lung volume. DTPA was aerosolized (Pari LC Plus nebulizer and Pulmo-Aide compressor; Pari Respiratory Equipment Inc.; Richmond, VA) to delineate airway deposition. The central to peripheral deposition ratio (C/P ratio) of each lung was analyzed in each study group. Central regions were represented by the inner one third of the (133)Xe scan as demonstrated in previous research models. The mean C/P ratio (+/- SD) for both lungs was 1.45 +/- 0.31 with HFCWO and 1.46 +/- 0.28 following SCPT (p = not significant [NS]). Right lung mean C/P ratio was 1.74 +/- 0.43 with HFCWO and 1.85 +/- 0.63 after SCPT (p = NS). Left lung mean C/P ratio was 1.25 +/- 0.29 with HFCWO and 1.21 +/- 0.35 after SCPT (p = NS). There was no correlation between C/P ratio and FEV(1) or FVC. Use of HFCWO in combination with aerosolized DTPA did not result in increased central deposition as compared with aerosolized DTPA administered after SCPT. Further study is required to determine if combining HFCWO with aerosolized medications can be modified to improve peripheral deposition.

177 Delivery of tobramycin via the I-nebTM adaptive aerosol delivery (AADO) system and the Pari LC Plus® nebulizer

177 Delivery of tobramycin via the I-nebTM adaptive aerosol delivery (AADO) system and the Pari LC Plus® nebulizer

175 Dosing tobramycin in the inhalation therapy of Cystic Fibrosis — a comparison of LC PLUS used in breath triggered mode and EFLOW RAPID

175 Dosing tobramycin in the inhalation therapy of Cystic Fibrosis — a comparison of LC PLUS used in breath triggered mode and EFLOW RAPID

Feasibility of Shortened Methacholine Challenge in Preschool Children

The aim of our study was to assess the feasibility and safety of a recently suggested tripling-dose methacholine (Mch) challenge in preschool children. Fifty-seven children aged 3-6 years were studied. Mch challenge was carried out using a tidal breathing method, with concentrations of 0.22, 0.66, 2.0, 6.0, and 18.0 mg/ml, at 5-min intervals, given by a Pari Turbo Boy compressor and Pari LC Plus nebulizer, for 1 min only. Oxygen saturation (SaO(2)) was monitored during the challenge. The challenge was terminated if there was wheeze, SaO(2) below 91%, or persistent cough. This final Mch dose was considered the provocative concentration inducing audible wheeze (PCW). Nine healthy children, 17 with cough and 25 with wheeze, completed the study. Mean output from nebulizers (SD) in these 51 children was 0.30 (0.05) ml/min. Geometric means for PCW in these groups were 2.88, 2.58, and 1.28 mg/ml Mch, respectively. The wheezing children were significantly more hyperresponsive than the coughing children (P < 0.05). A tripling-dose Mch protocol is safe and practicable in children over 3 years of age. A further reduction in nebulized dose may be needed for a more discriminatory test.

Evaluation of Nebulizer Performance under Various Humidity Conditions

Jet nebulizers are a drug delivery tool commonly used for treating respiratory diseases. When a nebulizer generates aerosols, the rate at which droplets evaporate depends on humidity conditions around the nebulizer outlet. Because the relative humidity (RH) of the air affects the evaporation rate, the aerosol distribution and drug delivery dose is also affected by RH. Four nebulizers were chosen for comparison in this study: PARI LC Plus (PARI Respiratory Equipment, Inc., Midlothian, VA), SideStream (Medic-Aid Ltd., UK), VixOne (Westmed, Inc., Tucson, AZ), and Micromist (Hudson Respiratory Care Inc., Temecula, CA). Two different formulations were used: albuterol (liquid solution) and budesonide (suspension). Particle distribution (mass median aerodynamic diameter [MMAD] and geometric standard deviation [GSD]), nebulizer efficiency (total efficiency and respirable fraction [RF] efficiency for particles less than 4.7 microm), and dead volume (the amount of solution remaining after nebulization) were compared at the RH of 5%, 50%, and 80%. Our results showed that the MMAD increased (p value varied from <0.001 to 0.016) with the increase in RH, except for with the VixOne unit with albuterol (p = 0.24). The MMAD from the budesonide always appeared higher than from the albuterol. The RF (and thus, the inhalation dose) was lower with a higher RH. Except for the PARI LC Plus with budesonide, the RF decreased approximately 15-27% when the RH rose from 5% to 50%. For the PARI LC Plus nebulizer, the lower dead volume (0.22 mL) with higher residual drugs (62.3% of total drug) was obtained at an RH of 5% comparing the RH of 50% and 80% because of the unit's unique design.

The influence of accelerating the setting rate by ultrasound or heat on the bond strength of glass ionomers used as orthodontic bracket cements

Conventional glass ionomer cements (GICs) may be a viable option for bracket bonding when the major disadvantages of these materials, such as the slow setting reaction and the weak initial bond strength, are solved. The aim of this in vitro study was to investigate the influence of ultrasound and heat application on the setting reaction of GICs, and to determine the tensile force to debond the brackets from the enamel. A conventional fast-setting GIC, Fuji IX Fast, and two resin-modified glass ionomer cements (RMGICs), Fuji Ortho LC and Fuji Plus, were investigated. Three modes of curing were performed (n = 10): (1) according to the manufacturer's prescription, (2) with 60 seconds application of heat, or (3) with 60 seconds application of ultrasound. The tensile force required to debond the brackets was determined as the tension 15 minutes after the start of the bonding procedure. The mode of failure was scored according to the Adhesive Remnant Index (ARI) to establish the relative amount of cement remnants on the enamel surface. Curing with heat and ultrasound shortened the setting reaction and significantly (P < 0.05) increased the bond strength to enamel. The ARI scores showed an increase for all materials after heat and ultrasound compared with the standard curing method, most notably after heat application.

In vitro comparison of an electronic micropump and jet nebulizer with budesonide

RATIONALE: Budesonide was approved for use with jet nebulizers. The Aeroneb® Go Nebulizer (Aerogen, Inc.) generates aerosol using the OnQ™ electronic micropump. To determine capabilities of this newer technology, we compared nebulization of budesonide respules 0.5 mg / 2.0mL (AstraZeneca) with the Go and the LC Plus® (Pari, Inc.). METHODS: : Inhaled mass of budesonide was collected on a filter placed between the nebulizer and breathing simulator (Hans Rudolph; adult pattern). Aerosol mass median aerodynamic diameter (MMAD), Geometric Standard Deviation (GSD) and fine particle fraction less than 5.8 μm (FPF) were determined by cascade impaction (Anderson Mk II). Three units of each device were tested in triplicate. Drug deliuvery determined by HPLC. RESULTS: The MMAD (μm) ± GSD of the Go (3.1 ± 1.6) was less than the LC Plus (3.8 + 1.7). Inhaled mass for the Aeroneb Go was 115±13 μg (22±3% of dose) and 91± 14 (18 ± 3% of dose) for the LC Plus (p=0.03:ANOVA). Respirable mass (inhaled mass x FPF) was greater for the Go (20±2 %) than the LC Plus (13±1 %) (p=0.001). Treatment time was 6 min for the Go and 5 min for the LC Plus. CONCLUSIONS: Aerosol delivery of budesonide suspension by the electronic micropump (Aeroneb Go) was similar to the most efficient jet nebulizer (LC Plus). Although budesonide is approved only for use with jet nebulizers, the Aeroneb Go delivered higher inhaled and respirable mass in this in vitro model.

112 In-Vitro equivalence and shorter nebulization time using a novel tobramycin formulation (150 mg/ 1.5 ml) in an eFlow® electronic nebulizer compared to TOBI® nebulized by the PARI LC PLUS®

112 In-Vitro equivalence and shorter nebulization time using a novel tobramycin formulation (150 mg/ 1.5 ml) in an eFlow® electronic nebulizer compared to TOBI® nebulized by the PARI LC PLUS®

Delivery of liposomes generated from proliposomes using air-jet, ultrasonic, and vibrating-mesh nebulisers

Abstact In this study, particulate-based proliposomes were investigated as a formulation which would form, an isotonic liposome dispersion in situ when nebulised within a medical nebuliser. Transmission electron microscopy and particle size analysis indicated that liposomes were generated from soyaphosphatidylcholine/cholesterol/sucrose proliposomes in air-jet (Pari LC Plus), ultrasonic (Liberty) and vibrating-mesh (Omron NE- U22) nebulisers, without the need for a prolonged hydration step. With jet and vibrating-mesh nebulisers, liposomes were efficiently delivered to the second (lower) stage of a two-stage impinger, indicating such liposomes would be predicted to be delivered to the peripheral airways. Phos- pholipid output from these nebulisers was less than the total mass output, suggesting some accumulation of liposomes in the nebuliser reservoir. The ultrasonic nebuliser delivered less than 6% of available phospholipid to the impinger, demonstrating that this device was inappropriate for delivering a therapeutic proliposome formulation for pulmonary administration. These results show that proliposomes offer a means of producing stable formulations which can readily generate isotonic liposome formulations in situ for delivery to the airways using either an air-jet or vibrating-mesh nebuliser.

Dose‐response to salbutamol via a novel palm sized nebuliser (Aerodose® Inhaler), conventional nebuliser (Pari LC Plus) and metered dose inhaler (Ventolin™ Evohaler™) in moderate to severe asthmatics

The Aerodose inhaler is a novel, palm-sized, breath actuated device which requires little patient coordination. This study compared the dose-response of salbutamol delivered by the Aerodose Inhaler (Aerogen Inc., Mountain View, USA) vs Pari LC Plus jet nebulizer (Pari LC Plus; Pari GmbH, Starnberg, Germany) and Ventolin Evohaler HFA pMDI (Evohaler; Allen & Hanburys [GlaxoSmithkline], Uxbridge, UK). Twenty-two moderate to severe asthmatic patients, mean (s.d.) age: 44.7 (9.4), FEV(1): 58.1 (12.0), received 4 cumulative doubling doses of salbutamol in a randomised, investigator blind, balanced crossover design. Spirometry and systemic safety variables (heart rate, blood pressure, T wave amplitude, QTc interval and potassium) were measured at baseline and after each dose. Parallel regression analysis revealed that microgram relative potency ratios for the Aerodose Inhaler to be five times more efficient for FEV(1) than either the Pari LC Plus (0.202, 90% CI: 0.189-0.216) or the Evohaler (0.202, 90% CI: 0.189-0.216), while there was no difference between Pari LC Plus vs Evohaler. Similarly, Aerodose Inhaler vs. Pari LC Plus showed approximately five-fold greater potency for all systemic parameters, except blood pressure. As compared to the Evohaler, Aerodose Inhaler had equivalent potency for plasma potassium and T wave amplitude, but demonstrated greater potency for heart rate and QT(c) interval. This study has indicated therefore, that Aerodose Inhaler is approximately five times as efficient as the Pari LC Plus and Evohaler in relative lung delivery of salbutamol in moderate to severe asthmatics.

Compatibility of budesonide inhalation suspension with four nebulizing solutions.

Nebulizable medications often are mixed to simplify asthma medication regimens. To establish the in vitro chemical compatibility and stability of budesonide inhalation suspension 0.25 mg/2 mL and 0.5 mg/2 mL mixed in Pari LC Plus jet nebulizer cups with 3 mL of levalbuterol hydrochloride 0.63 mg/3 mL and 1.25 mg/3 mL; 0.5 mL of albuterol sulfate 5 mg/mL; 2 mL of cromolyn sodium 20 mg/2 mL; or 2.5 mL of ipratropium bromide 0.2 mg/mL. We developed and validated isocratic HPLC methods to permit separation of the admixture components from aliquots taken 0, 5, 15, and 30 minutes after mixing. Admixtures were prepared and analyzed at room temperature. Each assay was conducted 3 times using separate nebulizer cups. All components were quantified by external standards using HPLC-derived peak area. Appearance and pH of the admixtures were recorded. No additional peaks occurred in any HPLC chromatogram for any medication from any admixture. With the exception of ipratropium bromide at 93%, each admixture retained >97% of the initial concentration of each medication in the nebulizer cup. There was no significant change in pH or visual identification of a precipitate in any admixture of active drugs. These data support the chemical compatibility of budesonide inhalation suspension for up to 30 minutes with other commonly used nebulized medications for controlling pediatric asthma symptoms.

Repeated Adeno-Associated Virus Serotype 2 Aerosol-Mediated Cystic Fibrosis Transmembrane Regulator Gene Transfer to the Lungs of Patients With Cystic Fibrosis: A Multicenter, Double-Blind, Placebo-Controlled Trial

The primary objective was to determine the safety and tolerability of repeated doses of aerosolized adeno-associated serotype 2 vector containing cystic fibrosis transmembrane conductance regulator (CFTR) complementary DNA (cDNA) [tgAAVCF], an adeno-associated virus (AAV) vector encoding the complete human CFTR cDNA. Secondary objectives included evaluation of pulmonary function assessed by spirometry, lung abnormalities by high-resolution CT (HRCT), airway cytokines, vector shedding, serum neutralizing antibody to AAV serotype 2 (AAV2), and gene transfer and expression in a subset of subjects undergoing bronchoscopy with bronchial brushings. Randomized, double-blind, placebo-controlled, phase II trial. Eight cystic fibrosis (CF) centers in the United States. CF patients with mild lung disease, defined as FEV(1) > or =60% predicted. Subjects were randomized to inhale three aerosolized doses of 1 x 10(13) deoxyribonuclease-resistant particles of tgAAVCF or matching placebo at 30-day intervals using the Pari LC Plus nebulizer (PARI; Richmond, VA). Of 42 subjects randomized, 20 subjects received at least one dose of tgAAVCF and 17 subjects received placebo. No difference in the pattern of adverse events or laboratory abnormalities was noted between the two treatment groups. Improvements in induced-sputum interleukin-8 (p = 0.03) and FEV(1) (p = 0.04) were observed at day 14 and day 30, respectively, in the group receiving tgAAVCF when compared to those receiving placebo. No significant differences in HRCT scans were noted. Vector shedding in sputum was observed at low levels up to 90 days after the third dose of vector. All subjects receiving tgAAVCF exhibited an increase (by at least fourfold) in serum AAV2-neutralizing antibodies and detectable levels in BAL fluid from five of six treated subjects undergoing BAL. Gene transfer but not gene expression was detected in a subset of six tgAAVCF subjects who underwent bronchoscopy. Repeat doses of aerosolized tgAAVCF were safe and well tolerated, and resulted in encouraging trends in improvement in pulmonary function in patients with CF and mild lung disease.

The choice of a compressor for the aerosolisation of tobramycin (TOBI ®) with the PARI LC PLUS ® reusable nebuliser

The performance of five different compressors (CR60 ®, Porta-Neb ®, Pulmo-Aide ®, TurboBoy ® and Freeway ® Freedom) was studied in combination with the widely recommended PARI LC PLUS ® nebuliser for the aerosolisation of a marketed tobramycin solution (TOBI ®). The droplet size distribution of the generated aerosol was measured with laser diffraction technique at stationary inspiratory flow rates through the nebuliser cup of 20, 30 and 40 l N/min. The different compressors showed a distinct difference in droplet size distribution of the aerosol and nebulisation time till dry running. The finest droplets with a volume (equals mass) median diameter (mmd) of 1.84 μm (which was the same at all flow rates), as well as the narrowest size distribution were obtained with a CR60 ®. The Freeway ® Freedom generated the largest droplets: mmd ranged between 2.63 and 3.72 μm depending on the inspiratory flow rate. The aerosol produced with this compressor also had the widest size distribution. The differences between the compressors could be explained with differences in the jet flow. A higher jet flow resulted in finer droplets, less dependence on the inspiratory flow rate and a shorter time till dry running. Thus, to obtain the required fineness of the aerosol for peripheral airway deposition of the tobramycin, independent of the inspiratory flow rate, the use of the CR60 ® compressor is preferred over the use of Porta-Neb ®, Pulmo-Aide ®, TurboBoy ® and Freeway ® Freedom (in order of decreasing preference). Finally, it was found that careful cleaning with warm water and liquid soap of the nebuliser cup is essential to obtain adequate performance of the LC PLUS ®.

Comparison of lung deposition of colomycin using the HaloLite and the Pari LC Plus nebulisers in patients with cystic fibrosis

Aim: To examine the effectiveness of delivery of nebulised colistin by the HaloLite nebuliser compared to the Pari LC Plus in patients with cystic fibrosis. Methods: Randomised crossover trial of...

Lung deposition in cystic fibrosis patients using an ultrasonic or a jet nebulizer.

This study was conducted to compare pulmonary deposition following inhalation with an ultrasonic and a jet nebulizer in CF patients under conditions relevant to practice. The marker substance used to estimate the relative lung bioavailability was sodium cromoglycate (SCG), which is poorly absorbed from the gastrointestinal tract, but is completely absorbed from the lungs. Ten CF patients (aged 9-21 years) used an ultrasonic nebulizer (Multisonic compact 2.4 MHz) and a jet nebulizer (Parimaster, LC Plus Turbo) in a crossover design to inhale a solution containing 20 mg of SCG and a beta(2)-agonist. Urine was collected in five fractions until 12 h p. a., and the excreted SCG was determined by means of HPLC. Prior to each inhalation, the patients' pulmonary function was measured employing a Pneumoscope. Using the ultrasonic nebulizer, the amount of SCG excreted in urine was significantly greater than that after inhalation with the jet nebulizer (1.43 +/- 0.47 mg vs. 1.04 +/- 0.47 mg; p = 0.002), despite the larger residual volume in the ultrasonic nebulizer. The absorption half-life for SCG following ultrasonic nebulization was significantly shorter when compared with jet nebulization (84 +/- 14 min vs. 101 +/- 19 min; p = 0.005), being suggestive of a more peripheral deposition. Furthermore, an inverse relationship was found between absorption half-life and FEV(1) (% pred.) (r = -0.655, p = 0.04) or MMEF(75/25) (% pred.) (r = -0.844, p = 0.031), but only with the ultrasonic nebulizer. In conclusion, the ultrasonic nebulizer tested when used for inhalation in CF patients was found to be at least equivalent to the jet nebulizer.

Efficiency of Pulmonary Administration of Tobramycin Solution for Inhalation in Cystic Fibrosis Using an Improved Drug Delivery System

To determine whether tobramycin solution for inhalation (TSI) can be administered safely and more efficiently with a new-generation aerosol device, the AeroDose 5.5 RP inhaler (Aerogen; Mountain View, CA) than with the approved PARI LC PLUS nebulizer (PARI Respiratory Equipment; Monterey, CA) with Pulmo-Aide compressor (DeVilbiss Corp; Somerset, PA). Second, we wanted to ascertain which AeroDose-delivered tobramycin dose is equivalent to the standard 300-mg dose administered with the PARI LC PLUS. Open-label, randomized, multicenter, single-dose, three-period, four-treatment, active- control, crossover trial. Nine US cystic fibrosis (CF) centers. Fifty-three patients >or= 12 years of age with a confirmed diagnosis of CF, the ability to expectorate sputum, and FEV(1) of >or= 40% of predicted. Subjects inhaled three single doses of TSI at 1-week intervals, as follows: conventional control treatment, 300 mg via the PARI LC PLUS; and two of three experimental treatments, 30, 60, or 90 mg via the AeroDose. FEV(1) was measured before and after dosing. After each dose, sputum and serum samples were collected at various intervals for 8 h, and urine was collected for 24 h to estimate lung and systemic tobramycin delivery. There were no significant differences between treatments in the change in FEV(1) 30 min after dosing or in the frequency of adverse events. Sputum and serum levels of tobramycin produced by the AeroDose 90-mg dose treatment approximated those achieved with the PARI LC PLUS 300-mg dose treatment. Nebulization times using the AeroDose inhaler were < 50% those of the PARI LC PLUS. Compared with the standard nebulizer, the AeroDose safely achieved an approximately threefold greater efficiency in the delivery of TSI to the lungs in less than half the time.

Inhaled tobramycin (TOBI): a review of its use in the management of Pseudomonas aeruginosa infections in patients with cystic fibrosis.

Specifically formulated for nebulisation using the PARI LC PLUS reusable nebuliser, tobramycin solution for inhalation (TSI) [TOBI] provides a high dose of tobramycin (an aminoglycoside antibacterial with good activity against Pseudomonas aeruginosa) to the lungs of patients with cystic fibrosis, while maintaining low serum concentrations of the drug, thus reducing the risk of systemic toxicity. Intermittent (28-day on/28-day off) treatment with TSI 300 mg twice daily significantly (p < 0.001) improved lung function and sputum P. aeruginosa density compared with placebo (randomised double-blind trials), and was significantly (p = 0.008) more effective than colistin for improvement in forced expiratory volume in 1 second (small nonblind trial) in patients aged > or =6 years with cystic fibrosis and chronic P. aeruginosa infection. Improvements in lung function were most marked in adolescent patients (aged 13-17 years) in placebo-controlled trials. Improvements were maintained for up to 96 weeks in patients in an open-label extension study. Fewer TSI than placebo recipients required parenteral antipseudomonal agents or hospitalisation. In addition, TSI 300 mg twice daily for 28 days reduced P. aeruginosa density in the lower airways of patients aged <6 years with early colonisation and cystic fibrosis, although TSI is not currently indicated in this patient group. A decrease in tobramycin susceptibility of P. aeruginosa isolates and an increase in fungal organisms (Candida albicans and Aspergillus species) during prolonged intermittent treatment with TSI 300 mg twice daily was not associated with adverse clinical outcome. There was no evidence of selection for the most resistant isolates. TSI is generally well tolerated, with no renal toxicity or hearing loss in clinical trials, although transient mild or moderate tinnitus occurred more frequently in TSI than placebo recipients. Bronchospasm after administration of TSI was transient and occurred with a similar incidence to that with placebo; TSI is preservative free and specifically formulated for the lung in terms of osmolality and pH. In conclusion, TSI provides an effective means of delivering tobramycin to the lungs of patients with cystic fibrosis with chronic P. aeruginosa infection, improving lung function and sputum P. aeruginosa density in these patients without the nephrotoxicity or ototoxicity of parenteral aminoglycosides. Further data on the potential for and clinical significance of increased tobramycin resistance and fungal colonisation during TSI treatment would be beneficial, as would longer-term data. In the meantime, TSI represents a valuable option for suppressive antipseudomonal therapy in patients with cystic fibrosis.