What Is the Best Nebulizer to Use on Copd

Int J Chron Obstruct Pulmon Dis. 2016; 11: 2585–2596.

A review of nebulized drug delivery in COPD

Donald P Tashkin

Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Abstract

Current guidelines recommend inhaled pharmacologic therapy as the preferred route of administration for treating COPD. Bronchodilators (β₂-agonists and antimuscarinics) are the mainstay of pharmacologic therapy in patients with COPD, with long-acting agents recommended for patients with moderate to astringent symptoms or those who are at a college risk for COPD exacerbations. Dry pulverisation inhalers and pressurized metered dose inhalers are the most commonly used drug commitment devices, only they may be inadequate in diverse clinical scenarios (eg, the elderly, the cognitively impaired, and hospitalized patients). Equally more than drugs become available in solution formulations, patients with COPD and their caregivers are becoming increasingly satisfied with nebulized drug delivery, which provides benefits like to drugs delivered by handheld inhalers in both symptom relief and improved quality of life. This article reviews recent innovations in nebulized drug delivery and the of import role of nebulized therapy in the treatment of COPD.

Keywords: COPD, nebulized drug commitment, pharmacologic therapy

Introduction

Inhaled pharmacologic therapy is a cornerstone of treatment for patients with COPD.ⁱ ^, ² 4 usually prescribed inhalation devices, pressurized metered dose inhalers (pMDIs), dry pulverization inhalers (DPIs), tiresome mist inhalers (SMIs), and nebulizers, take similar efficacies in patients with COPD,³ ^– ^half-dozen provided they are used appropriately. Although DPIs and pMDIs are the virtually commonly used devices⁷ ^, ⁸ and are recommended for long-term treatment in the vast majority of patients,ⁱⁱ the Global Initiative for Chronic Obstructive Lung Disease (Gold) strategy document recommends nebulizers for specific patient populations (eg, patients with very low inspiratory menstruation rates) in whom nebulizer treatment may provide more than benefits than DPIs or MDIs.² Further, Gold recommends evaluating the benefits of nebulizer treatment symptomatically and continuing treatment as long as similar benefits are not achievable by simpler, cheaper, and more portable alternatives. In add-on, both patients and their caregivers are condign increasingly satisfied with nebulized drug commitment and have reported benefits in symptom relief, ease of use, and improved quality of life when using this organization.⁹ ^, ¹⁰ Moreover, several of the emerging medications for COPD (both marketed and nether evolution) utilize nebulizer technology. This article reviews recent innovations in nebulized drug commitment and the of import office of nebulized therapy in the treatment of COPD.

Selection of articles for review

After dividing the review topic into specific subsections, articles were selected for inclusion based on comprehensive reviews of the literature according to each subsection. A PubMed search (January 1, 1996 to March 15, 2016) was conducted using multiple primary topic headers combined with appropriate terms for each department of the article (eg, COPD + nebulizers or COPD + nebulizer therapy). The results of the PubMed search were supplemented by relevant papers identified from reference lists of published articles and the author's noesis of the literature. Option of articles for word focused on information published within the past 5 years.

COPD

COPD, a mutual preventable and treatable disease, is characterized by progressive persistent airflow obstacle that is associated with an enhanced inflammatory response to noxious particles or gases in the lung and airways.² ^, ¹¹ ^, ¹² COPD represents a global health problem, is ranked as the fourth leading cause of expiry in the earth, and significantly affects patient quality of life.² ^, ¹³ ^, ^xiv The global social and economic burden of COPD is projected to increase, due to crumbling populations and the continued utilize of tobacco and exposure to biomass fuels,¹⁵ ^, ¹⁶ underscoring the demand for more than effective management of this disease. While >12 1000000 people in the US are known to have COPD, it is estimated that up to 24 million may have dumb lung role and undiagnosed disease.¹⁷ In 2010, the toll of COPD in the U.s.a. was projected to be ~$49.9 billion, which included ~$20 billion in indirect costs (eg, loss of work productivity and earnings) and $30 billion in direct health care expenditures (eg, prescription medicines and emergency department visits).¹⁷ ^, ¹⁸

To reduce symptoms, frequency, and severity of COPD exacerbations and improve health status and exercise tolerance, the GOLD strategy document² recommends that bronchodilators are the cornerstone of pharmacotherapy for COPD in the majority of patients.^ane ^, ² However, physical and/or cognitive symptoms that are mutual in some COPD patients (eg, the elderly¹⁹ ^, ^twenty) could interfere with the proper administration of inhaled therapies via handheld inhalers,²¹ resulting in insufficient dosing and jeopardizing wellness outcomes, reducing quality of life, and farther adding to the economical brunt of COPD.² ^, ²² Further, during exacerbations and in recovery, many COPD patients accept decreased peak inspiratory flow rate (PIFR) and are unable to use handheld inhalers finer. In these populations, inhaled therapies administered via nebulizers may offer improved symptom control²¹ ^, ²³ and quality of life⁹ over non-nebulized bronchodilator therapy.

Pharmacologic therapy

In full general, pharmacologic therapy is office of an integrated treatment arroyo in patients with COPD that begins with smoking cessation and vaccines (influenza and pneumococcal) for all current smokers and progresses to treatment with inhaled therapy.²⁴ Inhaled treatment is tailored to the patient and should be guided by the severity of COPD symptoms, risk of COPD exacerbations, drug availability, and patient response (Table i).² For patients at depression chance of COPD exacerbations with relatively few symptoms (eg, those in Aureate patient category A),² short-acting bronchodilators are available for acute relief of symptoms or for employ earlier physical activities²⁵ to prevent the onset of symptoms (a long-interim inhaled bronchodilator, as well as theophylline, is recommended equally an alternative choice).² For patients with more than severe symptoms or who are at a college risk of COPD exacerbations (eg, those in Gilded patient categories B, C, or D), long-interim bronchodilators are recommended over short-interim bronchodilators for maintenance therapy to better symptoms, exercise tolerance, and health-related quality of life and reduce the risk of exacerbations.² As a upshot, long-interim bronchodilators with or without inhaled corticosteroids (ICS) are the first- or second-choice drugs for the majority of patients with COPD.^ane

Table i

Initial pharmacologic management of COPD^*

GOLD patient category	Beginning choice	Culling pick	Other possible treatments^#
A: low take chances, less symptoms	SAMA prn or SABA prn	LAMA or LABA or SABA and SAMA	Theophylline
B: low risk, more symptoms	LAMA or LABA	LAMA and LABA	SABA and/or SAMA; theophylline
C: high take a chance, less symptoms	ICS + LABA or LAMA	LAMA and LABA or LAMA and PDE-4 inhibitor or LABA and PDE-4 inhibitor	SABA and/or SAMA; theophylline
D: high take a chance, more symptoms	ICS + LABA and/or LAMA	ICS and LABA and LAMA or ICS and LABA and PDE-four inhibitor or LAMA and LABA or LAMA and PDE-4 inhibitor	Carbocysteine; SABA and/or SAMA; theophylline

Although handheld pMDIs or DPIs are constructive in most patients with COPD, cognitively impaired and elderly patients may benefit more from the utilise of a nebulizer, since these patient populations may accept difficulty synchronizing inhalation with inhaler actuation or may be unable to generate a sufficient inspiratory flow rate confronting the resistance of a jiff-activated DPI to generate an constructive aerosol.^{half dozen} ^, ²² ^, ²⁶ ^– ²⁸ SMIs are compact portable multidose inhalers that apply liquid formulations similar to those in nebulizers but, like MDIs and DPIs, crave transmission manipulation to generate the aerosol and special animate techniques for constructive delivery of the aerosolized medication to the lungs.²⁹ The pick of therapy, yet, ultimately depends on a wide range of factors, including the prescribing physician, the availability of specific drug/device pairings, drug cost, and patient preferences and satisfaction.³ ^, ²² ^, ²⁶ ^, ²⁸ ^, ^xxx ^, ³¹ Each of the commitment devices that are available for administering drugs to patients with COPD (eg, pMDIs, DPIs, SMIs, and nebulizers) has advantages and disadvantages (Table two).³ ^, ⁶ ^, ²⁹ ^, ³¹ ^, ³²

Table 2

Advantages and disadvantages of aerosolized formulations

Inhalation device	Advantages	Disadvantages
DPI	Breath-actuated devices	Requires patient to generate moderate to high inspiratory flow^a
	User-friendly Portable Rapid medication delivery	Elderly patients and those with hyperinflation and flattened diaphragms may accept difficulty achieving adequate inspiratory catamenia
	Single- and multidose devices Counter indicates remaining doses	Can result in high pharyngeal and central airway degradation, which tin lead to agin events
pMDI	Multiple dosing (≥100 doses/canister)	Multiple steps involved Requires acceptable patient coordination to synchronize inhalation with pMDI actuation^b
	Short administration time	High pharyngeal degradation, which can lead to agin events
	Convenient	Only 10%–xx% of dose deposited in lungs from suspension MDIs^c
	Portable	While the addition of spacer eliminates the need to coordinate inhalation and reduces oropharyngeal deposition, spacers are bulky and require cleaning
SMI	Multiple dosing (1 calendar month's supply)	Multiple steps involved
	High lung deposition	Not breath actuated
	Portable No propellants Tedious-velocity aerosol generated Aerosol persists for 1.v seconds, increasing ease of synchronizing inhalation with actuation	Not bachelor in virtually countries
Jet nebulizer	Like shooting fish in a barrel for patients to utilise	Limited portability
	Requires minimal cognitive power	Device training required
	Does not require hand-jiff coordination, manual dexterity, or paw force	Lengthy assistants time Daily cleaning required Not all medications are bachelor in this format May non readily aerosolize drug suspensions
Loftier-efficiency vibrating mesh nebulizer	Portable	Loftier price
	Quiet	Device preparation required
	Brusque administration times	Daily cleaning required Not all medications are bachelor in this format May not readily aerosolize drug suspensions Optimal doses need to be defined by additional studies to avert overdosing

Nebulized drug delivery

In patients with COPD, nebulizers are an culling to pMDIs and DPIs for providing inhaled therapy, provided the drug is available and chemically stable in liquid form (Effigy 1).^six ^, ³¹ Despite some drawbacks associated with nebulizers (eg, variably long treatment times and daily cleaning), current show suggests that the efficacy of treatments administered to patients with moderate to astringent COPD via nebulizers is like to that observed with pMDIs and DPIs.³ ^– ^half-dozen Farther, marketplace analysis indicates that, in the US, ∼45% of patients with COPD take a nebulizer, 69% of whom employ it on a regular basis.^vi

An external file that holds a picture, illustration, etc. Object name is copd-11-2585Fig1.jpg

Examples of commercially available nebulizers that comprise newer aerosol generating technologies.

Notes: Akita^® Jet (Courtesy of Ventura, Great britain) and the I-bill^® (Courtesy of Philips Healthcare, USA) employ AAD technology to deliver and monitor nebulizer treatments. Trek^® S (Courtesy of PARI, U.s.; Trek^® S is a trademark of PARI Gmbh and its affiliates) is a portable jet nebulizer. MicroAir^® NE-U22 (Courtesy of Omron, The states) and the eFlow^® (Courtesy of PARI, USA; eFlow^® is a trademark of PARI Gmbh and its affiliates) are vibrating mesh aerosol nebulizers. Respimat^® is a loftier-efficiency soft mist inhaler (Reproduced with permission from Boehringer Ingelheim Pharmaceuticals, Inc. Respimat^® is a trademark of and/or used under license from Boehringer Ingelheim International GmbH or its affiliated companies. Materials may besides be bailiwick to copyright protection). Aeroneb^® Get (Courtesy of Philips Healthcare) is an ultrasonic nebulizer. All of these devices are approved for use in the United states of america.

Abridgement: AAD, adaptive aerosol delivery.

Several options exist for the type of nebulizer (eg, jet, ultrasonic, and vibrating mesh), with many models commercially available (Effigy i). The Akita® (Vectura, Chippenham, UK) jet nebulizer individualizes aerosol delivery using the adaptive aerosol delivery (AAD) control system (Effigy 2),³³ which results in high efficiency and depression variability in droplets drug delivery to patients. Despite these benefits, still, the Akita, in common with older jet nebulizers, is a big, poorly portable nebulizer that has a longer (x minutes) handling time than the newer vibrating mesh nebulizers.³⁴ The Trek^® Due south (PARI, Midlothian, VA, United states of america) portable jet nebulizer is a convenient culling to larger, more powerful tabletop compressors. In a comparative study of four portable nebulizer systems, the Trek S delivered 33% more than respirable dose than the adjacent all-time system, Mini Elite™ (Philips Healthcare, Andover, MA, USA).³⁵

An external file that holds a picture, illustration, etc. Object name is copd-11-2585Fig2.jpg

AAD technology used in the Akita^® and I-neb^® nebulizers.

Notes: During the outset three breaths, AAD calculates when to pulse the aerosol. In subsequent breaths, AAD pulses aerosol during the first fifty%–80% of inspiration (bluish shade). Republished with permission of Respiratory Care: the official science journal of the American Association for Respiratory Care, from New Aerosol Delivery Devices for Cystic Fibrosis, KC Kesser and DE Geller, volume 54, edition 6, 2009; permission conveyed through Copyright Clearance Center, Inc.¹⁰⁵

Abridgement: AAD, adaptive aerosol commitment.

The Aeroneb^® Go (Philips Healthcare) is a portable, compact, handheld ultrasonic nebulizer that is easily assembled, silent, and has short (five minutes) treatment elapsing.³ ^, ⁶ ^, ³⁴ The eFlow^® (PARI) is a bombardment-operated, meaty, portable vibrating mesh nebulizer that has been shown to improve patient compliance due to its comparatively brusk (5 minutes) handling time.³⁶ MicroAir^® NE-U22 (Omron, Chicago, IL, USA) is a mesh nebulizer that provides efficient droplets drug delivery with a predominantly fine particle fraction.³ ^, ⁶ ^, ³⁴ Similar the Aeroneb Go and eFlow devices, the MicroAir is expensive and can be hard to maintain, every bit it requires disassembly and cleaning later each use to preclude bottleneck of the mesh apertures.³⁴

The I-neb^® (Philips Healthcare) AAD nebulizer is a small, lightweight, battery-powered, silent smart nebulizer that combines mesh and AAD technologies to deliver a precise, reproducible dose.⁶ ^, ³⁴ With AAD technology, automatic timing of aerosol delivery (based on the patient'south animate pattern) improves the precision and reproducibility of dosing³⁴ (Figure 2) and, compared with previous nebulizers without AAD, significantly improves dyspnea and fatigue in patients with COPD.³⁷ A disadvantage of the newer mesh nebulizers is that little information is available concerning the ideal dose of the bronchodilator solution to add together to the nebulizer. Consequently, the potential for overdosing exists if the same dose of the bronchodilator that is conventionally used with jet nebulizers is added to these newer nebulizers. To address this business concern, device manufacturers are developing a new generation of closed-organisation mesh nebulizers that volition accept only the ampule containing the specific drug approved for apply with a specific device based on the sit-in of safety and efficacy.³¹

The Respimat^® (Boehringer Ingelheim, Ingelheim, Germany) is an SMI that delivers a tiresome-moving mist, allowing the inhalation of medication contained of inspiratory effort³⁸ (ie, via the release of stored energy from a tensed jump when the tension is released by pushing a push). Although not strictly classified as a nebulizer, the Respimat device, a compact handheld droplets commitment device similar in size to MDIs and DPIs, is included here considering information technology shares several performance characteristics with the nebulizers discussed before, such every bit liquid conception, propellant-free function, apply of mechanical energy for actuation, generation of an aerosol with a predominantly fine particle fraction (micronebulized), and lack of dependence on loftier inspiratory flow rates.³⁸ However, in contrast to more conventional nebulizers for which only tidal animate is required, use of the Respimat requires a special animate technique (total expiration followed past full inhalation and jiff holding).³⁸ Some coordination between inhalation and actuation is also necessary, although the timing for such is more than forgiving with the Respimat than for MDI devices, since the aerosol delivered from the Respimat lasts i.v seconds (as opposed to a fraction of a second from an MDI).

Nebulized pharmacologic therapy

Many of the drugs used for the handling of COPD were initially approved for use in pMDIs or DPIs³⁹ and are now available in solution class for employ with nebulizers (Table 3). The long-acting agents are indicated for maintenance handling of COPD-associated airflow obstacle, while short-acting bronchodilators are indicated for astute relief of bronchospastic symptoms of COPD. Clinical trials generally have demonstrated meaning improvement in forced expiratory book in i 2nd (FEV_one) over the dosing interval and reduction in rescue medication use with nebulized therapy.

Table iii

Nebulized medications ordinarily used for patients with COPD

Compound	Nebulizer system	Trough FEV₁ (L) improvement^*	Rescue medication use reduction	Remarks
LABA^#
Arformoterol tartrate⁴⁰	Jet or VM	0.051^¶	Yes	BID; less frequent exacerbations of COPD than placebo
Formoterol fumarate⁹⁹	Jet or VM	0.143^¶	Yes	BID; no tachyphylaxis during 12 weeks of regular dosing
Olodaterol hydrochloride¹⁰⁰	SMI^†	0.275^**	Yes	QD
LAMA^#
Tiotropium bromide¹⁰¹	SMI	0.232^**	Yes	QD; noninferior to tiotropium 18 mg HandiHaler^®
LABA–LAMA^#
Tiotropium bromide–olodaterol hydrochloride⁶²	SMI	0.068²	Yep	QD; additive bronchodilation without increasing side effects; less rescue medication vs components alone
SABA^‡
Albuterol sulfate¹⁰²	Jet or VM	NR	NA	prn rescue drug; requires 2–4 daily doses if used every bit maintenance treatment
Levalbuterol hydrochloride¹⁰³	Jet or VM	NR	NA	prn rescue drug
SAMA^‡
Ipratropium bromide⁶⁸	Jet or VM	NR	NA	Indicated every bit a bronchodilator for maintenance treatment of bronchospasm associated with COPD
SABA–SAMA^I
Albuterol–ipratropium⁶⁹	Jet or VM	NR	NA	Improved FEV_ane response vs components lone
Albuterol–ipratropium⁷⁰	SMI	NR	NA	Provides better bronchodilation than either therapy solitary without increasing side effects

Long-acting β₂-agonists (LABAs)

Arformoterol

Nebulized arformoterol tartrate is of potential do good to patients with hyperinflation and low PIFR.^xl Arformoterol is safe in combination therapy with certain handheld inhalers (eg, ICS, long-acting muscarinic antagonists [LAMAs], and curt-acting β₂-agonists [SABAs]), just it is contraindicated in combination with a handheld inhaled LABA (alone or in combination with an ICS or an LAMA). A 12-month Phase iv trial found no increased take chances of respiratory death or COPD exacerbation-related hospitalizations with nebulized arformoterol handling.⁴¹ Being a single enantiomer of formoterol, arformoterol may have hypothetically more strong bronchodilator backdrop, microgram per microgram, than racemic formoterol fumarate, only no major clinical differences between the two drugs have been observed in patients with COPD.⁴² Maintenance therapy with nebulized arformoterol or formoterol demonstrated a 37% reduction and a 42% reduction in rescue albuterol use, respectively.⁴³ ^, ⁴⁴ Fractional tolerance to the bronchodilator consequence of arformoterol was noted after 6 weeks of therapy, but the reduction in bronchodilator efficacy did non progress beyond half-dozen weeks and was non considered clinically meaning.⁴⁴ Finally, arformoterol can amend lung function in combination with LAMAs. In patients with COPD who were receiving twice-daily nebulized arformoterol, tiotropium bromide given in combination with arformoterol produced significantly greater bronchodilation than either arformoterol or tiotropium monotherapies (P<0.001).⁴⁵

Formoterol

Formoterol differentiates from some other β_ii-agonists by its rapid onset of significant bronchodilation within 5 minutes of administration.⁴⁶ ^, ⁴⁷ In patients with COPD, nebulized formoterol fumarate significantly increased FEV₁ relative to placebo (P<0.001) when administered for 12 weeks and had similar efficacy and safety compared with the original formoterol fumarate dry out powder conception.⁴⁶ Quality of life at week 12, as measured past the St George'south Respiratory Questionnaire, demonstrated significant and clinically meaningful improvements in total score, symptom, and touch scores for formoterol vs placebo. Patients treated with formoterol reported greater handling satisfaction and perception of affliction control compared with handling with brusque-interim bronchodilators delivered four times daily.⁴⁸ Furthermore, like to arformoterol,⁴⁵ nebulized formoterol significantly increased bronchodilation in patients receiving the LAMA tiotropium bromide,⁴⁹ which indicates that formoterol can improve lung office in combination with antimuscarinics. With regard to tachyphylaxis to the bronchodilator effect of formoterol + tiotropium, tachyphylaxis was not observed during half dozen weeks of formoterol improver treatment in patients receiving tiotropium maintenance therapy,⁵⁰ ^, ⁵¹ which is consequent with 12-week trials that did not evidence any tolerance to the upshot of formoterol lone in patients with COPD.⁴⁶

Olodaterol SMI

Olodaterol hydrochloride SMI is a long-term, once-daily maintenance treatment for controlling symptoms in adults with COPD.⁵² ^, ⁵³ In Phase iii trials, once-daily olodaterol improved lung function (FEV₁) compared with placebo over 48 weeks of treatment, with bronchodilation being achieved and maintained inside the 24-hour dosage interval, supporting its once-daily administration.⁵² ^, ⁵⁴ Olodaterol SMI is not indicated to care for either acute deterioration of COPD or asthma.

LAMA

Tiotropium SMI

Tiotropium bromide SMI provides a solution class of tiotropium bromide⁵⁵ that is efficacious at lower doses compared with the tiotropium bromide HandiHaler^® (Boehringer Ingelheim).⁵⁶ In patients with COPD, tiotropium SMI improved lung role, health-related quality of life, and dyspnea, reduced acute exacerbations of COPD, and was as constructive and safe every bit the tiotropium HandiHaler⁵⁷ ^, ⁵⁸ Tiotropium is mostly well tolerated in patients with COPD, but antimuscarinic side effects (eg, dry out rima oris) are amidst the most normally reported adverse events.⁵⁹

LABA–LAMA fixed-dose combination

Tiotropium–olodaterol SMI

Tiotropium bromide–olodaterol hydrochloride SMI, a stock-still-dose combination daily maintenance treatment for patients with COPD,^threescore ^, ⁶¹ has demonstrated superior efficacy compared with the private LABA and LAMA components alone.⁶² Two replicate 52-calendar week trials showed significantly greater comeback in FEV_one area under the curve (AUC) from time 0 to iii hours, trough FEV_one, quality of life (as measured by the St George'southward Respiratory Questionnaire), and dyspnea with tiotropium–olodaterol SMI compared with the private components delivered by SMI.⁶² Moreover, in a placebo-controlled trial, tiotropium–olodaterol SMI has been shown to result in a clinically meaningful improvement in quality of life compared with placebo.⁶³

SABA

Nebulized albuterol sulfate and levalbuterol hydrochloride are brusk-acting medications ordinarily used to care for acute episodes of bronchospasm and astute exacerbations in patients with COPD.⁶⁴ ^, ⁶⁵ Randomized, controlled clinical studies generally have not demonstrated any pregnant differences betwixt levalbuterol and albuterol in efficacy, occurrence of adverse effects, or hospital admissions.⁶⁶ Levalbuterol may take advantages over albuterol in patients with COPD admitted to the hospital, including shorter (i 24-hour interval) length of stay,⁶⁷ just albuterol was found to be 3-fold less expensive than levalbuterol in a 2009 study.⁶⁶

Short-acting muscarinic antagonist (SAMA)

Ipratropium

Ipratropium bromide, an SAMA in a nebulized inhalation solution administered either lone or with other bronchodilators (eg, β₂-agonists), is indicated equally a bronchodilator for the maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema, when administered on a regularly scheduled 4 times daily schedule.⁶⁸ In 12-calendar week clinical studies in patients with COPD-associated bronchospasm associated with COPD, significant improvements in pulmonary function (FEV_one increases of xv% or more) occurred within 15–thirty minutes and persisted for periods of 4–5 hours in the majority of patients.

SABA–SAMA fixed-dose combination

Albuterol–ipratropium

Nebulized albuterol sulfate–ipratropium bromide, a fixed-dose combination product, is indicated for the treatment of bronchospasm associated with COPD in patients requiring more than than one bronchodilator.⁶⁹ ^, ⁷⁰ Research has shown that patients with COPD treated with albuterol–ipratropium have lower hospital expenditures and therapy interruptions than patients taking the private components equally dual single agents (DSAs).⁷¹ In a population-based retrospective claims assay, patients who were taking nebulized albuterol–ipratropium (due north=468) had 31% fewer emergency department visits and costs compared with patients taking a DSA (P=0.03 and P<0.001, respectively). In addition, the albuterol–ipratropium accomplice was associated with statistically fewer individuals who reported treatment interruptions (10%; P=0.003).

Albuterol–ipratropium SMI

Albuterol sulfate–ipratropium bromide SMI is indicated for patients with COPD on a regular droplets bronchodilator who continue to have show of bronchospasm and who require a second bronchodilator.⁷² In a controlled clinical study, 652 patients with moderate to severe COPD received either albuterol, ipratropium, or albuterol–ipratropium SMI for 85 days.⁷⁰ Over the course of the written report, the acute pulmonary office response (peak expiratory flow rate) was significantly better with albuterol–ipratropium compared with albuterol or ipratropium solitary; quality of life and symptoms, nonetheless, were unchanged over the course of the written report in all treatment groups. The use of an SAMA either as a single amanuensis (eg, ipratropium) or in combination with a short-acting β-agonist (eg, albuterol) is not recommended in patients receiving concomitant therapy with an LAMA because of concern regarding possible additive anticholinergic side effects and, hypothetically, deportation of the more constructive long-acting agent past the short-acting drug from the muscarinic receptor.

Nebulized therapy in development

Despite the benefits of combination therapies, the late-stage evolution pipeline of nebulized medications for the treatment of COPD currently comprises two LAMA monotherapies, SUN-101 (Sunovion, Marlborough, MA, USA) and TD-4208 (Theravance, South San Francisco, CA, USA), that could provide improvements over existing drugs (Table 4).

Table 4

Nebulized therapies in clinical development for the treatment of COPD

Development chemical compound	Chemical name	Nebulizer system	Trough FEV₁ (L) improvement^*	Rescue medication use reduction	Stage of development
LAMA^#
SUN-101	Glycopyrrolate bromide	eFlow^® ^‡	0.1184^I,⁷³	NR	Phase 3⁷⁵–⁷⁷
TD-4208	Revefenacin (proposed international nonproprietary name)	Jet or VM	0.187^I,¹⁰⁴	Yes	Phase 3⁸³–⁸⁵

SUN-101

SUN-101, a soluble glycopyrrolate bromide formulation in Phase three development, is rapidly (inside 2 minutes) delivered to the lungs using a novel custom-designed, portable electronic nebulizer device (eFlow). Sun-101 is in Phase 3 evolution as a twice-daily maintenance treatment of bronchoconstriction in patients with COPD, including those with chronic bronchitis and emphysema. In controlled Stage 2 studies, SUN-101 demonstrated the rapid onset (≤v minutes) of dose-related bronchodilation following unmarried-dose administration (12.5–400 μg) in patients with moderate to astringent COPD.⁷³ SUN-101 produced clinically meaningful improvements in lung function (FEV₁) that were maintained over a 24-hour flow at all doses >l μg. Phase 2 clinical studies too demonstrated that SUN-101 has a safety profile similar to tiotropium,⁷⁴ with no clinically relevant changes in heart rate, systolic and diastolic blood pressure level, or in electrocardiographic parameters including QTc interval.⁷³ The Sunday-101 Stage 3 program consists of three clinical trials that volition enroll ~two,340 adults with moderate to very severe COPD.⁷⁵ ^– ⁷⁷

Revefenacin (TD-4208)

Revefenacin is a nebulized LAMA with like say-so to tiotropium bromide simply with less potential for antimuscarinic side effects (eg, dry out mouth).⁷⁸ ^, ⁷⁹ Revefenacin, administered via the PARI Trek S nebulizer, is in clinical evolution as a once-daily maintenance handling for COPD. The results of several Phase 2 studies support the ongoing Phase 3 program. Evaluation of the pharmacokinetics of revefenacin (n=127) demonstrated low plasma concentrations after inhaled administration, consistent with high systemic clearance and a lack of systemic antimuscarinic action.^lxxx A randomized, crossover, 7-solar day, multiple-dose written report demonstrated that the bronchodilator outcome of once-daily revefenacin was sustained for more 24 hours in patients with COPD.⁸¹ In a 28-day dose-ranging Phase ii written report in patients with COPD, revefenacin-treated patients' utilize of rescue medication was significantly reduced by more than 1 puff per twenty-four hours in a dose-dependent style (P<0.01).⁸² The Phase 3 programme consists of iii clinical trials that will enroll >ii,000 patients with moderate to very severe COPD⁸³ ^– ⁸⁵ and is designed to support regulatory approval of the drug in the US.

Discussion

With patients becoming increasingly satisfied with nebulized drug delivery,⁹ improved integration of nebulizers and nebulized therapies into the COPD handling paradigm should lead to improved clinical and wellness economic outcomes for patients with COPD. Certain COPD patient populations may especially benefit from the use of nebulizer therapy (eg, patients with low PIFR, the elderly, and those with cerebral or visual impairment or diminished transmission dexterity). It is therefore important to select the appropriate device for each patient, particularly in older or more severely impacted patients who may exist unable to apply handheld devices reliably or those who adopt the feeling of control with a nebulized product.⁴⁸

Many emerging COPD medications employ portable nebulizers that are typically battery operated, making them less cumbersome to carry. Compared with pMDIs and DPIs, these nebulizers crave no hand-breath coordination or extra effort during inhalation.⁶ Further, the wider availability of high-efficiency nebulizers will ensure accurate delivery of emerging nebulized medications in patients with COPD, which may pb to further reductions in symptoms and exacerbation rates in these patients. However, safety and efficacy studies will be required to define the optimal doses of medications using these loftier-efficiency nebulizers. Moreover, patient educational activity is crucially important to foster adherence to regular utilise of nebulized long-acting bronchodilators as office of maintenance therapy, rather than relying on short-acting nebulized agents that should be reserved for rescue treatment of acute symptoms.

When evaluating a nebulized drug delivery option for patients with COPD, important considerations include the availability of specific drug/nebulizer pairings, the need for drug combinations, the power to use the selected device correctly, drug/nebulizer cost and reimbursement, patient preference and satisfaction, and clinical scenario.^three ^, ²² ^, ²⁶ ^, ²⁸ ^, ^xxx Nebulized drug delivery is generally preferred by patients discharged from hospitals later an inpatient stay, who have demonstrated consistent difficulty using handheld inhalers, and who have impaired transmission dexterity, impaired cognition, or chronic muscle weakness.^six In these scenarios, the benefits of nebulization therapy can outweigh potential inconveniences and atomic number 82 to improved adherence and outcomes in patients with COPD.⁹ For some patients, use of both a nebulizer (as maintenance therapy) and a handheld inhaler (as rescue medication, peculiarly when outside the dwelling) may provide the all-time combination of efficacy and convenience.^{half dozen} ^, ²⁶ ^, ⁸⁶

Long-acting agents formoterol fumarate and arformoterol tartrate, which currently serve as the mainstays of nebulized maintenance therapy for COPD, have demonstrated a pregnant reduction in FEV₁, but there are no head-to-caput clinical trials comparing the efficacy and safe of these two nebulized therapies. While tolerance (tachyphylaxis) to the bronchodilator issue of arformoterol has been reported in clinical trials,^forty ^, ⁴⁴ ^, ⁸⁷ no other clinical manifestations of tolerance were axiomatic. In contrast, clinical trials with nebulized formoterol failed to show whatever evidence of tolerance, as indicated by maintained FEV₁ AUC and reduced rescue inhaler use with up to 12 weeks of treatment.⁴⁶

Combination therapy involving two long-acting bronchodilators with differing mechanisms of action is recommended in patients whose COPD is not well controlled with one drug lone.¹ ^, ⁸⁸ LABA and LAMA combinations, for example, have shown additive bronchodilator effects at doses used for monotherapy without additional prophylactic concerns⁸⁹ and may increase patient adherence.⁹⁰ Blessing of the two nebulized LAMA compounds in Phase three clinical trials, Sunday-101 and TD-4208, will likely increase the use of combination LABA/LAMA nebulized therapy, although a fixed-dose LABA/LAMA combination nebulized production would besides exist welcome from a patient compliance perspective. Farther, the evolution of a nebulized version of the widely used fixed-dose combination therapy, ICS/LABA, would do good patients who need or prefer nebulized treatments.

The recent approval of tiotropium–olodaterol SMI⁶² illustrates that demand for combination therapy is driving device innovation. Cosuspension-based pMDIs, for example, are in development,⁸⁹ ^, ⁹¹ ^, ⁹² which may facilitate further innovation in fixed-dose combination inhaler products. For example, the US Federal Drug Assistants recently canonical a novel LAMA/LABA cosuspension-based pMDI (glycopyrrolate and formoterol fumarate) for patients with COPD.⁹³ Triple therapy for COPD (ie, treatments containing LABA, LAMA, and ICS) has besides been proposed as a convenient treatment option for COPD.⁹⁴ ^, ⁹⁵ Indeed, the first triple inhaler containing formoterol, tiotropium, and ciclesonide is already on the marketplace in Bharat.⁹⁶

Future treatment of patients with COPD volition crave the continued evolution of novel nebulizer devices and drugs for patient groups and clinical scenarios where existing pMDI/DPI therapy is inadequate. Health intendance providers should stay up to date regarding emerging nebulized handling options that could provide boosted clinical benefits for their patients. In daily practise, prescribing the well-nigh appropriate nebulized therapy should take into consideration the available drug formulations, combinations, and devices, every bit well equally the patients' pulmonary part, skills, and preferences. Thus, health intendance providers and patients together can optimize the benefits of available nebulized treatments for patients with COPD.

Acknowledgments

Mylan Inc. (Canonsburg, PA, USA) funded medical writing support. Roger J Hill, PhD, of Ashfield Healthcare Communications (Haddam, CT, U.s.) drafted and revised the manuscript based on the input from the author, and Paula Stuckart of Ashfield Healthcare Communications copyedited and styled the manuscript as per journal requirements.

Footnotes

Disclosure

The writer reports personal fees from Mylan, grants and personal fees from Sunovion, grants and personal fees from Boehringer-Ingelheim, and personal fees from Theravance during the conduct of this study. Outside the conduct of this study, the author reports grants and personal fees from AstraZeneca and personal fees from Novartis.

References

i. Barjaktarevic IZ, Arredondo AF, Cooper CB. Positioning new pharmacotherapies for COPD. Int J Chron Obstruct Pulmon Dis. 2015;x:1427–1442. [PMC free commodity] [PubMed] [Google Scholar]

2. Global Initiative for Chronic Obstructive Lung Illness (Golden) [web-folio on the Internet] Global Strategy for Diagnosis, Management, and Prevention of COPD –2016. [Accessed May 4, 2016]. Available from: http://goo.gl/ItQL3a.

3. Dolovich MB, Ahrens RC, Hess DR, et al. American College of Chest Physicians; American College of Asthma, Allergy, and Immunology Device selection and outcomes of aerosol therapy: evidence-based guidelines: American Higher of Breast Physicians/American Higher of Asthma, Allergy, and Immunology. Breast. 2005;127(ane):335–371. [PubMed] [Google Scholar]

4. Ram FS, Brocklebank DM, Muers M, Wright J, Jones Pw. Pressurised metered-dose inhalers versus all other hand-held inhalers devices to evangelize bronchodilators for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2002;(ane):CD002170. [PMC free article] [PubMed] [Google Scholar]

5. Turner MO, Patel A, Ginsburg South, FitzGerald JM. Bronchodilator delivery in acute airflow obstacle. A meta-analysis. Curvation Intern Med. 1997;157(15):1736–1744. [PubMed] [Google Scholar]

half dozen. Dhand R, Dolovich M, Chipps B, Myers TR, Restrepo R, Farrar JR. The role of nebulized therapy in the management of COPD: evidence and recommendations. COPD. 2012;ix(1):58–72. [PubMed] [Google Scholar]

7. Bonini M, Usmani OS. The importance of inhaler devices in the treatment of COPD. COPD Res Pract. 2015;ane(one):1–9. [Google Scholar]

8. Lavorini F, Corrigan CJ, Barnes PJ, et al. Droplets Drug Management Improvement Squad Retail sales of inhalation devices in European countries: so much for a global policy. Respir Med. 2011;105(seven):1099–1103. [PubMed] [Google Scholar]

nine. Sharafkhaneh A, Wolf RA, Goodnight S, Hanania NA, Brand BJ, Tashkin DP. Perceptions and attitudes toward the use of nebulized therapy for COPD: patient and caregiver perspectives. COPD. 2013;10(4):482–492. [PubMed] [Google Scholar]

ten. Barta SK, Crawford A, Roberts CM. Survey of patients' views of domiciliary nebuliser treatment for chronic lung disease. Respir Med. 2002;96(6):375–381. [PubMed] [Google Scholar]

11. Qaseem A, Wilt TJ, Weinberger SE, et al. American College of Physicians. American College of Chest Physicians. American Thoracic Lodge. European Respiratory Society Diagnosis and management of stable chronic obstructive pulmonary illness: a clinical practice guideline update from the American Higher of Physicians, American Higher of Chest Physicians, American Thoracic Society, and European Respiratory Guild. Ann Intern Med. 2011;155(3):179–191. [PubMed] [Google Scholar]

12. Angelis N, Porpodis K, Zarogoulidis P, et al. Airway inflammation in chronic obstructive pulmonary disease. J Thorac Dis. 2014;6(suppl one):S167–S172. [PMC free article] [PubMed] [Google Scholar]

thirteen. Vos T, Flaxman Advertizement, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the global brunt of disease study 2010. Lancet. 2012;380(9859):2163–2196. [PMC gratis article] [PubMed] [Google Scholar]

14. Lozano R, Naghavi Thou, Foreman K, et al. Global and regional mortality from 235 causes of decease for xx age groups in 1990 and 2010: a systematic analysis for the global brunt of disease study 2010. Lancet. 2012;380(9859):2095–2128. [PubMed] [Google Scholar]

xv. Landis SH, Muellerova H, Mannino DM, et al. Standing to confront COPD international patient survey: methods, COPD prevalence, and illness burden in 2012–2013. Int J Chron Obstruct Pulmon Dis. 2014;9:597–611. [PMC gratuitous article] [PubMed] [Google Scholar]

16. Mannino DM, Buist As. Global burden of COPD: risk factors, prevalence, and hereafter trends. Lancet. 2007;370(9589):765–773. [PubMed] [Google Scholar]

xviii. Nhlbi.nih.gov [webpage on the Internet] National Heart Lung and Claret Institute. Morbidity and bloodshed: 2012 nautical chart book on cardiovascular, lung, and claret diseases. [Accessed March three, 2016]. Available from: http://www.nhlbi.nih.gov/resources/docs/cht-volume.htm.

19. Akinbami LJ, Liu 10. NCHS Data Cursory. 63. 2011. Chronic obstructive pulmonary illness amidst adults aged 18 and over in the Us, 1998–2009; pp. ane–8. [PubMed] [Google Scholar]

twenty. CDC.gov Centers for Disease Control and Prevention. National Centre for Health Statistics Data brief 63: chronic obstructive pulmonary affliction amid adults aged xviii and over in the United States, 1998–2009. [Accessed March four, 2016]. Available from: http://www.cdc.gov/nchs/data/databriefs/db63_tables.pdf#ii.

21. Quinet P, Immature CA, Heritier F. The apply of dry powder inhaler devices by elderly patients suffering from chronic obstructive pulmonary disease. Ann Phys Rehabil Med. 2010;53(two):69–76. [PubMed] [Google Scholar]

22. Taffet GE, Donohue JF, Altman PR. Considerations for managing chronic obstructive pulmonary disease in the elderly. Clin Interv Aging. 2014;ix:23–xxx. [PMC free commodity] [PubMed] [Google Scholar]

23. Mahler DA, Waterman LA, Ward J, Gifford AH. Comparison of dry powder versus nebulized beta-agonist in patients with COPD who have suboptimal peak inspiratory flow rate. J Aerosol Med Pulm Drug Deliv. 2014;27(ii):103–109. [PubMed] [Google Scholar]

24. Celli BR. Update on the direction of COPD. Chest. 2008;133(6):1451–1462. [PubMed] [Google Scholar]

26. Barrons R, Pegram A, Borries A. Inhaler device selection: special considerations in elderly patients with chronic obstructive pulmonary disease. Am J Health Syst Pharm. 2011;68(13):1221–1232. [PubMed] [Google Scholar]

27. Dekhuijzen PN, Bjermer Fifty, Lavorini F, Ninane V, Molimard G, Haughney J. Guidance on handheld inhalers in asthma and COPD guidelines. Respir Med. 2014;108(5):694–700. [PubMed] [Google Scholar]

28. Melani AS, Bonavia M, Cilenti V, et al. Gruppo Educazionale Associazione Italiana Pneumologi Ospedalieri Inhaler mishandling remains common in existent life and is associated with reduced disease control. Respir Med. 2011;105(6):930–938. [PubMed] [Google Scholar]

29. Newman SP. Inhaler treatment options in COPD. Eur Respir Rev. 2005;xiv(96):102–108. [Google Scholar]

30. Dolovich MB, Dhand R. Droplets drug commitment: developments in device design and clinical apply. Lancet. 2011;377(9770):1032–1045. [PubMed] [Google Scholar]

31. Berlinski A. Assessing new technologies in aerosol medicine: strengths and limitations. Respir Care. 2015;sixty(6):833–847. discussion 847–849. [PubMed] [Google Scholar]

32. Rau JL. Applied problems with aerosol therapy in COPD. Respir Care. 2006;51(2):158–172. [PubMed] [Google Scholar]

33. Rubin BK. Pediatric aerosol therapy: new devices and new drugs. Respir Care. 2011;56(9):1411–1421. discussion 1421–1423. [PubMed] [Google Scholar]

34. Ari A. Jet, ultrasonic, and mesh nebulizers: an evaluation of nebulizers for better clinical outcomes. Eurasian J Pulmonol. 2014;16:1–7. [Google Scholar]

35. Zeman Thou, Tiffin N. Efficiency of portable jet nebulizer systems using budesonide. Am J Respir Crit Care Med. 2010;181:A1347. [Google Scholar]

36. Lenney West, Edenborough F, Kho P, Kovarik JM. Lung deposition of inhaled tobramycin with eFlow rapid/LC Plus jet nebuliser in healthy and cystic fibrosis subjects. J Cyst Fibros. 2011;ten(1):9–fourteen. [PubMed] [Google Scholar]

37. Goodman Northward, Morgan Yard, Nikander K, Hinch Due south, Coughlin S. Evaluation of patient-reported outcomes and quality of life with the I-beak AAD organization in patients with chronic obstructive pulmonary disease. J Droplets Med Pulm Drug Deliv. 2010;23(suppl 1):S61–S70. [PMC complimentary article] [PubMed] [Google Scholar]

38. Anderson P. Use of Respimat^® Soft Mist™ Inhaler in COPD patients. Int J Chron Obstruct Pulmon Dis. 2006;i(three):251–259. [PMC free article] [PubMed] [Google Scholar]

39. Meyer KC. COPD 2013: an update on handling and newly canonical medications for pharmacists. J Am Pharm Assoc (2003) 2013;53(half-dozen):e219–e229. quiz e230-1. [PubMed] [Google Scholar]

40. Loh CH, Donohue JF, Ohar JA. Review of drug condom and efficacy of arformoterol in chronic obstructive pulmonary disease. Expert Opin Drug Saf. 2015;14(three):463–472. [PubMed] [Google Scholar]

41. Donohue JF, Hanania NA, Brand B, et al. One-year condom and efficacy written report of arformoterol tartrate in patients with moderate to severe COPD. Chest. 2014;146(6):1531–1542. [PMC free commodity] [PubMed] [Google Scholar]

42. King P. Role of arformoterol in the direction of COPD. Int J Chron Obstruct Pulmon Dis. 2008;3(3):385–391. [PMC free article] [PubMed] [Google Scholar]

43. Hanrahan JP, Hanania NA, Calhoun WJ, Sahn SA, Sciarappa K, Baumgartner RA. Issue of nebulized arformoterol on airway function in COPD: results from ii randomized trials. COPD. 2008;five(ane):25–34. [PubMed] [Google Scholar]

44. Baumgartner RA, Hanania NA, Calhoun WJ, Sahn SA, Sciarappa Grand, Hanrahan JP. Nebulized arformoterol in patients with COPD: a 12-week, multicenter, randomized, double-bullheaded, double-dummy, placebo- and active-controlled trial. Clin Ther. 2007;29(2):261–278. [PubMed] [Google Scholar]

45. Tashkin DP, Donohue JF, Mahler DA, et al. Effects of arformoterol twice daily, tiotropium once daily, and their combination in patients with COPD. Respir Med. 2009;103(iv):516–524. [PubMed] [Google Scholar]

46. Gross NJ, Nelson HS, Lapidus RJ, et al. Formoterol Study Grouping Efficacy and safety of formoterol fumarate delivered past nebulization to COPD patients. Respir Med. 2008;102(2):189–197. [PubMed] [Google Scholar]

47. Kottakis J, Cioppa GD, Creemers J, et al. Faster onset of bronchodilation with formoterol than with salmeterol in patients with stable, moderate to severe COPD: results of a randomized, double-blind clinical report. Can Respir J. 2002;9(2):107–115. [PubMed] [Google Scholar]

48. Sutherland ER, Brazinsky S, Feldman G, McGinty J, Tomlinson L, Denis-Mize K. Nebulized formoterol effect on bronchodilation and satisfaction in COPD patients compared to QID ipratropium/albuterol MDI. Curr Med Res Opin. 2009;25(3):653–661. [PubMed] [Google Scholar]

49. Tashkin DP, Hanania NA, McGinty J, Denis-Mize Chiliad, Chaudry I. Nebu-lized formoterol provides added benefits to tiotropium treatment in chronic obstructive pulmonary illness. Adv Ther. 2009;26(11):1024–1034. [PubMed] [Google Scholar]

50. Hanania NA, Boota A, Kerwin E, Tomlinson 50, Denis-Mize K. Efficacy and safety of nebulized formoterol every bit add-on therapy in COPD patients receiving maintenance tiotropium bromide: results from a 6-week, randomized, placebo-controlled, clinical trial. Drugs. 2009;69(9):1205–1216. [PubMed] [Google Scholar]

51. Tashkin DP, Littner M, Andrews CP, Tomlinson Fifty, Rinehart M, Denis-Mize K. Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: a placebo-controlled trial. Respir Med. 2008;102(4):479–487. [PubMed] [Google Scholar]

52. Deeks ED. Olodaterol: a review of its use in chronic obstructive pulmonary disease. Drugs. 2015;75(six):665–673. [PubMed] [Google Scholar]

53. Boehringer Ingelheim . Newly published caput-to-caput data bear witness stiolto™ respimat® (tiotropium bromide and olodaterol) improved lung function across range of measures [press release] Boehringer Ingelheim; 2016. Feb 9, [Accessed September 28, 2016]. Bachelor from: https://goo.gl/VpstiJ. [Google Scholar]

54. Feldman GJ, Bernstein JA, Hamilton A, Nivens MC, Korducki 50, LaForce C. The 24-h FEV1 time contour of olodaterol once daily via Respimat^® and formoterol twice daily via Aerolizer^® in patients with Gilded 2–4 COPD: results from two 6-week crossover studies. Springerplus. 2014;3:419. [PMC free article] [PubMed] [Google Scholar]

55. Keating GM. Tiotropium Respimat^® soft mist inhaler: a review of its utilize in chronic obstructive pulmonary disease. Drugs. 2014;74(15):1801–1816. [PubMed] [Google Scholar]

56. Hochrainer D, Holz H, Kreher C, Scaffidi L, Spallek M, Wachtel H. Comparison of the aerosol velocity and spray duration of Respimat soft mist inhaler and pressurized metered dose inhalers. J Droplets Med. 2005;eighteen(iii):273–282. [PubMed] [Google Scholar]

57. Iacono P, Velicitat P, Guemas E, Leclerc V, Thebault JJ. Improved delivery of ipratropium bromide using Respimat (a new soft mist inhaler) compared with a conventional metered dose inhaler: cumulative dose response study in patients with COPD. Respir Med. 2000;94(five):490–495. [PubMed] [Google Scholar]

58. Dahl R, Calverley PM, Anzueto A, et al. Safe and efficacy of tiotropium in patients switching from HandiHaler to Respimat in the TIOSPIR trial. BMJ Open. 2015;five(12):e009015. [PMC free article] [PubMed] [Google Scholar]

59. Barr RG, Bourbeau J, Camargo CA, Ram FS. Inhaled tiotropium for stable chronic obstructive pulmonary affliction. Cochrane Database Syst Rev. 2005;(2):CD002876. [PMC free article] [PubMed] [Google Scholar]

60. ZuWallack R, Allen 50, Hernandez Thousand, Ting Northward, Abrahams R. Efficacy and safety of combining olodaterol Respimat^® and tiotropium HandiHaler^® in patients with COPD: results of two randomized, double-blind, active-controlled studies. Int J Chron Obstruct Pulmon Dis. 2014;nine:1133–1144. [PMC free article] [PubMed] [Google Scholar]

61. Ferguson GT, Flezar One thousand, Korn S, et al. Efficacy of tiotropium + olodaterol in patients with chronic obstructive pulmonary disease by initial disease severity and handling intensity: a post hoc analysis. Adv Ther. 2015;32(6):523–536. [PMC free commodity] [PubMed] [Google Scholar]

62. Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol stock-still-dose combination versus mono-components in COPD (GOLD 2–4) Eur Respir J. 2015;45(iv):969–979. [PMC free article] [PubMed] [Google Scholar]

63. Singh D, Ferguson GT, Bolitschek J, et al. Tiotropium + olodaterol shows clinically meaningful improvements in quality of life. Respir Med. 2015;109(10):1312–1319. [PubMed] [Google Scholar]

64. Datta D, Vitale A, Lahiri B, ZuWallack R. An evaluation of nebulized levalbuterol in stable COPD. Chest. 2003;124(3):844–849. [PubMed] [Google Scholar]

65. Nair Due south, Thomas E, Pearson SB, Henry MT. A randomized controlled trial to appraise the optimal dose and result of nebulized albuterol in acute exacerbations of COPD. Chest. 2005;128(1):48–54. [PubMed] [Google Scholar]

66. Borkowski J, Crader M. Nebulized albuterol versus levalbuterol in pediatric and adult patients: a review. Formulary. 2009;44:108–118. [Google Scholar]

67. Truitt T, Witko J, Halpern Thou. Levalbuterol compared to racemic albuterol: efficacy and outcomes in patients hospitalized with COPD or asthma. Chest. 2003;123(1):128–135. [PubMed] [Google Scholar]

lxx. The COMBIVENT Inhalation Solution Study Group Routine nebulized ipratropium and albuterol together are better than either alone in COPD. The COMBIVENT Inhalation Solution Report Group. Breast. 1997;112(6):1514–1521. [PubMed] [Google Scholar]

71. York JM, Smeeding J, Brook RA, Hoehler F, Klein GL. Exploratory economic evaluation of patients with COPD on a combination product versus individual components (ipratropium bromide and albuterol) Adv Ther. 2007;24(iv):757–771. [PubMed] [Google Scholar]

73. Leaker BR, Barnes PJ, Jones CR, Tutuncu A, Singh D. Efficacy and condom of nebulized glycopyrrolate for administration using a loftier efficiency nebulizer in patients with chronic obstructive pulmonary disease. Br J Clin Pharmacol. 2015;79(3):492–500. [PMC free commodity] [PubMed] [Google Scholar]

74. Fogarty C, Dunn Chiliad, Singh D, Tutuncu A, Kerwin East. Cardiovascular safety of nebulized glycopyrrolate (SUN-101) compared with tiotropium, ipratropium and placebo in patients with COPD. Clin Res. 2013;2(three):4. [Google Scholar]

75. Sunovion Respiratory Evolution Inc Randomized, double-blind, placebo-controlled, parallel-group, multicenter, efficacy and safety trial of 12 weeks of treatment with nebulized Dominicus-101 in patients with COPD: Golden-3 (glycopyrrolate for obstructive lung disease via electronic nebulizer) [Accessed March 13, 2016]. Bachelor from: https://clinicaltrials.gov/ct2/bear witness/{"blazon":"clinical-trial","attrs":{"text":"NCT02347761","term_id":"NCT02347761"}}NCT02347761?term=NLMidentifier&rank=1. NCT02347761.NLM identifier: NCT02347761.

76. Sunovion Respiratory Development Inc A randomized, double-blind, placebo-controlled, parallel-group, multicenter, efficacy and safety trial of 12 weeks of handling with nebulized SUN-101 in patients with COPD: Golden-4 (glycopyrrolate for obstructive lung affliction via electronic nebulizer) [Accessed March 13, 2016]. Available from: https://clinicaltrials.gov/ct2/testify/{"type":"clinical-trial","attrs":{"text":"NCT02347774","term_id":"NCT02347774"}}NCT02347774?term={"type":"clinical-trial","attrs":{"text":"NCT02347774","term_id":"NCT02347774"}}NCT02347774&rank=1. NLM identifier: NCT02347774.

77. Sunovion Respiratory Development Inc A randomized, open up-characterization, active-controlled, parallel-group, multicenter, long-term safe trial of handling with nebulized SUN-101 in patients with COPD: Golden-5 (glycopyrrolate for obstructive lung illness via electronic nebulizer) [Accessed March xiii, 2016]. Available from: https://clinicaltrials.gov/ct2/show/{"blazon":"clinical-trial","attrs":{"text":"NCT02276222","term_id":"NCT02276222"}}NCT02276222?term={"type":"clinical-trial","attrs":{"text":"NCT02276222","term_id":"NCT02276222"}}NCT02276222&rank=1. NLM identifier: NCT02276222.

79. Pulido-Rios MT, McNamara A, Obedencio GP, et al. In vivo pharmacological characterization of TD-4208, a novel lung-selective inhaled muscarinic adversary with sustained bronchoprotective upshot in experimental animal models. J Pharmacol Exp Ther. 2013;346(2):241–250. [PubMed] [Google Scholar]

lxxx. Lo A, Nicholls AJ, Haumann B, Moran EJ, Bourdet DL. A population PK model of once-daily TD-4208, a nebulized long-acting muscarinic antagonist (LAMA) in patients with chronic obstructive pulmonary disease (COPD) Am J Respir Crit Care Med. 2015;191:A5764. Abstract. [Google Scholar]

81. Nicholls AJ, Barnes C, Yates W, Moran EJ, Singh D. A randomized, crossover, 7-day study of once-daily TD-4208, a long-interim muscarinic antagonist, in subjects with COPD. Am J Respir Crit Care Med. 2014;189:A6003. Abstract. [Google Scholar]

82. Haumann BK, Nicholls AJ, Barnes C, Bourdet DL, Moran EJ. Dose-ranging study of once-daily TD-4208, an inhaled long-acting muscarinic antagonist (LAMA) in patients with chronic obstructive pulmonary disease (COPD) Am J Respir Crit Care Med. 2015;191:A5750. Abstract. [Google Scholar]

83. Theravance Biopharma R & D, Inc A phase 3, 12-week, randomized, double-blind placebo-controlled parallel group report of nebulized TD-4208 in subjects with chronic obstructive pulmonary affliction. [Accessed March 13, 2016]. Bachelor from: https://goo.gl/ab2VxL?term=NLMidentifier&rank={"type":"clinical-trial","attrs":{"text":"NCT02459080","term_id":"NCT02459080"}}NCT02459080. NLM identifier: NCT02459080.

84. Theravance Biopharma R & D, Inc A phase 3, 12-week, randomized, double-blind placebo-controlled parallel group written report of nebulized TD-4208 in subjects with chronic obstructive pulmonary disease. [Accessed March 13, 2016]. Bachelor from: https://goo.gl/fPyjfM?term=NLMidentifier&rank={"type":"clinical-trial","attrs":{"text":"NCT02512510","term_id":"NCT02512510"}}NCT02512510. NLM identifier: NCT02512510.

85. Theravance Biopharma R & D, Inc A phase 3, 52-week, random-ized, active-controlled parallel group study to evaluate the rubber and tolerability of nebulized TD-4208 in subjects with chronic obstructive pulmonary affliction. [Accessed March 13, 2016]. Bachelor from: https://goo.gl/83EjwX?term=NLMidentifier&rank={"type":"clinical-trial","attrs":{"text":"NCT02518139","term_id":"NCT02518139"}}NCT02518139. NLM identifier: NCT02518139.

86. Tashkin DP, Klein GL, Colman SS, Zayed H, Schonfeld WH. Comparing COPD treatment: Nebulizer, metered dose inhaler, and concomitant therapy. Am J Med. 2007;120(five):435–441. [PubMed] [Google Scholar]

88. The Global Initiative for Chronic Obstructive Lung Disease The 2016 Global Strategy for Diagnosis, Direction, and Prevention of COPD. [Accessed March 3, 2016]. Bachelor from: http://goo.gl/ItQL3a.

89. Tashkin DP, Ferguson GT. Combination bronchodilator therapy in the management of chronic obstructive pulmonary affliction. Respir Res. 2013;14:49. [PMC gratuitous commodity] [PubMed] [Google Scholar]

90. Cazzola M, Segreti A, Matera MG. New developments in the combination treatment of COPD: focus on umeclidinium/vilanterol. Drug Des Devel Ther. 2013;7:1201–1208. [PMC gratuitous article] [PubMed] [Google Scholar]

91. Adi H, Immature PM, Traini D. Co-deposition of a triple therapy drug formulation for the treatment of chronic obstructive pulmonary disease using solution-based pressurised metered dose inhalers. J Pharm Pharmacol. 2012;64(9):1245–1253. [PubMed] [Google Scholar]

92. Lechuga-Ballesteros D, Noga B, Vehring R, Cummings RH, Dwivedi SK. Novel cosuspension metered-dose inhalers for the combination therapy of chronic obstructive pulmonary illness and asthma. Time to come Med Chem. 2011;iii(thirteen):1703–1718. [PubMed] [Google Scholar]

94. Barnes PJ. Triple inhalers for obstructive airways illness: will they be useful? Expert Rev Respir Med. 2011;5(3):297–300. [PubMed] [Google Scholar]

95. Lipworth B. Triple inhaler therapy for COPD. Thorax. 2015;70(10):991. [PubMed] [Google Scholar]

96. Trivedi RK, Chendake DS, Patel MC. A rapid, stability-indicating RP-HPLC method for the simultaneous determination of formoterol fumarate, tiotropium bromide, and ciclesonide in a pulmonary drug product. Sci Pharm. 2012;80(iii):591–603. [PMC gratuitous commodity] [PubMed] [Google Scholar]

97. Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(four):347–365. [PubMed] [Google Scholar]

98. Laube BL, Janssens HM, Jongh FH, Devadason SG, Dhand R, Diot P. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J. 2011;37(half dozen):1308–1331. [PubMed] [Google Scholar]

99. Gross NJ, Donohue JF. Nebulized formoterol: a review of clinical efficacy and condom in COPD. Int J Chron Obstruct Pulmon Dis. 2010;v:223–232. [PMC free article] [PubMed] [Google Scholar]

100. Ferguson GT, Feldman GJ, Hofbauer P, et al. Efficacy and safety of olodaterol in one case daily delivered via Respimat^® in patients with GOLD 2–4 COPD: results from two replicate 48-week studies. Int J Chron Obstruct Pulmon Dis. 2014;9:629–645. [PMC free article] [PubMed] [Google Scholar]

101. van Noord JA, Cornelissen PJ, Aumann JL, Platz J, Mueller A, Fogarty C. The efficacy of tiotropium administered via Respimat soft mist inhaler or HandiHaler in COPD patients. Respir Med. 2009;103(1):22–29. [PubMed] [Google Scholar]

104. Theravance Biopharma Theravance Biopharma announces positive tiptop-line results from phase 2b dose-ranging study of its investigational LAMA, TD-4208, for the treatment of COPD [press release]. Thera-vance Biopharma; 2014 [September 8] [Accessed September 28, 2016]. Available from: https://goo.gl/fhudYX.

105. Kesser KC, Geller DE. New aerosol commitment devices for cystic fibrosis. Respir Care. 2009;54(6):754–767. [PubMed] [Google Scholar]

Articles from International Journal of Chronic Obstructive Pulmonary Disease are provided hither courtesy of Dove Press

perreaultsciusurturs.blogspot.com

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076803/