Pooled analysis of tiotropium Respimat(®) pharmacokinetics in cystic fibrosis.

Tiotropium is the first bronchodilator to be studied systematically in cystic fibrosis (CF). We investigated whether any intrinsic or extrinsic factors affected pharmacokinetic (PK) parameters of inhaled tiotropium delivered by Respimat(®) in adults and children with CF. Tiotropium PK in patients with CF was compared with that of healthy volunteers and patients with chronic obstructive pulmonary disease (COPD). This pooled analysis summarizes the PK parameters of inhaled tiotropium Respimat(®) across 9 early- and late-phase trials involving 27 healthy volunteers (1 trial), 409 patients with CF (3 trials), and 281 patients with COPD (5 trials). Patients with CF aged 5 to 11, 12 to 17, and ≥ 18 years had similar tiotropium plasma concentrations (geometric mean C(0.083,ss,norm): 2.22 pg/mL/µg; not determined for patients aged <5 years). The fraction excreted unchanged in the urine was 3.4-fold lower for patients aged 0.4 to <5 years than for those aged 5 to 11 years (fe(0-4,ss): 1.19% vs 4.09%). Tiotropium PK parameters were similar between CF patients and COPD patients.

Influences of cannula size and flow rate on aerosol drug delivery through the Vapotherm humidified high-flow nasal cannula system.

OBJECTIVE: We investigated the in vitro inspired dose and particle size distribution of albuterol delivered by a vibrating mesh nebulizer through the Vapotherm (Stevensville, MD) humidified high-flow nasal cannula system. DESIGN: Albuterol (2.5 mg/3 mL) was delivered by an Aeroneb Solo (Aerogen, Galway, Ireland) nebulizer that was connected via adaptor proximal to the nasal cannula and downstream from the Vapotherm 2000i. Albuterol was collected onto an inspiratory filter mounted to a breath simulator programmed with age-appropriate breathing patterns. Particle sizing was completed by cascade impaction. Albuterol was quantified using ultraviolet spectrometry. Measurements were made using varying flow rates through infant, pediatric, and adult nasal cannulae. SETTING: Aerosol research laboratory. MEASUREMENTS AND MAIN RESULTS: The inspired dose (percent of nominal dose) for each cannula size and flow rate was 2.5%, 0.8%, 0.4%, and 0.2% for the adult cannula at 5, 10, 20, and 40 L/min, respectively; 1.2%, 0.6%, 0.1%, and 0.0% for the pediatric cannula at 3, 5, 10, and 20 L/min, respectively; and 0.6%, 0.6%, and 0.5% for the infant cannula at 3, 5, and 8 L/min, respectively. Most (62-80%) of the loaded albuterol dose accumulated within the adaptor. For each cannula size, there was a significant decrease in the inspired dose with increasing flow rates, p = 0.026 (infant), p = 0.001 (pediatric), and p < 0.001(adult). The inspired dose increased with increasing cannula size for 5, 10, and 20 L/min (p = 0.007, p < 0.001, and p = 0.005, respectively). The mass median aerodynamic diameter for all trials was less than 5 µm. CONCLUSION: The amount of albuterol delivered with the Vapotherm system using this model was lower than the amount expected for a clinical response for the majority of flow rates and cannula size combinations. Further studies are needed before routine use of aerosolized albuterol through a Vapotherm high-flow system can be recommended.

Fosfomycin/tobramycin for inhalation in patients with cystic fibrosis with pseudomonas airway infection.

RATIONALE: Fosfomycin/tobramycin for inhalation (FTI), a unique, broad-spectrum antibiotic combination, may have therapeutic potential for patients with cystic fibrosis (CF). OBJECTIVES: To evaluate safety and efficacy of FTI (160/40 mg or 80/20 mg), administered twice daily for 28 days versus placebo, in patients greater than or equal to 18 years of age, with CF, chronic Pseudomonas aeruginosa (PA) airway infection, and FEV(1) greater than or equal to 25% and less than or equal to 75% predicted. METHODS: This double-blind, placebo-controlled, multicenter study assessed whether FTI/placebo maintained FEV(1) % predicted improvements achieved following a 28-day, open-label, run-in course of aztreonam for inhalation solution (AZLI). MEASUREMENTS AND MAIN RESULTS: A total of 119 patients were randomized to FTI (160/40 mg: n = 41; 80/20 mg: n = 38) or placebo (n = 40). Mean age was 32 years and mean FEV(1) was 49% predicted at screening. Relative improvements in FEV(1) % predicted achieved by the AZLI run-in were maintained in FTI groups compared with placebo (160/40 mg vs. placebo: 6.2% treatment difference favoring FTI, P = 0.002 [primary endpoint]; 80/20 mg vs. placebo: 7.5% treatment difference favoring FTI, P < 0.001). The treatment effect on mean PA sputum density was statistically significant for the FTI 80/20 mg group versus placebo (-1.04 log(10) PA colony-forming units/g sputum difference, favoring FTI; P = 0.01). Adverse events, primarily cough, were consistent with CF disease. Respiratory events, including dyspnea and wheezing, were less common with FTI 80/20 mg than FTI 160/40 mg. No clinically significant differences between groups were reported for laboratory values. CONCLUSIONS: FTI maintained the substantial improvements in FEV(1) % predicted achieved during the AZLI run-in and was well tolerated. FTI is a promising antipseudomonal therapy for patients with CF.

Long-term inhaled dry powder mannitol in cystic fibrosis: an international randomized study.

RATIONALE: New treatment strategies are needed to improve airway clearance and reduce the morbidity and the time burden associated with cystic fibrosis (CF). OBJECTIVES: To determine whether long-term treatment with inhaled mannitol, an osmotic agent, improves lung function and morbidity. METHODS: Double-blind, randomized, controlled trial of inhaled mannitol, 400 mg twice a day (n = 192, "treated" group) or 50 mg twice a day (n = 126, "control" group) for 26 weeks, followed by 26 weeks of open-label treatment. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was absolute change in FEV(1) from baseline in treated versus control groups, averaged over the study period. Secondary endpoints included other spirometric measurements, pulmonary exacerbations, and hospitalization. Clinical, microbiologic, and laboratory safety were assessed. The treated group had a mean improvement in FEV(1) of 105 ml (8.2% above baseline). The treated group had a relative improvement in FEV(1) of 3.75% (P = 0.029) versus the control group. Adverse events and sputum microbiology were similar in both treatment groups. Exacerbation rates were low, but there were fewer in the treated group (hazard ratio, 0.74; 95% confidence interval, 0.42-1.32; P = 0.31), although this was not statistically significant. In the 26-week open-label extension study, FEV(1) was maintained in the original treated group, and improved in the original control group to the same degree. CONCLUSIONS: Inhaled mannitol, 400 mg twice a day, resulted in improved lung function over 26 weeks, which was sustained after an additional 26 weeks of treatment. The safety profile was also acceptable, demonstrating the potential role for this chronic therapy for CF. Clinical trial registered with www.clinicaltrials.gov (NCT 00630812).

The CHOICE survey: high rates of persistent and uncontrolled asthma in the United States.

BACKGROUND: Surveys have consistently shown that many patients with asthma do not have their disease well controlled. OBJECTIVES: The CHOICE (Comprehensive Survey of Healthcare Professionals and Asthma Patients Offering Insight on Current Treatment Gaps and Emerging Device Options) survey was designed to evaluate the current status of inhalation devices used in asthma treatment, but questions also were included about asthma severity and control. METHODS: A total of 1,000 patients with asthma were interviewed about their use of inhalation devices and asthma-related burden, medication use, and hospital/emergency care. Based on the responses to these questions, asthma severity and control were categorized using methods established in the Expert Panel Report III (EPR 3). RESULTS: Almost half (490) of the patients with asthma participating in the CHOICE survey were not using controller medications. Most of those not using controllers (79%) had persistent asthma; 47% had either mild or moderate persistent asthma. Of those on controllers (510), only 14.3% were well controlled. Acute care utilization was greater for patients with persistent asthma than those with intermittent asthma and for patients with not well and poorly controlled asthma than those with well-controlled asthma. CONCLUSION: The CHOICE survey is particularly pertinent clinically, because it demonstrates for the first time, using EPR 3 methods, the current extent of poor asthma control in the United States. This situation falls far short of national asthma management targets.

Levofloxacin inhalation solution (MP-376) in patients with cystic fibrosis with Pseudomonas aeruginosa.

RATIONALE: Lower respiratory tract infection with Pseudomonas aeruginosa (PA) is associated with increased morbidity in patients with cystic fibrosis (CF). Current treatment guidelines for inhaled antibiotics are not universally followed due to the perception of decreased efficacy, increasing resistance, drug intolerance, and high treatment burden with current aerosol antibiotics. New treatment options for CF pulmonary infections are needed. OBJECTIVES: This study assessed the efficacy and safety of a novel aerosol formulation of levofloxacin (MP-376, Aeroquin) in a heavily treated CF population with PA infection. METHODS: This study randomized 151 patients with CF with chronic PA infection to one of three doses of MP-376 (120 mg every day, 240 mg every day, 240 mg twice a day) or placebo for 28 days. The primary efficacy endpoint was the change in sputum PA density. Secondary endpoints included changes in pulmonary function, the need for other anti-PA antimicrobials, changes in patient-reported symptom scores, and safety monitoring. MEASUREMENTS AND MAIN RESULTS: All doses of MP-376 resulted in reduced sputum PA density at Day 28, with MP-376 240 mg twice a day showing a 0.96 log difference compared with placebo (P = 0.001). There was a dose-dependent increase in FEV(1) for MP-376, with a difference of 8.7% in FEV(1) between the 240 mg twice a day group and placebo (P = 0.003). Significant reductions (61-79%) in the need for other anti-PA antimicrobials were observed with all MP-376 treatment groups compared with placebo. MP-376 was generally well tolerated relative to placebo. CONCLUSIONS: Nebulized MP-376was well tolerated and demonstrated significant clinical efficacy in heavily treated patients with CF with PA lung infection. Clinical trial registered with www.clinicaltrials.gov (NCT00677365).

Pharmacokinetics and safety of MP-376 (levofloxacin inhalation solution) in cystic fibrosis subjects.

The pharmacokinetics and tolerability of nebulized MP-376 (levofloxacin inhalation solution [Aeroquin]) were determined in cystic fibrosis (CF) subjects. Ten CF subjects received single 180-mg doses of two formulations of MP-376, followed by a multiple-dose phase of 240 mg once daily for 7 days. Serum and expectorated-sputum samples were assayed for levofloxacin content. Safety was evaluated following the single- and multiple-dose study phases. Nebulized MP-376 produced high concentrations of levofloxacin in sputum. The mean maximum plasma concentration (C(max)) ranged between 2,563 and 2,932 mg/liter for 180-mg doses of the 50- and 100-mg/ml formulations, respectively. After 7 days of dosing, the mean C(max) for the 240-mg dose was 4,691 mg/liter. The mean serum levofloxacin C(max) ranged between 0.95 and 1.28 for the 180-mg doses and was 1.71 for the 240-mg dose. MP-376 was well tolerated. Nebulized MP-376 produces high sputum and low serum levofloxacin concentrations. The pharmacokinetics, safety, and tolerability were similar for the two formulations. MP-376 240 mg (100 mg/ml) is being advanced into late-stage clinical development.

Risk factors associated with depressive symptoms in caregivers of children with type 1 diabetes or cystic fibrosis.

OBJECTIVE: Evaluate depressive symptoms in caregivers of children with type 1 diabetes (T1D) or cystic fibrosis (CF) and identify associated risk factors. METHODS: A total of 195 caregivers completed demographic, stress, and depressive symptoms questionnaires. Children's health status was obtained from medical records. RESULTS: Approximately 33% of caregivers reported elevated symptoms of depression (i.e., exceeded clinical cutoff of 16 on the Center for Epidemiological Studies-Depression Scale). For caregivers of children with T1D, elevations were associated with less caregiver education, more family stress, older child age, and worse glycemic control. For caregivers of children with CF, more family stress and lack of employment outside of the home were associated with elevated depressive symptoms. CONCLUSIONS: Many caregivers of children with T1D or CF experience depressive symptoms, although risk factors may differ in these two populations. Screening of caregiver depressive symptoms as part of routine clinic visits may provide opportunities for needed intervention.

The safety and clinical benefit of budesonide/formoterol pressurized metered-dose inhaler versus budesonide alone in children.

Few studies have evaluated inhaled corticosteroid (ICS)/long-acting beta(2)-adrenergic agonist combination therapy in asthmatic children. This study was designed to evaluate the safety (primary) and clinical benefits (secondary) of budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus budesonide dry powder inhaler (DPI) in children with persistent asthma. This was a 26-week, multicenter, randomized, open-label U.S. study of 187 children 6-11 years of age previously receiving ICS. After 1 week of usual ICS therapy, subjects received twice-daily budesonide/formoterol pMDI 160/4.5 micrograms x 2 inhalations (320/9 micrograms; n = 124) or budesonide DPI 200 micrograms x 2 inhalations (400 micrograms [320 micrograms delivered ex-mouthpiece]; n = 63). Budesonide/formoterol and budesonide were well tolerated with a similar incidence of adverse events (AEs) (84.6% and 85.7%, respectively), most of mild or moderate intensity. Treatment-related AE incidence was low (5.4%) and similar across groups (budesonide/formoterol, 4.9%; budesonide, 6.3%). No clinically important treatment differences were observed for 12-lead electrocardiograms, hematology, serum glucose and potassium, and 24-hour urinary cortisol. Compared with budesonide, budesonide/formoterol decreased health care use (urgent care visits and interference with daily activities [child] or work [caregiver]; p < or = 0.012) and improved health-related quality of life (Pediatric Asthma Quality of Life Questionnaire [standardized] and Pediatric Asthma Caregiver Quality of Life Questionnaire overall scores; p < or = 0.006) and pulmonary function (predose forced expiratory volume in 1 second and forced expiratory flow during the middle half of exhalation; p < or = 0.007). In this 26-week study of asthmatic children (6-11 years), safety profiles were similar and clinical benefits were greater with budesonide/formoterol than with budesonide.

Aerosol antibiotics in cystic fibrosis.

Chronic airways infection and inflammation is the greatest source of morbidity and mortality in cystic fibrosis (CF) patients. Many organisms can be found in the lower respiratory tract of CF patients, but infection with mucoid Pseudomonas aeruginosa is common, is associated with poorer outcomes, and is the main target for antimicrobial strategies in CF. Aerosol antibiotics achieve high local concentrations in the airways, reduce systemic toxicity, and have been used successfully for chronic suppressive treatment for established P. aeruginosa infections. Eradication of early P. aeruginosa airway infection has also been tried with aerosol antibiotics, though the ideal treatment strategy is still being investigated. There are several variables to consider when choosing an antibiotic formulation to develop for topical inhalation. Tobramycin solution for inhalation (TSI) is currently the only approved inhaled antibiotic in the United States. The time burden for patients to administer TSI by jet nebulizer is substantial, so efforts have focused on more efficient, faster delivery methods. Novel formulations of aerosol antibiotics are being studied for CF, including beta-lactams, fluoroquinolones and aminoglycosides. Phase-3 studies of aztreonam lysinate for inhalation delivered via a proprietary eFlow nebulizer showed improved outcomes and a short (< 3 min) delivery time. Liposome formulations are being studied as a way to penetrate mucoid biofilms and prolong the residence time of the antibiotic in the lungs. Light, porous, dry-powder formulations are also in clinical trials to reduce delivery time. These new formulations and delivery systems promise to expand our armamentarium against microbes while reducing the time burden for patients.

New aerosol delivery devices for cystic fibrosis.

Cystic fibrosis (CF) patients use several therapies to treat chronic inflammation and infection in the lungs and to improve airway clearance. Inhaled therapies in CF typically include bronchodilators, airway wetting agents, mucus-active agents, and antibiotics, among others. There are many variables to take into account when prescribing aerosolized therapies to CF patients, including aerosol factors, patient variables (eg, age, disease severity, and breathing patterns), and the limitations of current aerosol delivery systems. The greatest challenge for patients is dealing with the time burden placed on them to try to fit all the treatments into their day-a burden that is likely to be even greater in the near future due to the exciting pipeline of novel therapies that target the genetic defect of CF as well as the pathophysiologic consequences. Fortunately, novel aerosol delivery systems and drug formulations are being developed to tackle the many challenges of aerosol delivery in CF. If successful, these systems will reduce the time burden and improve the clinical outcomes for the CF community.

Respiratory care and cystic fibrosis.

The 43rd Respiratory Care Journal Conference brought together experts from the United States, Canada, and the United Kingdom to review the art and science of cystic fibrosis (CF). This is the first time that CF was the topic for the Journal Conference, and it came about 6 decades after the disease was named, and 20 years after the gene was discovered on chromosome 7. Though CF is a multisystem disease, it is the chronic and progressive lung disease that causes most of the morbidity and mortality. The participants at the conference reviewed the epidemiology, pathophysiology, treatment, and novel therapies in the pipeline for CF lung disease. They also emphasized the many crucial roles that the respiratory therapist plays in CF, including diagnostic testing, aerosol therapies, airway clearance, infection control, patient and peer education, and patient advocacy. The May and June 2009 issues of the Journal reflect how diligently the participants worked to provide up-to-date reviews and lively discussions of these topics.

CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials.

BACKGROUND: Several treatment approaches in cystic fibrosis (CF) aim to correct CF transmembrane conductance regulator (CFTR) function; the efficacy of each approach is dependent on the mutation(s) present. A need remains for more effective treatments to correct functional deficits caused by the F508del mutation. METHODS: Two placebo-controlled, phase 2a studies evaluated GLPG2222, given orally once daily for 29 days, in subjects homozygous for F508del (FLAMINGO) or heterozygous for F508del and a gating mutation, receiving ivacaftor (ALBATROSS). The primary objective of both studies was to assess safety and tolerability. Secondary objectives included assessment of pharmacokinetics, and of the effect of GLPG2222 on sweat chloride concentrations, pulmonary function and respiratory symptoms. RESULTS: Fifty-nine and 37 subjects were enrolled into FLAMINGO and ALBATROSS, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.2% (14/48) of subjects in FLAMINGO and 40.0% (12/30) in ALBATROSS; most were mild to moderate in severity and comprised primarily respiratory, gastrointestinal, and infection events. There were no deaths or discontinuations due to TEAEs. Dose-dependent decreases in sweat chloride concentrations were seen in GLPG2222-treated subjects (maximum decrease in FLAMINGO: -17.6 mmol/L [GLPG2222 200 mg], p < 0.0001; ALBATROSS: -7.4 mmol/L [GLPG2222 300 mg], p < 0.05). No significant effects on pulmonary function or respiratory symptoms were reported. Plasma GLPG2222 concentrations in CF subjects were consistent with previous studies in healthy volunteers and CF subjects. CONCLUSIONS: GLPG2222 was well tolerated. Sweat chloride reductions support on-target enhancement of CFTR activity in subjects with F508del mutation(s). Significant improvements in clinical endpoints were not demonstrated. Observed safety results support further evaluation of GLPG2222, including in combination with other CFTR modulators. FUNDING: Galapagos NV. Clinical trial registration numbers FLAMINGO, NCT03119649; ALBATROSS, NCT03045523.

Novel tobramycin inhalation powder in cystic fibrosis subjects: pharmacokinetics and safety.

Aerosolized antibiotics are associated with a high treatment burden that can result in non-adherence to chronic therapy. We evaluated the pharmacokinetics (PK) and safety of tobramycin inhalation powder (TIP), a novel dry-powder formulation designed to deliver a high payload of tobramycin topically to the lungs for management of chronic Pseudomonas aeruginosa infections. This was a multi-center, open-label, sequential-cohort, single-dose, dose-escalation study using the standard 300 mg dose of tobramycin solution for inhalation (TSI) as an active control. Subjects were randomized to TIP or TSI in a 3:1 ratio in each of five cohorts. Measurements included serum and sputum tobramycin concentrations, administration time, serum chemistries, acute change in lung function, and adverse events (AEs). Out of 90 randomized subjects, 86 had data for safety analysis; and 84 had data for PK analysis. Serum tobramycin PK profiles were similar for TIP and TSI. Four capsules of 28 mg TIP (total tobramycin dose 112 mg) produced comparable systemic exposure to 300 mg TSI, in less than one-third the administration time. The most common AEs associated with TIP were cough (20%) and dysgeusia (17%). TIP allows for faster and more efficient pulmonary delivery of tobramycin than TSI and has a safety profile that supports continued clinical investigation. The increased rate of local respiratory tract irritation noted with TIP is not unexpected with a high-payload powder formulation. The development of dry powder inhaled antibiotics may represent an important advance in the treatment of chronic lung infections.

Clinical side effects during aerosol therapy: cutaneous and ocular effects.

Aerosolized medications maximize clinical benefit by targeting the airways and minimize side effects by reducing (though not eliminating) systemic exposure. Aerosolized drugs delivered with a facemask may inadvertently deposit on the face and in the eyes, raising concerns about cutaneous and ocular side effects with these drugs. Cases of anisocoria have been reported from exposure of the eyes to aerosol bronchodilators. Whether inhaled corticosteroids (ICS) can cause skin and eye problems like those seen with systemic or topical steroids is more difficult to answer. Patients who take ICS may have other corticosteroid exposures, or have other conditions that predispose them to side effects, making the analysis of the ICS risk challenging. Also, many studies were not designed to search for cutaneous or ocular effects, or may have been too short to detect these effects. Nevertheless, ICS have been associated with an increased risk of skin thinning, bruising, cataracts and possibly glaucoma in adults, but not in children. The risks increase with advanced age, higher doses, and longer duration of use. In children, the risks of cataracts and glaucoma were negligible with ICS, whether a mouthpiece or a mask interface was used. Side effects like skin rash and conjunctivitis occurred at low frequencies similar to placebo or comparator drugs. We do not know whether exposed children will have increased risks from ICS later in life. Therefore, it is wise to avoid face and eye deposition when possible, and to use the minimally effective dose.

Less common etiologies of exocrine pancreatic insufficiency.

Exocrine pancreatic insufficiency (EPI), an important cause of maldigestion and malabsorption, results from primary pancreatic diseases or secondarily impaired exocrine pancreatic function. Besides cystic fibrosis and chronic pancreatitis, the most common etiologies of EPI, other causes of EPI include unresectable pancreatic cancer, metabolic diseases (diabetes); impaired hormonal stimulation of exocrine pancreatic secretion by cholecystokinin (CCK); celiac or inflammatory bowel disease (IBD) due to loss of intestinal brush border proteins; and gastrointestinal surgery (asynchrony between motor and secretory functions, impaired enteropancreatic feedback, and inadequate mixing of pancreatic secretions with food). This paper reviews such conditions that have less straightforward associations with EPI and examines the role of pancreatic enzyme replacement therapy (PERT). Relevant literature was identified by database searches. Most patients with inoperable pancreatic cancer develop EPI (66%-92%). EPI occurs in patients with type 1 (26%-57%) or type 2 diabetes (20%-36%) and is typically mild to moderate; by definition, all patients with type 3c (pancreatogenic) diabetes have EPI. EPI occurs in untreated celiac disease (4%-80%), but typically resolves on a gluten-free diet. EPI manifests in patients with IBD (14%-74%) and up to 100% of gastrointestinal surgery patients (47%-100%; dependent on surgical site). With the paucity of published studies on PERT use for these conditions, recommendations for or against PERT use remain ambiguous. The authors conclude that there is an urgent need to conduct robust clinical studies to understand the validity and nature of associations between EPI and medical conditions beyond those with proven mechanisms, and examine the potential role for PERT.

A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients.

RATIONALE: For patients with cystic fibrosis (CF), the use of inhaled antibiotics has become standard of care to suppress chronic Pseudomonas airways infection. There are limited antibiotic options formulated and approved for inhaled use and antibiotic efficacies attenuate over time, making additional inhaled antibiotic classes desirable. APT-1026 (levofloxacin inhalation solution, LIS) is a fluoroquinolone in development for management of chronic P. aeruginosa airways infection in patients with CF. OBJECTIVES: To compare the safety and efficacy of a 28-day course of treatment with LIS 240mg or placebo BID in persons ≥12years old with CF and chronic P. aeruginosa infection. METHODS: A multinational, randomized (2:1), double-blinded study of LIS and placebo over 28days in CF patients ≥12years with chronic P. aeruginosa infection. Time to exacerbation was the primary endpoint. FEV1 (% predicted) and patient-reported quality of life were among secondary endpoints. MAIN RESULTS: Baseline demographics for 330 subjects (LIS=220) were similar although significantly more patients randomized to LIS had experienced multiple exacerbations in the year prior to study entry. There was no statistically significant difference in protocol-defined pulmonary exacerbations between treatment arms. Relative change in FEV1% predicted from baseline was significantly greater for patients randomized to LIS compared to those randomized to placebo (mean difference 1.31%, p=0.01 [95% CI 0.27, 2.34%]). LIS was well-tolerated, with dysguesia the most frequent adverse event. CONCLUSIONS: LIS did not demonstrate a difference in time to next exacerbation when compared to placebo. Reasons for this result are discussed but may be due to an imbalance in the frequency of prior pulmonary exacerbations between the two groups. An improvement in FEV1 (% predicted) at 28days was observed and LIS was well tolerated. LIS is safe and has a potential role in the management of CF patients with chronic P. aeruginosa.

Comparing clinical features of the nebulizer, metered-dose inhaler, and dry powder inhaler.

Topically inhaled bronchodilators and corticosteroids are the mainstay of treatment for asthma and chronic obstructive pulmonary disease. These medications are delivered via jet or ultrasonic nebulizer, metered-dose inhaler (MDI), or dry powder inhaler (DPI). While the number of devices may be confusing to patients and clinicians, each device has distinct advantages and disadvantages. Most clinical evidence shows that any of these devices will work for most situations, including exacerbations and in the stable outpatient setting. There is a high rate of errors in device use with all these devices, especially the MDI. In choosing a drug/device combination for a patient, the clinician must take into account several factors, including the cognitive and physical ability of the patient, ease of use, convenience, costs, and patient preferences. Clinicians should also have a rudimentary understanding of aerosol principles in order to be able to teach appropriate use of aerosol devices to their patients.

Positive expiratory pressure changes aerosol distribution in patients with cystic fibrosis.

HYPOTHESIS: We hypothesized that aerosol distribution in the lungs of patients with cystic fibrosis changes with positive expiratory pressure (PEP). METHODS: Eight patients were randomized to one of 2 conditions. On one study day, patients inhaled saline aerosol containing 99mtechnetium generated by a Pari LC Plus nebulizer and exhaled through a Pari PEP device. On another day, the same patients exhaled through a low-resistance Pari filter (no PEP). Afterwards, they underwent gamma-camera lung imaging. Images were analyzed for lung deposition fraction, expressed as a percent of the initial nebulizer activity, and deposition pattern, expressed in terms of inner-outer and apical-basal ratios. RESULTS: Lung deposition fraction was significantly lower with the Pari PEP device; the mean + SD deposition fraction was 6.10 + 3.05% (median 6.20%) with PEP, compared to 10.76 + 4.52% (median 10.32%) (p = 0.0078) without PEP. The inner-outer ratio was 2.01 + 0.69 (median 2.23) with PEP, which was significantly lower than without PEP (2.76 + 1.33, median 2.55) (p = 0.004). The apical-basal ratio was 0.82 + 0.31 (median 0.80) with PEP, which was not significantly different from no PEP (1.00 + 0.49, median 0.90). CONCLUSION: These results indicate that less aerosol is deposited in the lungs of patients with cystic fibrosis when the Pari LC Plus nebulizer is used with the Pari PEP device, as described in these experiments. Nevertheless, aerosol administration with this nebulizer and PEP device also results in a proportional redistribution of aerosol to the peripheral airways, compared to nebulization without the PEP device. The clinical relevance of this subtle redistribution of aerosol in cystic fibrosis patients will probably depend on the drug administered and disease severity.