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Knights Inn Fort Smith Airport
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In Arksansas
Forgot to post pictures of Arkansas in the previous post. Attached are pictures when we arrive in Arkansas and the roads we travelled. In addition, I posted pictures of the Lake Fort Smith State Park where we stayed. It was an awesome park...our #1 park throughout our travels.
Hope everyone is well.
Next stop is Oklahoma and then into Texas.
Stay ...
Missouri and Arkansas
... nights, but immediately changed our minds....we are here for 4 nights. This park has won our #1 park choice since we've been travelling. This place is beautiful.....truly beautiful. The park offers....a marina, fishing, camping, cabin rentals, beautiful views/scenary, peace & quiet. This is a perfect place to find tranquility and a little piece of heaven on earth. We did try to find somewhere that sold beer, but the counties are ...
The trip home
... sad that a word used to describe such a persistent problem has now gained such notoriety.
It is noteworthy that the power outages have sparked such consternation among Ghanaians that a public demonstration against the government is scheduled in Accra for this coming Saturday. One always hopes that such demonstrations will be peaceful, but with promise after promise from the government going unfulfilled, and more businesses laying off or closing their doors ...
Little Rock to Fort Smith 190 miles
... it all looks Art Deco but I'm not sure it can be that old. Maybe tomorrow we will get to see the old part of town that the book talks about. Had dinner in the hotel as it's still so cold outside and watched a bit of the superbowl while we ate our pork with potatoes & beans (a $6.95 Super Bowl special). An old couple there were from Seattle but unfortunately for them the New England Patriots beat their Seattle ...
The trip to Ghana
... or locate their baggage and get it off the plane. We should be underway in about 15 minutes.
Nearly 30 minutes later he came on again to say they had no idea where those passengers were, but their baggage was mixed in through all the cargo in the holds, and it was taking the crew some time to find it all. But we should be on our way in about 15 minutes.
Another 30 or so minutes later he came on to tell us they had ...


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'Little House on the Prairie' Actress Melissa Gilbert To Run for Congress in Michigan's 8th District as a Democrat
Damn, Laura "Half Pint" Ingalls is a Democrat …
51 year old Laura Ingalls is going to run for Congress in 2016 in Michigan's 8th District. Melissa Gilbert is going to run as a Democrat in a district that has lately become a GOP stronghold in recent elections. Although Laura Ingalls has not held political office before, which is probably a good thing in this day and age, but she was president of the Screen Actors Guild serving two terms from 2001 to 2005. However, it appears that Melissa Gilbert's campaign may have difficulties before it begins. In June 2015, the Daily Press & Argus in Livingston County reported that the IRS filed a lien against Gilbert, alleging she owes more than $360,000 in back taxes. Who thinks that Michigan Republicans will use this as political ad fodder and rightfully so. One would think that locals in her district might have an issue with this as well, one would think.
Oh those tax and spend liberals and the hypocrisy of it all.
Actress Melissa Gilbert, best known for her portrayal of Laura Ingalls Wilder on NBC's "Little House on the Prairie" in the 1970s and '80s, said Monday she will run for Congress in Michigan's 8th District — though her campaign will have to tamp down questions about a tax bill.
Gilbert, who lives in Livingston County with her husband, actor Timothy Busfield, is running as a Democrat in a district that has been a Republican stronghold in recent elections: U.S. Rep. Mike Bishop, R-Rochester, won the race to replace former U.S. Rep. Mike Rogers, R-Howell, last year, beating Democrat Eric Schertzing, 54%-42%.
But someone with Gilbert's celebrity could make a splash, especially when it comes to raising funds for her campaign. Bishop was recently added to the Republican's Patriot Program, an effort to help potentially vulnerable incumbents maintain their seats in Congress, though it's unclear why he was marked for such aid.
"I'm running for Congress to make life a little easier for all the families who feel they have fallen through the cracks in today's economy," Gilbert said in a statement released on her website, www.gilbertformichigan.com. "I believe building a new economy is a team effort, and we need to bring fresh voices to the table to get the job done."
Posted August 11, 2015 by Scared Monkeys
2016 Elections, Congress, Democrats, Liberals, Progressives, Tax & Spend Liberals, Taxes | one comment
Your Tax Dollars at Work … CIA Cash Ended Up Financing Radical Islamist Terrorist Group Al Qaeda
As reported at the New York Times, your hard earned tax dollars financing Islamist terrorists. This is just another example that the US government has become too big to succeed. As stated in the article, it was just another in a long list of examples of how the United States, largely because of poor oversight and loose financial controls. In this case, the poor oversight and lack of attention to detail gives hard earned American tax payer dollars to the very evil radical Islamist terrorists we are looking to defeat. UNREAL.
Why does this sound exactly like the brilliance of 'Fast & Furious'?
In the spring of 2010, Afghan officials struck a deal to free an Afghan diplomat held hostage by Al Qaeda. But the price was steep — $5 million — and senior security officials were scrambling to come up with the money.
They first turned to a secret fund that the Central Intelligence Agency bankrolled with monthly cash deliveries to the presidential palace in Kabul, according to several Afghan officials involved in the episode. The Afghan government, they said, had already squirreled away about $1 million from that fund.
Within weeks, that money and $4 million more provided from other countries was handed over to Al Qaeda, replenishing its coffers after a relentless C.I.A. campaign of drone strikes in Pakistan had decimated the militant network's upper ranks.
The C.I.A.'s contribution to Qaeda's bottom line, though, was no well-laid trap. It was just another in a long list of examples of how the United States, largely because of poor oversight and loose financial controls, has sometimes inadvertently financed the very militants it is fighting.
While refusing to pay ransoms for Americans kidnapped by Al Qaeda, the Taliban or, more recently, the Islamic State, the United States has spent hundreds of billions of dollars over the last decade at war in Iraq and Afghanistan, some of which has been siphoned off to enemy fighters.
Posted March 15, 2015 by Scared Monkeys
al-Qaeda, America - United States, CIA, Hostages, Islamist, Jihad, Radical Islam, Tax & Spend Liberals, Taxes, Terrorism, War on Terror, We the People, WTF | no comments
Barack Obama Family's 2014 Christmas Vacation in Hawaii Cost Taxpayers $3,672,798 in Transportation Expenses
Did you get a thank you card America? Don't worry, neither did I. As announced at Judicial Watch, the Obama Family's 2014 Christmas vacation in Hawaii cost taxpayers $3,672,798 in transportation expenses. This while many hard working, tax paying families struggled to put presents under the tree for their children. Obama is pretty good at giving gifts away at the expense of the American tax payer. Then there is his vacations …
Judicial Watch announced today it obtained records from the U.S. Department of the Air Force revealing that the Obama family's 2014 Christmas vacation to Honolulu, Hawaii, cost taxpayers $3,672,798 in flight expenses alone. Christmas in Hawaii is an annual tradition for the family and their most recent visit, from December 19, 2014, to January 4, 2015, marked their seventh Hawaiian vacation. The documents came from the Department of the Air Force in response to a Freedom of Information Act (FOIA) request filed on January 5, 2015. Costs for the trip to Hawaii, to the West Coast, and to Martha's Vineyard last year, cost nearly $3 million alone in transportation.
According to the documents, the Obama's spent 17.8 hours in the air round-trip at $206,337.00 per hour, bringing the total cost to taxpayers to $3,672,798.60.
According to other figures obtained by Judicial Watch over the past three years, Obama Hawaii Christmas vacations have cost taxpayers $15,540,515.10 in transportation expenses alone. This includes outbound and return flight expenses in 2012 totaling $4,086,355.20. (The Secret Service provided documents for Obama's Christmas 2012 trip to Honolulu. The grand total is $654,599.40 including $409,225.78 in hotels.) Flight expenses for the Obamas' Christmas vacations to Hawaii cost taxpayers $7,781,361.30.
And the Christmas 2014 flight expense of $3,672,798.60. The average American family spent $4,580 on Christmas in 2014.
Posted March 11, 2015 by Scared Monkeys
Barack Obama, class warfare, Divider in Chief, Epic Fail, Government, Misleader, Narcissist in Chief, Out of Control Spending, Tax & Spend Liberals, Taxes, WTF | one comment
Barack Obama "Very Interested" In Raising Taxes Through Executive Action
THE IMPERIAL PRESIDENT STRIKES AGAIN … When does it stop with this president? Now through his mouth piece White House Press Secretary Josh Earnest, he confirmed that President Obama is "very interested" in the idea of raising taxes through unilateral executive action. When does it stop with this law-breaking President? Does Barack Obama care that there is a US Constitution, or is he just hell-bent to do as much damage as he possibly can before he leaves office as a bunch of gutless Republicans sit back and do nothing. How sad is it that America has become a country with a Democrat president who shreds the Constitution and Republican Congress who is too afraid to defend it.
America, just because some one uses the world "Middle class" does not mean that you are allowed to shred the Constitution. This is the Obama BS and his way to get low information folks on his side, say middle class and that makes it perfectly okay that he could give a lick of the founding documents of this country.
Go to the 1:10:45 mark of the VIDEO for the tax raising BS
White House Press Secretary Josh Earnest confirmed Monday that President Obama is "very interested" in the idea of raising taxes through unitlateral executive action.
"The president certainly has not indicated any reticence in using his executive authority to try and advance an agenda that benefits middle class Americans," Earnest said in response to a question about Sen. Bernie Sanders (I-VT) calling on Obama to raise more than $100 billion in taxes through IRS executive action.
"Now I don't want to leave you with the impression that there is some imminent announcement, there is not, at least that I know of," Earnest continued. "But the president has asked his team to examine the array of executive authorities that are available to him to try to make progress on his goals. So I am not in a position to talk in any detail at this point, but the president is very interested in this avenue generally," Earnest finished.
Daily Commentary – Friday, August 29, 2014 – Burger King Set to Purchase Canadian Compony Tim Horton's for 11 Billion
- Then transfer it's headquarters to Canada so it can take advantage of the lower taxes. Some say it's time to boycott Burger King
Posted August 29, 2014 by Klaasend
Dana Pretzer, Main, Scared Monkeys Radio, Taxes | no comments

subset: commoncrawl


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This is the March 26, 2013 news archive. View today's Mavericks rumors and news.
Dallas Mavericks
Dallas Mavericks News and Rumors
Clips' Odom says he would apologize to CubanESPN.com Updated Mar 26, 2013Los Angeles Clippers forward Lamar Odom told ESPNDallas.com on Tuesday he would apologize to Dallas Mavericks owner Mark Cuban if they had a conversation but felt no guilt about the role he played in his premature departure from Dallas last season.Share Tweet
Paul starts vs. Mavericks despite knee injuryESPN.com Mar 26, 2013Los Angeles Clippers guard Chris Paul will start Tuesday against the Dallas Mavericks despite swelling in his left knee that made him a game-time decision.Share Tweet
With Jamal Crawford, Part IIMar 26Clippers guard Jamal Crawford on the origin of shake n' bake, playing with Chris Paul and more.
THTV: Jamal CrawfordMar 26Clippers guard Jamal Crawford on the state of the Clippers, the importance of coming off the bench and more.
Mavericks Stun Clippers In OvertimeMar 26Dirk Nowitzki scored a season-high 33 points to help the Mavericks overcome the Clippers 109-102.


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Prices are as of Dec. 31, 2011.
The meltdown in U.S. bank stocks is incredible. My 11 stock universe of the largest banks has seen its collective market cap. melt from $856M to $580M, a drop of 33%. The big losers were Bank of America (NYSE:BAC) (-58%), Goldman Sachs (NYSE:GS) (-49%), Citigroup (NYSE:C) (-46%), Morgan Stanley (NYSE:MS) (-39%) and Suntrust (NYSE:STI) (-37%).
By contrast, the 6 Canadian banks covered lost only 7% collectively.
The 6 Canadian banks are trading at an average P/BV of 1.8x (2.2x one year ago) compared with 0.8x (1.1x) for the 11 U.S. banks. Four U.S. banks trade at less than 50% of their book value.
The Canadian banks are selling at 2.3x tangible BV (2.7x) while the U.S. banks are selling at 1.1x TBV (1.1x). In effect, the TBV of Canadian banks represents 78% of their BV compared with 72% for the U.S. banks.
All but four U.S. banks are selling below TBV (JPM = 1.02x), including C and BAC at 0.5x and 0.4x respectively, highlighting the low confidence level the market has on asset quality at these banks. All Canadian banks but BMO (1.7x) are well over 2x TBV.
All 6 Canadian banks earn a ROE (2012e) of more than 15% with an average of 18.0%,up from (17.5 one year ago). The U.S. banks' average ROE is 8.9%, down from 10.3% last year. Only KEY is expected to earn a higher ROE in 2012 than the what was expected in early 2011.
The price of growth:
Canadian banks' P/BV is 2.3x that of the U.S. banks but their average ROE is 2.0x that of the U.S. banks. Canadian banks' valuation is thus not out of line when ROE is considered. Alternatively, U.S. banks are not all that cheap when their profitability is considered.
For Canadian banks, investors are paying 0.10 units of BV for each 1% of ROE. For the U.S. banks, that ratio is 0.08, a 16% discount (13% one year ago). In March 2010, the ratios were 0.11 and 0.14 respectively, the U.S. banks then trading at a 27% premium. In March 2010, U.S. banks' average estimated ROE was 4.9% for 2010 while Canadian banks' estimated average ROE was 17.1%. U.S. banks outlook for 2012 is for ROE averaging 8.9%, half that of Canadian banks.
Another way to look at this is that investors are willing to pay 25% more for Canadian banks' profitability, a clear indication that stability has a higher value than recovery potential at this time.
Last August, I had identified a clear pricing anomaly between WFC and TD reflecting investors' nervousness on WFC's balance sheet quality. Even though WFC's results were worst than expected in 2011, the valuation gap has been closed.
Current valuation anomalies are between KeyCorp (NYSE:KEY) and C, and between BB&T (NYSE:BBT) and GS and JP Morgan (NYSE:JPM). Investors are more positive on regional banks than large money center banks. They may well be right as we enter an election year when politicians will find it much more politically smart to hit banks than ordinary people.


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A. 'Oriental Limelight ' came back on a small basis for me the year
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Villa Alle Rampe
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... from home that night. It was an excellent meal with 2 free courses included and very reasonably priced for the quality. We were introduced to Barbolo wine which was decanted and poured at the table with much ceremony by our sommelier.
On Wednesday we did our Italian cooking class, along with a young Malaysian couple from Singapore. It was held in the apartment of the Sicilian instructor Manuela, in a suburb of Florence, a 4 km walk from our apartment. We set ...
Gypsies should man up and get a job
... taking the requisite pictures of course and on to Via Santa Maria. As we walked down the street, I found number 8 but couldn't find the doorbell to be buzzed in since the jeweler is located on the 2nd floor. We wanted back and forth, I asked people in the stores and on the street but no one seemed to know of the jeweler. Hilary said "perhaps the numbers start over again" to which I said "that can't be it because ...
Day 55- Florence
... the effort for the breathtaking views over Florence. After that we deserved a gelato! We decided to wander around the streets for a while , staying in the shadey side of the street, before doing the next part of our historic building day. The next stop was a beautiful domed building- Brunelleschi's Dome which is next to the cathedral and had an incredible decorated dome ceiling. The decoration is ...
From the sea to the tower to the Medici
... taken a taxi" from Joe. We picked up our luggage from check in and grabbed the next fast train to Florence. We were flagging so we taxied the 500 meters to the hotel as poor Joe had had to manhandle our very heavy luggage up and down a lot of steps at the various small train stations. Our hotel has a great sized room and lovely check in with breakfast room at the top floor but it is a little hard to get into if you don't ...
Checking Mick's David
... check and we're in. We were greeted with an onslaught of religious iconic paintings. It was Jesus getting stabbed or nailed, the virgin breastfeeding, Saint one or the other! I reckon that the subject matters in those days were very restrictive. to add insult to injury, every one seem to copy from one master or the other. Its blatant plagiarism.
Finally got to the ...


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Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease
- Donald P Tashkin1Email author and
- Gary T Ferguson2
© Tashkin and Ferguson; licensee BioMed Central Ltd. 2013
Received: 28 January 2013
Accepted: 24 April 2013
Published: 8 May 2013
Chronic obstructive pulmonary disease (COPD) represents a significant cause of global morbidity and mortality, with a substantial economic impact. Recent changes in the Global initiative for chronic Obstructive Lung Disease (GOLD) guidance refined the classification of patients for treatment using a combination of spirometry, assessment of symptoms, and/or frequency of exacerbations. The aim of treatment remains to reduce existing symptoms while decreasing the risk of future adverse health events. Long-acting bronchodilators are the mainstay of therapy due to their proven efficacy. GOLD guidelines recommend combining long-acting bronchodilators with differing mechanisms of action if the control of COPD is insufficient with monotherapy, and recent years have seen growing interest in the additional benefits that combination of long-acting muscarinic antagonists (LAMAs), typified by tiotropium, with long-acting β2-agonists (LABAs), such as formoterol and salmeterol. Most studies have examined free combinations of currently available LAMAs and LABAs, broadly showing a benefit in terms of lung function and other patient-reported outcomes, although evidence is limited at present. Several once- or twice-daily fixed-dose LAMA/LABA combinations are under development, most involving newly developed monotherapy components. This review outlines the existing data for LAMA/LABA combinations in the treatment of COPD, summarizes the ongoing trials, and considers the evidence required to inform the role of LAMA/LABA combinations in treatment of this disease.
KeywordsCOPD Combination therapy Bronchodilation Beta 2 agonist Antimuscarinic
Currently the fourth leading cause of death globally [1], chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, projected to become the world's third leading cause of mortality by 2020 [2]. Characterized by progressive airflow limitation, COPD also has a major economic impact, contributing to US$53.7 billion in related direct costs in 2008 in the US [3].
As an area of interest for physicians, and a logical progression from monotherapy for those seeking to further improve outcomes in patients with respiratory disease, the subject of combined bronchodilation with bronchodilators of differing modes of action has been discussed in the literature previously [4–8]. The aim of this review is to focus more specifically on the combination of long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) for the treatment of COPD, summarizing data from recent peer-reviewed publications and published abstracts.
Evolving COPD guidelines
Long-acting bronchodilators: the cornerstone of COPD maintenance therapy
GOLD guidelines (2013): pharmacologic therapies for stable COPD a [[9]]
Patient group
1st choice
2nd choice
Short-acting anticholinergic prn OR SABA prn
LAMA OR LABA OR SABA and short-acting anticholinergic
Low risk of exacerbation, less symptoms
LAMA and LABA
SABA and/or short-acting anticholinergic
Low risk of exacerbation, more symptoms
LAMA and LABA OR LAMA and PDE-4 inhibitor OR LABA and PDE-4 inhibitor
SABA and/or short-acting anticholinergic
High risk of exacerbation, less symptoms
ICS + LABA and/or LAMA
ICS and LABA and LAMA OR ICS + LABA and PDE-4 inhibitor OR LAMA and LABA OR LAMA and PDE-4 inhibitor
High risk of exacerbation, more symptoms
SABA and/or short-acting anticholinergic
LABAs and LAMAs in development for combination therapies
Time to onset
Trough FEV1(difference from placebo)
Twice daily
5 min [26]
50–90 mL [26]
4.5 μg (MDI) and 12 μg (DPI)
Once daily 150 and 300 μg (EU) (DPI) [20]
5 min [22]
130–180 mL (p < 0.001) [22]
Once daily 75 μg (US) (DPI) [21]
5 min [22]
Boehringer Ingelheim
Once daily 5 and 10 μg (Respimat®)
Not available
61–132 mL (p < 0.01) [24]
Once daily 25 and 50 μg (DPI)
Median 6 min [25]
137–165 mL (p < 0.001) [25]
Almirall/Forest Laboratories
Twice daily 200–400 μg (DPI)
86–124 mL (p < 0.0001) [29]
Once daily 50 μg (DPI)
Pearl Therapeutics
Twice daily 36 μg (MDI)
5 min [19]
Statistically superior to placebo (p < 0.0001) [31]
Twice daily 200 μg
Not available
130 mL (p < 0.001) [32]
Boehringer Ingelheim
Once daily 18 μg (DPI) and 5 μg (via SMI)
15 min [18]
120–150 mL (p < 0.001) [18]
Umeclidinium (GSK573719)
Once daily
Not available
Not available
Combination bronchodilation: rationale
Guidelines recommend combination therapy involving two long-acting bronchodilators with differing modes of action in patients whose COPD is not sufficiently controlled with monotherapy (Table 1) [9]. The mechanistic rationale for combination of a muscarinic antagonist and a β2-agonist has been reviewed in detail recently [35, 36]; as such, we will only briefly discuss it here. Airway smooth muscle relaxation (leading to bronchodilation) can be achieved via two main routes: inhibition of acetylcholine signaling via muscarinic M3 receptors on airway smooth muscle with a muscarinic antagonist, or stimulation of β2-adrenoceptors with a β2-agonist [35, 36]. Targeting these two mechanisms of bronchoconstriction, theoretically, has the potential to maximize the bronchodilator response without increasing the dose of either component, and helps to overcome the inter- and intra-patient variability in response to individual agents seen in COPD [35]. The interaction between the two systems has yet to be fully elucidated; however, β2-agonists can amplify the bronchial smooth muscle relaxation directly induced by the muscarinic antagonist by decreasing the release of acetylcholine via modulation of cholinergic neurotransmission. Additionally, muscarinic antagonists have been demonstrated to augment β2-agonist-stimulated bronchodilation by reducing the bronchoconstrictor effects of acetylcholine in preclinical models [35].
The rationale for improved bronchodilation has been tested in preclinical models with a specific investigational LAMA/LABA combination, tiotropium plus olodaterol, demonstrating synergistic effects on bronchoprotection in vivo[37, 38]. Combination treatment in ovalbumin-induced bronchoconstriction in anesthetized guinea pigs has demonstrated improved bronchoprotection in a dose-dependent manner, with effective dose (ED) 50 values 10-fold lower than the ED50 of olodaterol alone (p < 0.05) [38]; similar results were reported versus tiotropium monotherapy in acetylcholine-induced bronchoconstriction in anesthetized dogs [37]. Indacaterol synergistically potentiates the effects of glycopyrronium to inhibit metacholine-induced contraction of airway smooth muscle in vitro[39]. However, specifically designed clinical studies are required to assess whether such synergistic effects can be observed with therapeutic doses in humans.
Combination bronchodilation: existing evidence and ongoing studies
Short-acting muscarinic antagonist plus short-acting β2-agonist
The concept of adding a muscarinic antagonist to a β2-agonist is by no means new. A fixed-dose combination (FDC) of the short-acting agents ipratropium and albuterol (Combivent®) and of fenoterol and ipratropium (Berodual®) clearly provides benefits over monotherapy with either component [40–42]. Additionally, dual bronchodilation with ipratropium and albuterol resulted in a consistently longer response and more patients achieved a pre-specified response level (12-15%) in forced expiratory volume in 1 second (FEV1) with the combination versus individual components (p < 0.05) [40, 41, 43–45], with an equivalent or improved safety profile.
Free combinations of LAMA plus LABA
LABA and LAMA combinations: current evidence
Combination (manufacturer)
Reported results
Free combinations
GSK233705: 20 or 50 μg BID; salmeterol: 50 μg BID
Beier et al. [61]
Larger mean increases from baseline trough FEV1 vs placebo with 20 μg GSK233705 + salmeterol (203 mL) and 50 μg GSK233705 + salmeterol (215 mL) vs monotherapy with tiotropium (101 mL) or salmeterol (118 mL)
Tiotropium: 18 μg QD; arformoterol: 15 μg BID
Tashkin et al. [60]
Greater improvement in FEV1 AUC0-24 from baseline with combination (0.22 L) vs monotherapy with either arformoterol (0.10 L) or tiotropium (0.08 L); p < 0.001
Greater improvement in TDI with combination (3.1) vs monotherapy with either arformoterol (2.3; CI 0.03, 1.70) or tiotropium (1.8; CI 0.50, 2.20)
Tiotropium: 18 μg QD; formoterol: 20 μg BID
Hanania et al. [65]
FEV1 AUC0-3 greater with combination (1.57 L) vs tiotropium alone (1.38 L); p < 0.0001
Reduced use of rescue medication vs tiotropium alone; p < 0.05
Tiotropium: 18 μg QD; formoterol: 20 μg BID
Tashkin et al. [56]
Greater FEV1 AUC0-3 with combination (1.52 L) vs tiotropium alone (1.34 L); p < 0.0001
Greater improvement in TDI with combination than tiotropium alone (2.30 vs 0.16; mean difference of 1.80); 95% CI 0.86, 2.74, p < 0.0002
Tiotropium: 18 μg QD; formoterol: 12 μg BID
Tashkin et al. [55]
Greater improvement in FEV1 AUC0-4 from baseline with combination (0.34 L) vs tiotropium alone (0.17 L); p < 0.001
Dyspnea significantly improved with combination at week 8 (1.86) vs tiotropium alone (1.01); p = 0.013
Reduced use of rescue medication vs tiotropium alone; p < 0.04
Tiotropium: 18 μg QD; formoterol: 12 μg QD or BID
Terzano et al. [66]
Greater improvement in FEV1 with combination vs tiotropium alone at day 30 (0.16 L); p = 0.0001
Improvement in dyspnea with combinations (2.32-2.61) vs tiotropium alone (1.0); p < 0.05
Lower rescue medication use with combinations (0.71-0.80 puffs/day) vs tiotropium alone (2.14 puffs/day); p < 0.05
Tiotropium: 18 μg QD; formoterol: 12 μg QD or BID
van Noord et al. [47]
Greater average improvement in FEV1 AUC0-24 0.16-0.20 L with combinations vs 0.08 L with tiotropium alone; p < 0.05
Lower rescue medication use with combinations vs tiotropium alone; p < 0.01 (daily rescue medication use with tiotropium + formoterol QD or BID) and p < 0.05 (tiotropium + formoterol BID)
Tiotropium: 18 μg QD; formoterol: 12 μg QD or BID
van Noord et al. [49]
Average improvement in daytime (0.234 L) and night-time FEV1 (0.086 L) with combination vs monotherapy with tiotropium (p ≤ 0.001) or formoterol (p ≤ 0.01)
Lower rescue medication use with combination (1.81 puffs/day) vs monotherapies (2.37-2.41 puffs/day); p < 0.01
Tiotropium: 18 μg QD; formoterol: 10 μg BID
Vogelmeier et al. [54]
Improvement in FEV1 2 h post-dose after 24 weeks with combination vs formoterol alone (p = 0.044)
Tiotropium: 18 μg QD; indacaterol: 150 μg QD
Mahler et al. [50]
Greater increase in trough FEV1 from baseline with combination: 70–80 mL difference vs tiotropium alone (p < 0.001)
Improved trough IC with combination vs tiotropium alone: 100–130 mL; p < 0.01
Less use of albuterol as rescue medication with combination: reduction of 0.8–1.3 puffs/day from baseline vs tiotropium alone
Tiotropium: 18 μg QD; salmeterol: 50 μg BID
Aaron et al. [48]
No statistical improvement in lung function or hospitalization rates with combination compared to tiotropium monotherapy
Tiotropium: 18 μg QD; salmeterol: 50 μg BID
van Noord et al. [59]
Improved average FEV1 (0–24 h) with combination (0.142 L) vs monotherapy with either tiotropium (0.07 L) or salmeterol (0.045 L); p < 0.0001
Combination associated with clinically relevant improvements in TDI focal score (p < 0.001)
Fixed-dose combinations
Glycopyrrolate: 36 and 72 μg BID; formoterol: 9.6 μg BID (Pearl Therapeutics)
Reisner et al. [53]
Increase in FEV1 AUC0–12 on day 7 with combination compared to monotherapy with either of the components, tiotropium, and placebo (p < 0.0001)
Glycopyrrolate: 36 and 72 μg BID; formoterol: 9.6 μg BID (Pearl Therapeutics)
Reisner et al. [52]
Higher morning pre-trough and peak IC with combination vs placebo (p < 0.0005 and p < 0.005, respectively) or tiotropium monotherapy (p < 0.05 for all comparisons)
Glycopyrrolate: 36 and 72 μg BID; formoterol: 9.6 μg BID (Pearl Therapeutics)
Reisner et al. [62]
Similar metabolic and cardiac safety profile to tiotropium
Glycopyrronium: 50 μg QD; indacaterol: 300 μg QD (Novartis)
van Noord et al. [58]
Improved trough FEV1 with combination: 0.226 L difference in trough FEV1 vs placebo (p < 0.001)
Greater peak FEV1 with combination (1.709 L) vs 300 μg indacaterol (1.579 L) and 600 μg indacaterol (1.573 L); p < 0.0001 for both comparisons
Glycopyrronium: 100 μg QD; indacaterol: 600 μg QD (Novartis)
Van de Maele et al. [57]
Increased trough FEV1 with combination (1.61 L) vs indacaterol monotherapy 300 μg (1.46 L); p < 0.05
Glycopyrronium: 50 μg QD; indacaterol: 110 μg QD (Novartis)
Bateman et al. [68]
Improved trough FEV1 with combination vs placebo (0.20 L mean difference), indacaterol (0.07 L), glycopyrronium (0.09 L), and tiotropium (0.08 L) monotherapy; p < 0.001
Improved TDI score with combination vs placebo (mean difference 1.09); p < 0.001 and tiotropium (0.51 mean difference); p < 0.05
Improved SGRQ score with combination vs tiotropium (-2.13 mean difference); p < 0.05
Reduced use of rescue medication with combination vs monotherapies (-0.30 to -0.54 mean difference); p < 0.05
Glycopyrronium: 50 μg QD; indacaterol: 110 μg QD (Novartis)
Vogelmeier et al. [69]
Improvement in trough FEV1 with combination vs salmeterol/fluticasone (mean difference 0.103 L); p < 0.0001
Improvements in TDI score with combination vs salmeterol/fluticasone (mean difference 0.76); p = 0.003
Lower use of rescue medication with combination vs salmeterol/fluticasone (-0.39 puffs/day); p = 0.019)
Glycopyrronium: 50 μg QD; indacaterol: 110 μg QD (Novartis)
Dahl et al. [67]
Combination increased FEV1 and FVC vs placebo over a 52-week period; p < 0.001
Tiotropium: 5 μg QD; olodaterol: 2, 5, and 10 μg QD (Boehringer Ingelheim)
Maltais et al. [51]
Higher peak FEV1 for all doses of combination investigated vs tiotropium alone (p ≤ 0.05); higher trough FEV1 response with tiotropium + olodaterol 5/10 μg vs tiotropium alone (p = 0.034)
Tiotropium: 1.25, 2.5, and 5 μg QD; olodaterol: 5 and 10 μg QD (Boehringer Ingelheim)
Aalbers et al. [64]
Significant improvements in FEV1 for all doses of combination vs olodaterol alone, with evidence of a dose-dependent response
Umeclidinium (GSK573719): 500 μg QD; vilanterol: 25 μg QD (GSK)
Feldman et al. [63]
Adverse-event rate of 26%, with no single adverse event reported in >1 patient
Combination similar to placebo in terms of cardiac parameters
Greater change from baseline in trough FEV1 and FEV1 from 0–6 h post-dose with combination vs placebo
Following proof of concept in terms of a benefit on FEV1 and in patients with acute exacerbations [70–72], several randomized controlled trials have reported improved lung function for tiotropium plus formoterol versus tiotropium alone [54–56, 60, 65, 73]. Some trials have also identified significant improvements in symptom scores [55, 56, 60] and reductions in rescue medication use [47, 49, 55, 56, 65]. A recent meta-analysis confirmed the benefits of tiotropium plus formoterol on average FEV1, trough FEV1, and Transition Dyspnea Index (TDI) [74] (Table 3), with initial reports also suggesting that the combination may provide statistically significant improvements in effort-induced dynamic hyperinflation and exercise tolerance [75].
Currently available data on tiotropium plus salmeterol are conflicting. Initial investigations indicated the benefits of tiotropium plus salmeterol versus either monotherapy alone, while suggesting co-administration of once-daily salmeterol plus tiotropium was inadvisable, due to the shorter duration of bronchodilation provided by salmeterol [76]. The Canadian Optimal Therapy of COPD trial investigated the impact of tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus salmeterol/fluticasone on clinical outcomes in 449 patients with moderate to severe COPD [48]. Tiotropium plus salmeterol/fluticasone (but not tiotropium plus salmeterol) statistically improved lung function and quality of life, and, while no improvement in overall exacerbation rate was seen, reduced the number of hospitalizations for exacerbations compared to tiotropium plus placebo [48] (Table 3). A more recent study, however, demonstrated significant improvements in FEV1 with salmeterol once or twice daily plus tiotropium [59], and the combination was also associated with clinically significant improvements in TDI (Table 3). These inconclusive data suggest that further research is necessary to determine any advantage of salmeterol plus tiotropium. Initial investigation of other free combinations has also been reported (Table 3); tiotropium plus indacaterol has been demonstrated to improve lung function and inspiratory capacity, as well as providing a further reduction in use of rescue medication [50]. The LAMA GSK233705 twice daily plus salmeterol has also demonstrated significantly improved trough FEV1 from baseline compared to monotherapy [61]. Overall, these data broadly confirm that combination therapy has the potential to improve outcomes versus monotherapy and justify further research in this area.
Fixed-dose combinations (FDCs)
FDCs of LAMAs and LABAs offer the potential of improved convenience and compliance over use of separate inhalers, and, during their development, the dose of each agent to be used in combination can be optimized.
A major challenge associated with development of an FDC is provision of improved bronchodilation over monotherapy components while balancing the associated adverse effects [77]. Dose-finding studies are required to establish minimal effective doses for each agent in the combination, as it cannot be assumed that these doses are the same as would be used in monotherapy. Regulatory bodies also require investigation into any pharmacodynamic or pharmacokinetic interactions that may occur between the constituents, along with evidence of the safety profile for the combination [77, 78].
LABA and LAMA combinations under investigation: ongoing trials
Trial numbers
Summary of ongoing Phase II/III studies
4 Phase III studies and 1 Phase II study, examining the long-term efficacy and safety of 2 different doses of aclidinium + formoterol vs monotherapy with either component and placebo
2 Phase II studies (both recently completed), examining efficacy of the combination vs the monotherapy components and tiotropium
NCT01120691 (SPARK), NCT01202188 (GLEAM) (pivotal studies, both completed), NCT0171251, NCT01604278, NCT01727141, NCT01529632, NCT01709903
2 recently completed pivotal Phase III studies investigating efficacy and safety, exacerbations, exercise, and TDI, and 5 ongoing Phase III studies, examining safety and efficacy of combination vs placebo, monotherapy components, and salmeterol/fluticasone
NCT01431274, NCT01431287 (pivotal studies), NCT01525615, NCT01533922, NCT01533935, NCT01559116, NCT01536262
7 Phase III studies, investigating efficacy and safety of combination vs monotherapy components and effects on exercise
Umeclidinium (GSK573719)
NCT01313637, NCT01316900, NCT01316913, NCT01313650 (pivotal studies, recently completed), NCT01716520, NCT01491802
6 Phase III studies (4 recently completed, 2 ongoing), focused primarily on efficacy, with other studies examining AE incidence, exercise endurance time, and exertional dyspnea
Clinical Phase II trials have investigated the optimal dosing for olodaterol added to a fixed dose of tiotropium [51] and for tiotropium added to a fixed dose of olodaterol [64]. Significant improvements in peak FEV1 were demonstrated with tiotropium/olodaterol 5/2 μg (p = 0.008), 5/5 μg (p = 0.012), and 5/10 μg (p < 0.0001) versus tiotropium monotherapy [51]. Significant improvements were also seen in trough FEV1 with tiotropium/olodaterol 5/10 μg versus tiotropium monotherapy (p = 0.034) [51], and with all doses of the combination tested versus olodaterol monotherapy, with evidence of dose ordering [64] (Table 3).
There is little information available from studies of aclidinium plus formoterol; only initial results of preclinical cardiac safety in beagle dogs have been reported [80].
Of the LAMA/LABA FDCs currently under investigation, tiotropium plus olodaterol, umeclidinium plus vilanterol, aclidinium plus formoterol, and glycopyrronium plus indacaterol have the largest Phase III programs, focusing on efficacy, safety, exacerbations, exercise, and dyspnea (Table 4). The development program for umeclidinium plus vilanterol involves four large pivotal trials, one large safety study, and two studies assessing exercise endurance, with two ongoing trials investigating lung function and efficacy. Phase III studies of glycopyrronium plus indacaterol will compare the combination with a range of comparators, including fluticasone/salmeterol combination and tiotropium, across a variety of end points (FEV1, exacerbations, TDI, and safety). The tiotropium plus olodaterol development program includes two main registration trials, three examining exercise and functional capacity, one examining long-term safety, and a comprehensive lung function trial.
Several of the LAMA/LABA FDCs in development will be delivered once daily (such as umeclidinium plus vilanterol and tiotropium plus olodaterol) while others will have twice-daily dosing (e.g., aclidinium plus formoterol). This diversity has the potential to increase the personalization of medication to individual needs; for instance, twice-daily combinations could be considered where patients suffer from night-time symptoms [81], while once-daily combinations may be prescribed to improve adherence [82].
Delivery devices
Inhalation devices are intrinsically linked to the medication they deliver. As such, careful consideration of the most appropriate delivery device is crucial to optimal COPD therapy, along with adequate training and observation of patient technique.
Devices for delivery of combination bronchodilators
Type of delivery device
Combination products in development
Drug is dissolved in propellant (generally HFA). When activated, a valve system releases a metered volume of propellant containing the medication
Can be more cost-effective than DPIs [84]
Can be difficult to synchronize actuation with inhalation [89, 90]
Pearl inhaler for glycopyrrolate + formoterol (Pearl Therapeutics) [86]
High fine-particle fraction, leading to better peripheral lung deposition
Evidence suggests fewer patients use pMDIs correctly without teaching [84]
Breath-actuated DPIs require no hand-lung coordination
Drug is delivered in powder form on inspiration by the patient; de-aggregation of the powder and generation of the aerosol provided by the patient's inspiratory effort
Activated by inhalation, avoiding synchronization issues [84]
Can be more expensive vs MDIs [84]
Breezhaler® for indacaterol + glycopyrronium (single-dose, Novartis) [87]
Evidence suggests more patients have an accurate inhaler technique with DPIs without teaching [84]
Errors in inhaler technique can still occur [92]
Ellipta® Vilanterol (single-dose, GSK)
Pressair® for aclidinium (multi-dose, Almirall) [88]
Soft Mist™ Inhaler
Delivers a metered dose of medication as a slow-moving "soft mist" through a unique nozzle system, which should lead to improved lung and reduced oropharyngeal deposition vs other types of inhaler [85, 93]
Drug delivery is not dependent on patient's inspiratory capacity or inspiratory effort, allowing consistent deposition regardless of lung function [85] and higher lung deposition in patients with poor inhaler technique [91]
Less clinical experience with this device; more safety data are required
Respimat® for tiotropium + olodaterol (Boehringer Ingelheim) [85]
Non-adherence is a well-documented issue in COPD and is associated with detrimental effects on patient outcomes [96, 97]. Irrespective of the device type, a single device with once-daily dosing may provide a significant advantage, potentially improving adherence and, therefore, patient outcomes. Adherence is inversely related to the number of medications patients take [96] and both treatment persistence and adherence in patients with COPD have been demonstrated to be lower in multiple long-acting inhaler users, compared to single long-acting inhaler users [98]. Additionally, a recent large retrospective study reported that adherence was significantly higher in those who initiated treatment with once-daily dosing versus more frequent dosing [82]. On the other hand, apart from the possible advantage of once- over twice-daily dosing on adherence, a twice-daily preparation has the potential advantage of greater improvement in night-time airflow and symptoms, an issue that has recently been reappraised [81].
Consideration of potential adverse effects of LAMA/LABA combinations
The safety profiles of both LAMAs and LABAs are well understood. However, when combining two entities, it is important to understand both the similarities and differences in adverse events. Given that both muscarinic antagonists and β2-agonists can have a detrimental effect on the cardiovascular system [26, 99], these adverse events need to be monitored carefully in development programs for combination products. Initial results suggest that the cardiovascular safety profile of glycopyrronium plus indacaterol is similar to placebo, with no clinically significant differences observed versus placebo [57, 68], and, to date, no safety concerns have been identified with tiotropium plus olodaterol [51]. Free combinations of LAMA/LABA also seem well tolerated. No differences in blood pressure and pulse rate were observed with tiotropium plus salmeterol versus single-agent therapies [59] and the meta-analysis of tiotropium plus formoterol data reported no differences in cumulative incidence of adverse events for the combination (33.2%) versus tiotropium alone (36.0%), stating that drug-related severe adverse events and cardiac effects were relatively rare [74].
Emerging therapeutic approaches
Triple therapy
Triple therapy with LAMA plus LABA/ICS has also been investigated, demonstrating benefits over monotherapy on lung function [48, 100–102]. Additionally, a pilot study of patients with advanced COPD reported that triple therapy combined with pulmonary rehabilitation provided a benefit in terms of lung function [103]. Some reports also suggest that triple therapy can provide additional benefits, such as reduction in exacerbation rate and mortality [104], although a recent systematic review concluded that further, longer-term studies are required to determine the benefits of tiotropium plus LABA and ICS [105], or the additional benefit of ICS on top of LAMA/LABA combinations.
Dual muscarinic antagonist-β2-agonists (MABAs)
Another interesting concept is that of single molecules with muscarinic antagonist-β2-agonist (MABA) activity. While the prospect of combining muscarinic antagonism and β2-agonism into one entity is highly attractive, this is a new and challenging area of research [106]. The optimal MABA should be designed to achieve balanced, high potencies at both muscarinic and β2 receptors, for consistency. The furthest developed MABA is GSK961081, which has demonstrated effective bronchoprotection in vivo as proof of concept (NCT00478738) [106] and is currently in Phase IIb studies. MABAs provide a fixed ratio of muscarinic antagonist and β2-agonist activity at a cellular level, have a single pharmacokinetic profile, and deliver a fixed ratio of muscarinic antagonist and β2-agonist to the whole lung, simplifying both combination delivery device and clinical development programs [4, 5, 107]. These properties suggest that MABAs have the potential to act as a useful platform for triple therapy with an anti-inflammatory agent.
Novel bronchodilators
A number of new bronchodilators with novel modes of action are currently in early stages of development, including K+ channel openers, Rho kinase inhibitors, and analogs of vasoactive intestinal peptide; these have been reviewed more extensively elsewhere [7]. Given the substantial evidence supporting a role of Rho kinase in bronchoconstriction [108], Rho kinase inhibitors such as Y-27632, Y-30141, Y-30694, and fasudil may currently hold the most promise, demonstrating smooth muscle relaxant properties in vitro[7]. Once further evidence of efficacy and safety is available, these newer classes might be used in combination with more conventional bronchodilators, leading to additional therapeutic options and increased potential for individualized medication.
In summary, there is considerable evidence and guidance to support use of the combination of a LAMA and a LABA in COPD, a number of free LAMA and LABA combinations have been studied, and several LABA/LAMA FDCs are under development.
Analysis of medical and prescription claims, May 2011-April 2012[109]
Mean monthly patient volumea
Total COPD
COPD only
COPD + asthma
Tiotropium monotherapy
Tiotropium + ICS/LABA
The very limited clinical use of LAMA/LABA combination therapy indicated by these data is perhaps surprising, given the current evidence base and GOLD guidance. However, the evidence from ongoing programs will be much more substantial and the future availability of LAMA/LABA FDCs should make this therapeutic option more convenient than separate administration by two inhalers (typically with different dosing schedules), currently the only option.
The rising number of both single-agent and combination therapies for COPD increases the number of treatment options, and, hence, makes treatment choice more complex. Further studies should be designed to provide substantial evidence for future guideline recommendations. In particular, investigation into the optimal sequencing of monotherapies and combination bronchodilators would be of use to determine where LAMA/LABA FDC therapy may be positioned in the treatment algorithm for COPD. Furthermore, examination of the benefits of using dual bronchodilation as initial maintenance therapy would be of interest, along with which groups of patients may benefit from this approach.
There is a growing appreciation of the benefits of bronchodilation beyond lung function, such as exacerbations [110], patient-reported outcomes, exercise tolerance [111] and exercise capacity, and daily activities [16, 112]. Trials of LABA/LAMA FDCs should assess this wider range of outcomes in order to more fully understand the broader benefits of increased bronchodilation on a patient's life as a whole.
Area under the curve from 0–12 hours
Chronic obstructive pulmonary disease
Dry powder inhaler
Effective dose
Fixed-dose combination
Forced expiratory volume in 1 second
Global initiative for chronic Obstructive Lung Disease
Inhaled corticosteroid
Long-acting β2-agonist
Long-acting muscarinic antagonist
Muscarinic antagonist-β2-agonist
- pMDI:
Pressurized metered dose inhaler
Soft Mist™ Inhaler
Transition Dyspnea Index.
The authors take full responsibility for the scope, direction, content of, and editorial decisions relating to, the manuscript, were involved at all stages of development, and have approved the submitted manuscript. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Caitlin Watson, PhD, of Complete HealthVizion under the authors' conceptual direction and based on feedback from both authors. Boehringer Ingelheim was given the opportunity to check the data used in the review for factual accuracy only.
Authors' Affiliations
- World Health Organization: World health statistics 2008. http://www.who.int/whosis/whostat/2008/en/index.html,
- Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist AS, Thun MJ, Connell C, Jemal A, Lee TA, Miravitlles M, Aldington S, Beasley R: Epidemiology and costs of chronic obstructive pulmonary disease. Eur Respir J. 2006, 27: 188-207. 10.1183/09031936.06.00024505.PubMedGoogle Scholar
- National Institutes of Health, National Heart, Lung, and Blood Institute: Morbidity & Mortality: 2012 Chart Book on Cardiovascular, Lung, and Blood Diseases. http://www.nhlbi.nih.gov/resources/docs/2012_ChartBook.pdf,
- Cazzola M, Matera MG: Emerging inhaled bronchodilators: an update. Eur Respir J. 2009, 34: 757-769. 10.1183/09031936.00013109.PubMedGoogle Scholar
- Cazzola M, Calzetta L, Matera MG: β2-adrenoceptor agonists: current and future direction. Br J Pharmacol. 2011, 163: 4-17. 10.1111/j.1476-5381.2011.01216.x.PubMedPubMed CentralGoogle Scholar
- Matera MG, Page CP, Cazzola M: Novel bronchodilators for the treatment of chronic obstructive pulmonary disease. Trends Pharmacol Sci. 2011, 32: 495-506. 10.1016/j.tips.2011.04.003.PubMedGoogle Scholar
- Cazzola M, Page CP, Calzetta L, Matera MG: Pharmacology and therapeutics of bronchodilators. Pharmacol Rev. 2012, 64: 450-504. 10.1124/pr.111.004580.PubMedGoogle Scholar
- Cazzola M, Rogliani P, Segreti A, Matera MG: An update on bronchodilators in Phase I and II clinical trials. Expert Opin Investig Drugs. 2012, 21: 1489-1501. 10.1517/13543784.2012.710602.PubMedGoogle Scholar
- Global initiative for chronic Obstructive Lung Disease: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Revised 2013. http://www.goldcopd.org/guidelines-global-strategy-for-diagnisis-management.pdf,
- US Food and Drug Administration: FDA approved drug products. Ipratropium. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm]
- Yohannes AM, Willgoss TG, Vestbo J: Tiotropium for treatment of stable COPD: a meta-analysis of clinically relevant outcomes. Respir Care. 2011, 56: 477-487. 10.4187/respcare.00852.PubMedGoogle Scholar
- Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M, for the UPLIFT Study Investigators: A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008, 359: 1543-1554. 10.1056/NEJMoa0805800.PubMedGoogle Scholar
- Dahl R, Greefhorst LAPM, Nowak D, Nonikov V, Byrne AM, Thomson MH, Till D, Della Cioppa G, on behalf of the Formoterol in Chronic Obstructive Pulmonary Disease I (FICOPD I) Study Group: Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001, 164: 778-784. 10.1164/ajrccm.164.5.2007006.PubMedGoogle Scholar
- Cazzola M, Santangelo G, Piccolo A, Salzillo A, Matera MG, D'Amato G, Rossi F: Effect of salmeterol and formoterol in patients with chronic obstructive pulmonary disease. Pulm Pharmacol. 1994, 7: 103-107. 10.1006/pulp.1994.1012.PubMedGoogle Scholar
- O'Donnell DE, Sciurba F, Celli B, Mahler DA, Webb KA, Kalberg CJ, Knobil K: Effect of fluticasone propionate/salmeterol on lung hyperinflation and exercise endurance in COPD. Chest. 2006, 130: 647-656. 10.1378/chest.130.3.647.PubMedGoogle Scholar
- O'Donnell DE, Flüge T, Gerken F, Hamilton A, Webb K, Aguilaniu B, Make B, Magnussen H: Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J. 2004, 23: 832-840. 10.1183/09031936.04.00116004.PubMedGoogle Scholar
- Aguilaniu B: Impact of bronchodilator therapy on exercise tolerance in COPD. Int J Chron Obstruct Pulmon Dis. 2010, 5: 57-71.PubMedPubMed CentralGoogle Scholar
- Casaburi R, Briggs DD, Donohue JF, Serby CW, Menjoge SS, Witek TJ, for the US Tiotropium Study Group: The spirometric efficacy of once-daily dosing with tiotropium in stable COPD. A 13-week multicenter trial. Chest. 2000, 118: 1294-1302. 10.1378/chest.118.5.1294.PubMedGoogle Scholar
- Verkindre C, Fukuchi Y, Flémale A, Takeda A, Overend T, Prasad N, Dolker M: Sustained 24-h efficacy of NVA237, a once-daily long-acting muscarinic antagonist, in COPD patients. Respir Med. 2010, 104: 1482-1489. 10.1016/j.rmed.2010.04.006.PubMedGoogle Scholar
- Novartis Europharm Limited: SPC. Onbrez Breezhaler 150 and 300 microgram inhalation powder, hard capsules. http://www.medicines.org.uk/EMC/medicine/23260/SPC/Onbrez+Breezhaler+150+and+300+microgram+inhalation+powder%2c+hard+capsules/,
- Novartis Pharmaceutical Corporation: ARCAPTA NEOHALER. Full prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022383s0002mg.pdf,
- Moen MD: Indacaterol. In chronic obstructive pulmonary disease. Drugs. 2010, 70: 2269-2280. 10.2165/11203960-000000000-00000.PubMedGoogle Scholar
- Kerwin EM, Meli J, Peckitt C, Lassen C, Kramer B, Filcek S: Efficacy and safety of indacaterol 75 g [sic] once daily in patients with moderate-to-severe COPD [abstract]. Am J Respir Crit Care Med. 2011, 183: A1595-10.1164/rccm.201011-1783OC.Google Scholar
- van Noord JA, Korducki L, Hamilton A, Koker P: Four weeks once daily treatment with BI 1744 CL, a novel long-acting β2-agonist, is effective in COPD patients [abstract A6183]. Am J Respir Crit Care Med. 2009, 179: A6183-Google Scholar
- Hanania NA, Feldman G, Zachgo W, Shim JJ, Crim C, Sanford L, Lettis S, Barnhart F, Haumann B: Dose-related efficacy of vilanterol trifenatate (VI) in COPD [abstract P1227]. Eur Respir J. 2010, 36 (Suppl 54): 217s-Google Scholar
- Tashkin DP, Fabbri LM: Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Respir Res. 2010, 11: 149-10.1186/1465-9921-11-149.PubMedPubMed CentralGoogle Scholar
- Vestbo J, Vogelmeier C, Creemers J, Falques M, Ribera A, Garcia Gil E: Onset of effect of aclidinium, a novel, long-acting muscarinic antagonist, in patients with COPD. COPD. 2010, 7: 331-336. 10.3109/15412555.2010.510158.PubMedGoogle Scholar
- Gavaldà A, Miralpeix M, Ramos I, Otal R, Carreño C, Viñals M, Doménech T, Carcasona C, Reyes B, Vilella D, Gras J, Cortijo J, Morcillo E, Llenas J, Ryder H, Beleta J: Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile. J Pharmacol Exp Ther. 2009, 331: 740-751. 10.1124/jpet.109.151639.PubMedGoogle Scholar
- Kerwin E, D'Urzo A, Gelb A, Lakkis H, Garcia Gil E, Caracta C: Twice-daily aclidinium bromide in COPD patients: efficacy and safety results from ACCORD COPD I [abstract P1235]. Eur Respir J. 2010, 36 (Suppl 54): 219s-Google Scholar
- D'Urzo A, Ferguson GT, van Noord JA, Hirata K, Martin C, Horton R, Lu Y, Banerji D, Overend T: Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respir Res. 2011, 12: 156-10.1186/1465-9921-12-156.PubMedPubMed CentralGoogle Scholar
- Orevillo C, St Rose E, Strom S, Fischer T, Golden M, Thomas M, Reisner C: Glycopyrrolate MDI demonstrates comparable efficacy and safety to tiotropium DPI in a randomized, double-blind, placebo-controlled phase 2b study in patients with COPD [abstract P3975]. Eur Respir J. 2011, 38 (Suppl 55): 724s-Google Scholar
- Bateman E, Feldman G, Kilbride S, Brooks J, Mehta R, Harris S, Maden C, Crater G: Efficacy and safety of the long-acting muscarinic antagonist GSK233705 delivered once daily in patients with COPD. Clin Respir J. 2012, 6: 248-257. 10.1111/j.1752-699X.2011.00278.x.PubMedGoogle Scholar
- Donohue JF, Siler T, Kerwin EM, Williams J, Kianifard F, McBryan D: Efficacy and safety of indacaterol 75 μg once daily in patients with moderate-to-severe COPD: pooled analysis of two phase III trials [abstract A2258]. Am J Respir Crit Care Med. 2012, 185: A2258-Google Scholar
- Kerwin EM, Hebert J, Pedinoff A, Gallagher N, Martin C, Banerji D, Lu Y, Overend T: NVA237 once daily provides rapid and sustained bronchodilation in COPD patients, with efficacy similar to tiotropium: the GLOW2 trial [abstract]. Am J Respir Crit Care Med. 2012, 185: A2920-Google Scholar
- Cazzola M, Tashkin DP: Combination of formoterol and tiotropium in the treatment of COPD: effects on lung function. COPD. 2009, 6: 404-415. 10.1080/15412550903156333.PubMedGoogle Scholar
- Cazzola M, Molimard M: The scientific rationale for combining long-acting β2-agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther. 2010, 23: 257-267. 10.1016/j.pupt.2010.03.003.PubMedGoogle Scholar
- Bouyssou T, Schnapp A, Casarosa P, Pieper MP: Addition of the new once-daily LABA BI 1744 to tiotropium results in superior bronchoprotection in pre-clinical models [abstract A4445]. Am J Respir Crit Care Med. 2010, 181: A4445-Google Scholar
- Bouyssou T, Casarosa P, Pieper M, Schnapp A, Gantner F: Synergistic bronchoprotective activity of the long-acting beta 2-agonist olodaterol with tiotropium (long-acting M3 antagonist) and ciclesonide (inhaled steroid) on the ovalbumin-induced bronchoconstriction in anaesthetized guinea pigs [abstract 3451]. Eur Respir J. 2011, 38 (Suppl 55): 613s-Google Scholar
- Kume H, Imbe S, Iwanaga T, Tohda Y: Presented at the European Respiratory Society Annual Congress, Vienna, Austria, September 1–5. Synergistic effects between glycopyrronium bromide and indacaterol on a muscarinic agonist-induced contraction in airway smooth muscle [abstract 4835]. 2012Google Scholar
- COMBIVENT Inhalation Solution Study Group: Routine nebulized ipratropium and albuterol together are better than either alone in COPD. Chest. 1997, 112: 1514-1521.Google Scholar
- COMBIVENT Inhalation Aerosol Study Group: In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85-day multicenter trial. Chest. 1994, 105: 1411-1419.Google Scholar
- Guleria R, Behera D, Jindal SK: Comparison of bronchodilatation produced by an anticholinergic (ipratropium bromide), a beta-2 adrenergic (fenoterol) and their combination in patients with chronic obstructive airway disease. An open trial. J Assoc Physicians India. 1991, 39: 680-682.PubMedGoogle Scholar
- ZuWallack R, De Salvo MC, Kaelin T, Bateman ED, Park CS, Abrahams R, Fakih F, Sachs P, Pudi K, Zhao Y, Wood CC, on behalf of the Combivent Respimat® inhaler Study Group: Efficacy and safety of ipratropium bromide/albuterol delivered via Respimat® inhaler versus MDI. Respir Med. 2010, 104: 1179-1188. 10.1016/j.rmed.2010.01.017.PubMedGoogle Scholar
- Dorinsky PM, Reisner C, Ferguson GT, Menjoge SS, Serby CW, Witek TJ: The combination of ipratropium and albuterol optimizes pulmonary function reversibility testing in patients with COPD. Chest. 1999, 115: 966-971. 10.1378/chest.115.4.966.PubMedGoogle Scholar
- Campbell S: For COPD a combination of ipratropium bromide and albuterol sulfate is more effective than albuterol base. Arch Intern Med. 1999, 159: 156-160. 10.1001/archinte.159.2.156.PubMedGoogle Scholar
- van der Molen T, Cazzola M: Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes. Prim Care Respir J. 2012, 21: 101-108. 10.4104/pcrj.2011.00102.PubMedGoogle Scholar
- van Noord JA, Aumann JL, Janssens E, Verhaert J, Smeets JJ, Mueller A, Cornelissen PJG: Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest. 2006, 129: 509-517. 10.1378/chest.129.3.509.PubMedGoogle Scholar
- Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M, O'Donnell D, McIvor A, Sharma S, Bishop G, Anthony J, Cowie R, Field S, Hirsch A, Hernandez P, Rivington R, Road J, Hoffstein V, Hodder R, Marciniuk D, McCormack D, Fox G, Cox G, Prins HB, Ford G, Bleskie D, Doucette S, Mayers I, Chapman K: Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease. A randomized trial. Ann Intern Med. 2007, 146: 545-555. 10.7326/0003-4819-146-8-200704170-00152.PubMedGoogle Scholar
- van Noord JA, Aumann J-L, Janssens E, Smeets JJ, Verhaert J, Disse B, Mueller A, Cornelissen PJG: Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J. 2005, 26: 214-222. 10.1183/09031936.05.00140404.PubMedGoogle Scholar
- Mahler DA, D'Urzo A, Peckitt C, Lassen C, Kramer B, Filcek S: Combining once-daily bronchodilators in COPD: indacaterol plus tiotropium versus tiotropium alone [abstract]. Am J Respir Crit Care Med. 2011, 183: A1591-Google Scholar
- Maltais F, Beck E, Webster D, Maleki-Yazdi MR, Seibt J-V, Arnoux A, Hamilton A: Four weeks once daily treatment with tiotropium + olodaterol (BI 1744) fixed dose combination compared with tiotropium in COPD patients [abstract 5557]. Eur Respir J. 2010, 36 (Suppl 54): 1014s-Google Scholar
- Reisner C, St Rose E, Strom S, Fischer T, Golden M, Thomas M, Orevillo C: Fixed combination of glycopyrrolate and formoterol MDI (GFF-MDI) demonstrates superior inspiratory capacity (IC) compared to tiotropium DPI (Tio) following 7 days dosing, in a randomized, double-blind, placebo-controlled phase 2b study in patients with COPD [abstract P879]. Eur Respir J. 2011, 38 (Suppl 55): 150s-Google Scholar
- Reisner C, Fogarty C, Spangenthal S, Dunn L, Kerwin EM, Quinn D, Seale JP, Thomas M, St Rose E, Orevillo CJ: Novel combination of glycopyrrolate and formoterol MDI (GFF-MDI) provides superior bronchodilation compared to its components administered alone, tiotropium DPI, and formoterol DPI in a randomized, double-blind, placebo-controlled Phase 2b study in patients with COPD [abstract]. Am J Respir Crit Care Med. 2011, 183: A6453-Google Scholar
- Vogelmeier C, Kardos P, Harari S, Gans SJM, Stenglein S, Thirlwell J: Formoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month study. Respir Med. 2008, 102: 1511-1520. 10.1016/j.rmed.2008.07.020.PubMedGoogle Scholar
- Tashkin DP, Pearle J, Iezzoni D, Varghese ST: Formoterol and tiotropium compared with tiotropium alone for treatment of COPD. COPD. 2009, 6: 17-25. 10.1080/15412550902724073.PubMedGoogle Scholar
- Tashkin DP, Littner M, Andrews CP, Tomlinson L, Rinehart M, Denis-Mize K: Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: a placebo-controlled trial. Respir Med. 2008, 102: 479-487. 10.1016/j.rmed.2007.12.019.PubMedGoogle Scholar
- Van de Maele B, Fabbri LM, Martin C, Horton R, Dolker M, Overend T: Cardiovascular safety of QVA149, a combination of indacaterol and NVA237, in COPD patients. COPD. 2010, 7: 418-427. 10.3109/15412555.2010.528812.PubMedGoogle Scholar
- van Noord JA, Buhl R, LaForce C, Martin C, Jones F, Dolker M, Overend T: QVA149 demonstrates superior bronchodilation compared with indacaterol or placebo in patients with chronic obstructive pulmonary disease. Thorax. 2010, 65: 1086-1091. 10.1136/thx.2010.139113.PubMedGoogle Scholar
- van Noord JA, Aumann J-L, Janssens E, Smeets JJ, Zaagsma J, Mueller A, Cornelissen PJG: Combining tiotropium and salmeterol in COPD: effects on airflow obstruction and symptoms. Respir Med. 2010, 104: 995-1004. 10.1016/j.rmed.2010.02.017.PubMedGoogle Scholar
- Tashkin DP, Donohue JF, Mahler DA, Huang H, Goodwin E, Schaefer K, Hanrahan JP, Andrews WT: Effects of arformoterol twice daily, tiotropium once daily, and their combination in patients with COPD. Respir Med. 2009, 103: 516-524. 10.1016/j.rmed.2008.12.014.PubMedGoogle Scholar
- Beier J, van Noord J, Deans A, Brooks J, Maden C, Baggen S, Mehta R, Cahn A: Safety and efficacy of dual therapy with GSK233705 and salmeterol versus monotherapy with salmeterol, tiotropium, or placebo in a crossover pilot study in partially reversible COPD patients. Int J Chron Obstruct Pulmon Dis. 2012, 7: 153-164.PubMedPubMed CentralGoogle Scholar
- Reisner C, Fernandez C, Orevillo C, St Rose E, Kollar C: Pearl Therapeutics' combination LAMA/LABA MDI (GFF MDI, PT003) provides comparable metabolic and ECG safety to Spiriva® HandiHaler® and placebo in patients with COPD [abstract]. Am J Respir Crit Care Med. 2012, 185: A2925-Google Scholar
- Feldman G, Walker RR, Brooks J, Mehta R, Crater G: Safety and tolerability of the GSK573719/vilanterol combination in patients with COPD [abstract A2938]. Am J Respir Crit Care Med. 2012, 185: A2938-Google Scholar
- Aalbers R, Maleki-Yazdi MR, Hamilton A, Waitere-Wijker S, Pivovarova A, Schmidt O, Bjermer L: Presented at the European Respiratory Society Annual Congress, Vienna, Austria, September 1–5. [abstract 2882]. Dose-finding study for tiotropium and olodaterol when administered in combination via the Respimat® inhaler in patients with COPD. 2012Google Scholar
- Hanania NA, Boota A, Kerwin E, Tomlinson L, Denis-Mize K: Efficacy and safety of nebulized formoterol as add-on therapy in COPD patients receiving maintenance tiotropium bromide: results from a 6-week, randomized, placebo-controlled, clinical trial. Drugs. 2009, 69: 1205-1216. 10.2165/00003495-200969090-00005.PubMedGoogle Scholar
- Terzano C, Petroianni A, Conti V, Ceccarelli D, Graziani E, Sanduzzi A, D'Avelli S: Rational timing of combination therapy with tiotropium and formoterol in moderate and severe COPD. Respir Med. 2008, 102: 1701-1707. 10.1016/j.rmed.2008.07.012.PubMedGoogle Scholar
- Dahl R, Chapman K, Rudolf M, Mehta R, Kho P, Alagappan V, Berhane I, Chen H, Banerji D: Presented at the European Respiratory Society Annual Congress, Vienna, Austria, September 1–5. QVA149 administered once daily provides significant improvements in lung function over 1 year in patients with COPD: the ENLIGHTEN study [abstract 2896]. 2012Google Scholar
- Bateman E, Ferguson GT, Barnes N, Gallagher N, Green Y, Horton R, Henley M, Banerji D: Presented at the European Respiratory Society Annual Congress, Vienna, Austria, September 1–5. Benefits of dual bronchodilation with QVA149 once daily versus placebo, indacaterol, NVA237 and tiotropium in patients with COPD: the SHINE study [abstract 2810]. 2012Google Scholar
- Vogelmeier CF, Bateman ED, Pallante J, Alagappan VKT, D'Andrea P, Chen H, Banerji D: Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Resp Med. 2013, 1: 51-60.Google Scholar
- Cazzola M, Di Marco F, Santus P, Boveri B, Verga M, Matera MG, Centanni S: The pharmacodynamic effects of single inhaled doses of formoterol, tiotropium and their combination in patients with COPD. Pulm Pharmacol Ther. 2004, 17: 35-39. 10.1016/j.pupt.2003.09.001.PubMedGoogle Scholar
- Cazzola M, Noschese P, Salzillo A, De Giglio C, D'Amato G, Matera MG: Bronchodilator response to formoterol after regular tiotropium or to tiotropium after regular formoterol in COPD patients. Respir Med. 2005, 99: 524-528. 10.1016/j.rmed.2004.10.004.PubMedGoogle Scholar
- Di Marco F, Verga M, Santus P, Morelli N, Cazzola M, Centanni S: Effect of formoterol, tiotropium, and their combination in patients with acute exacerbation of chronic obstructive pulmonary disease: a pilot study. Respir Med. 2006, 100: 1925-1932. 10.1016/j.rmed.2006.03.007.PubMedGoogle Scholar
- Rabe KF, Timmer W, Sagkriotis A, Viel K: Comparison of a combination of tiotropium plus formoterol to salmeterol plus fluticasone in moderate COPD. Chest. 2008, 134: 255-262. 10.1378/chest.07-2138.PubMedGoogle Scholar
- Wang J, Jin D, Zuo P, Wang T, Xu Y, Xiong W: Comparison of tiotropium plus formoterol to tiotropium alone in stable chronic obstructive pulmonary disease: a meta-analysis. Respirology. 2011, 16: 350-358. 10.1111/j.1440-1843.2010.01912.x.PubMedGoogle Scholar
- Berton DC, Reis M, Siqueira AC, Barroco AC, Takara LS, Bravo DM, Andreoni S, Neder JA: Effects of tiotropium and formoterol on dynamic hyperinflation and exercise endurance in COPD. Respir Med. 2010, 104: 1288-1296. 10.1016/j.rmed.2010.05.017.PubMedGoogle Scholar
- Cazzola M, Centanni S, Santus P, Verga M, Mondoni M, Di Marco F, Matera MG: The functional impact of adding salmeterol and tiotropium in patients with stable COPD. Respir Med. 2004, 98: 1214-1221. 10.1016/j.rmed.2004.05.003.PubMedGoogle Scholar
- European Medicines Agency: Guideline on the non-clinical development of fixed combinations of medicinal products. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/10/WC500003976.pdf,
- US Department of Health and Human Services, US Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Guidance for industry. Chronic obstructive pulmonary disease: developing drugs for treatment. Draft guidance. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071575.pdf,
- Chowdhury BA, Seymour SM, Michele TM, Durmowicz AG, Liu D, Rosebraugh CJ: The risks and benefits of indacaterol — the FDA's review. N Engl J Med. 2011, 365: 2247-2249. 10.1056/NEJMp1109621.PubMedGoogle Scholar
- Gavalda A, Vinyals M, Aubets J, Gras J: Presented at the European Respiratory Society Annual Congress, Vienna, Austria, September 1–5. Effect of formoterol alone and in combination with aclidinium on electrocardiograms in dogs [abstract 2116]. 2012Google Scholar
- Agusti A, Hedner J, Marin JM, Barbé F, Cazzola M, Rennard S: Night-time symptoms: a forgotten dimension of COPD. Eur Respir Rev. 2011, 20: 183-194. 10.1183/09059180.00004311.PubMedGoogle Scholar
- Toy EL, Beaulieu NU, McHale JM, Welland TR, Plauschinat CA, Swensen A, Duh MS: Treatment of COPD: relationships between daily dosing frequency, adherence, resource use, and costs. Respir Med. 2011, 105: 435-441. 10.1016/j.rmed.2010.09.006.PubMedGoogle Scholar
- Yawn BP, Colice GL, Hodder R: Practical aspects of inhaler use in the management of chronic obstructive pulmonary disease in the primary care setting. Int J Chron Obstruct Pulmon Dis. 2012, 7: 495-502.PubMedPubMed CentralGoogle Scholar
- Brocklebank D, Ram F, Wright J, Barry P, Cates C, Davies L, Douglas G, Muers M, Smith D, White J: Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature. Health Technol Assess. 2001, 5: 1-149.PubMedGoogle Scholar
- Dalby R, Spallek M, Voshaar T: A review of the development of Respimat® Soft Mist™ Inhaler. Int J Pharm. 2004, 283: 1-9. 10.1016/j.ijpharm.2004.06.018.PubMedGoogle Scholar
- Lechuga-Ballesteros D, Noga B, Vehring R, Cummings RH, Dwivedi SK: Novel cosuspension metered-dose inhalers for the combination therapy of chronic obstructive pulmonary disease and asthma. Future Med Chem. 2011, 3: 1703-1718. 10.4155/fmc.11.133.PubMedGoogle Scholar
- Pavkov R, Mueller S, Fiebich K, Singh D, Stowasser F, Pignatelli G, Walter B, Ziegler D, Dalvi M, Dederichs J, Rietveld I: Characteristics of a capsule based dry powder inhaler for the delivery of indacaterol. Curr Med Res Opin. 2010, 26: 2527-2533. 10.1185/03007995.2010.518916.PubMedGoogle Scholar
- Chrystyn H, Niederlaender C: The Genuair® inhaler: a novel, multidose dry powder inhaler. Int J Clin Pract. 2012, 66: 309-317. 10.1111/j.1742-1241.2011.02832.x.PubMedGoogle Scholar
- Larsen JS, Hahn M, Ekholm B, Wick KA: Evaluation of conventional press-and-breathe metered-dose inhaler technique in 501 patients. J Asthma. 1994, 31: 193-199. 10.3109/02770909409044826.PubMedGoogle Scholar
- Goodman DE, Israel E, Rosenberg M, Johnston R, Weiss ST, Drazen JM: The influence of age, diagnosis, and gender on proper use of metered-dose inhalers. Am J Respir Crit Care Med. 1994, 150: 1256-1261. 10.1164/ajrccm.150.5.7952549.PubMedGoogle Scholar
- Brand P, Hederer B, Austen G, Dewberry H, Meyer T: Higher lung deposition with Respimat® Soft Mist™ Inhaler than HFA-MDI in COPD patients with poor technique. Int J Chron Obstruct Pulmon Dis. 2008, 3: 763-770.PubMedPubMed CentralGoogle Scholar
- Lavorini F, Magnan A, Dubus JC, Voshaar T, Corbetta L, Broeders M, Dekhuijzen R, Sanchis J, Viejo JL, Barnes P, Corrigan C, Levy M, Crompton GK: Effect of incorrect use of dry powder inhalers on management of patients with asthma and COPD. Respir Med. 2008, 102: 593-604. 10.1016/j.rmed.2007.11.003.PubMedGoogle Scholar
- Hochrainer D, Hölz 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 Aerosol Med. 2005, 18: 273-282. 10.1089/jam.2005.18.273.PubMedGoogle Scholar
- Geller DE: Comparing clinical features of the nebulizer, metered-dose inhaler, and dry powder inhaler. Respir Care. 2005, 50: 1313-1321.PubMedGoogle Scholar
- Wieshammer S, Dreyhaupt J: Dry powder inhalers: which factors determine the frequency of handling errors?. Respiration. 2008, 75: 18-25. 10.1159/000109374.PubMedGoogle Scholar
- Lareau SC, Yawn BP: Improving adherence with inhaler therapy in COPD. Int J Chron Obstruct Pulmon Dis. 2010, 5: 401-406.PubMedPubMed CentralGoogle Scholar
- Melani AS, Bonavia M, Cilenti V, Cinti C, Lodi M, Martucci P, Serra M, Scichilone N, Sestini P, Aliani M, Neri M, on behalf of the Gruppo Educazionale Associazione Italiana Pnemologi Ospedalieri (AIPO): Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med. 2011, 105: 930-938. 10.1016/j.rmed.2011.01.005.PubMedGoogle Scholar
- Yu AP, Guérin A, Ponce de Leon D, Ramakrishnan K, Wu EQ, Mocarski M, Blum S, Setyawan J: Therapy persistence and adherence in patients with chronic obstructive pulmonary disease: multiple versus single long-acting maintenance inhalers. J Med Econ. 2011, 14: 486-496.PubMedGoogle Scholar
- Kesten S, Jara M, Wentworth C, Lanes S: Pooled clinical trial analysis of tiotropium safety. Chest. 2006, 130: 1695-1703. 10.1378/chest.130.6.1695.PubMedGoogle Scholar
- Jung KS, Park HY, Park SY, Kim SK, Kim Y-K, Shim J-J, Moon HS, Lee KH, Yoo J-H, Lee SD: Comparison of tiotropium plus fluticasone propionate/salmeterol with tiotropium in COPD: a randomized controlled study. Respir Med. 2012, 106: 382-389. 10.1016/j.rmed.2011.09.004.PubMedGoogle Scholar
- Chatterjee A, Shah M, D'Souza AO, Bechtel B, Crater G, Dalal AA: Observational study on the impact of initiating tiotropium alone versus tiotropium with fluticasone propionate/salmeterol combination therapy on outcomes and costs in chronic obstructive pulmonary disease. Respir Res. 2012, 13: 15-10.1186/1465-9921-13-15.PubMedPubMed CentralGoogle Scholar
- Welte T, Miravitlles M, Hernandez P, Eriksson G, Peterson S, Polanowski T, Kessler R: Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009, 180: 741-750. 10.1164/rccm.200904-0492OC.PubMedGoogle Scholar
- Pasqua F, Biscione G, Crigna G, Auciello L, Cazzola M: Combining triple therapy and pulmonary rehabilitation in patients with advanced COPD: a pilot study. Respir Med. 2010, 104: 412-417. 10.1016/j.rmed.2009.10.005.PubMedGoogle Scholar
- Short PM, Williamson PA, Elder DHJ, Lipworth SIW, Schembri S, Lipworth BJ: The impact of tiotropium on mortality and exacerbations when added to inhaled corticosteroids and long-acting β-agonist therapy in COPD. Chest. 2012, 141: 81-86. 10.1378/chest.11-0038.PubMedGoogle Scholar
- Karner C, Cates CJ: The effect of adding inhaled corticosteroids to tiotropium and long-acting beta2-agonists for chronic obstructive pulmonary disease (Review). Cochrane Database Syst Rev. 2011, 9: CD009039-PubMedGoogle Scholar
- Hughes AD, Jones LH: Dual-pharmacology muscarinic antagonist and β2 agonist molecules for the treatment of chronic obstructive pulmonary disease. Future Med Chem. 2011, 3: 1585-1605. 10.4155/fmc.11.106.PubMedGoogle Scholar
- Steinfeld T, Hughes AD, Klein U, Smith JAM, Mammen M: THRX-198321 is a bifunctional muscarinic receptor antagonist and β2-adrenoceptor agonist (MABA) that binds in a bimodal and multivalent manner. Mol Pharmacol. 2011, 79: 389-399. 10.1124/mol.110.069120.PubMedGoogle Scholar
- Fernandes LB, Henry PJ, Goldie RG: Rho kinase as a therapeutic target in the treatment of asthma and chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2007, 1: 25-33. 10.1177/1753465807080740.PubMedGoogle Scholar
- IMS Health, LifeLink Solutions: IMS data 5/2011-4/2012. 2012Google Scholar
- Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Mölken MPMH, Beeh KM, Rabe KF, Fabbri LM, for the POET-COPD Investigators: Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011, 364: 1093-1103. 10.1056/NEJMoa1008378.PubMedGoogle Scholar
- Casaburi R, Kukafka D, Cooper CB, Witek TJ, Kesten S: Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest. 2005, 127: 809-817. 10.1378/chest.127.3.809.PubMedGoogle Scholar
- Maltais F, Hamilton A, Marciniuk D, Hernandez P, Sciurba FC, Richter K, Kesten S, O'Donnell D: Improvements in symptom-limited exercise performance over 8 h with once-daily tiotropium in patients with COPD. Chest. 2005, 128: 1168-1178. 10.1378/chest.128.3.1168.PubMedGoogle Scholar
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More than 8 in 10 mobile owners use their devices in-store to inform their shopping decisions, a Google study found. Among those using their devices in stores, 82% begin their in-store mobile quest with a search rather than an application or a brand's website. In addition, one-third of shoppers opt for their devices over store personnel to find information.
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1956 Porsche 356 SPEEDSTER REPLICA WIDE BODY CALIFORNIA VERSIO$16900 Additional Photos Vehicle Description 1956 PORSCHE 356 SPEEDSTER WIDE BODY CALIFORNIA VERSION, NOT THE COMMON REGULAR SPEEDSTER. THE C BODY CREATES A MORE MUSCULAR HI TEC EUROPEAN LOOK AND ACCOMMODATES WIDER TIRES FOR INCREASED PERFORMANCE. THE LOOK IS EVEN MORE STARTLING BECAUSE OF THE REMOVABLE HARD PONTOON BOOT WHICH COVERS TH
1 year ago
New Jersey, NJ


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'Betty Lacca Bow - Small' Tote
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Chat with a designer specialist or call 1.877.543.7463.
HideDetails & Care
A prominent bow centers a lacquered, liquid-shine tote suspended from slender rolled handles and branded with a raised goldtone logo plate at one side.
- Magnetic-snap closure.
- Interior zip, wall and cell-phone pockets.
- Protective metal feet.
- Coated cotton canvas.
- Made in Italy.


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Jackson Creek needs dredging
The channel at the mouth of Jackson Creek in Deltaville is narrowing and officials met last week at Deltaville Boat Yard to discuss the possibility of having the U.S. Army Corps of Engineers widen the entrance, reported supervisor Carlton Revere at a September 21 board meeting.
posted 09.29.2010Wings & Wheels wows 3,600
SLIDESHOW: Early on, basic transportation evolved into a metallic art form, and transportation took to the air. Some fine examples from the first 100 years of transportation technology assembled for Wings & Wheels 2010 last Saturday at Hummel Field in Topping.
posted 09.29.2010County meals tax on ballot
Counties may only enact a meals tax if approved by voters in a binding referendum. The exact wording of the referendum on the ballot reads: "Should the Board of Supervisors levy a Food and Beverage Tax within Middlesex County, Virginia?"
posted 09.29.2010Middlesex considers joining Civil War memorial
The Middlesex County Board of Supervisors is considering creating a local Sesquicentennial Committee to join the State of Virginia in the commemoration of the 150th anniversary of the Civil War. Middlesex has a colorful Civil War history which, if promoted properly, could be beneficial to the county.
posted 09.29.2010
More News: page 363 of 522 pages « First < 361 362 363 364 365 > Last »


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My MG nursery group is made up of people who have their hands in many
projects. This one woman is a perpetual thorn because she simply is
involved in so many things but insists on being there for our
projects, then
falls back because something else came up. It's a bear trying to
schedule a
day to work. Last time, we finally came up with a day she could make,
not until afternoon. The rest of us started in at 9am and then she
up to join us for a pizza lunch that one of the other members bought.
said she had a meeting downtown and couldn't get dirty. So she finally
joined us at 4pm and potted 6 plants. The time b4 that we had gone
with her afternoon time. However, when the day came, she said it was
hot and she couldn't work in the sun. We found her a shade job which
reluctantly did, but after 40 min she said she was tired and went
home. She
was tired because she had worked on other projects all day. She is on
several volunteer org. boards and volunteers for so many things, it is
pain to work around her. Don't get me wrong, I admire how much she
does do,
she's a Type A and accomplishes a lot, but our group always gets the
last of her energy and I resent it. She finally shows up and asks,
"So how
are WE doing?" I don't reply out loud.
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Summary | Excerpt | Reading Guide | Reviews | Beyond the book | Readalikes | Genres & Themes | Author Bio
The wonder of Francine Prose's terrific historical novel, Lovers at the Chameleon Club, Paris 1932, is how she takes inspiration from a work of visual art and builds, not just one story, not just one voice, but a kaleidoscope of voices and angles about individuals whose lives intersect at a particular time and place. The visual piece is a gelatin silver print by famed Hungarian photographer Brassai called "Lesbian Couple at Le Monocle, 1932." It shows two people having cocktails and cigarettes seated at a cabaret table. One is a woman in a diaphanous evening gown and the other is also a woman, but she is dressed in a tailored man's suit, shirt and necktie. It is perhaps as evocative of Paris during the Jazz Age as any picture and it has clearly evoked brilliance in this author.
The main character in Lovers is the mannish woman depicted in a similar, fictional photograph, ...
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The Muppets Music Video - "Man or Muppet" (2011) - Jason Segel Movie HD
The Muppets - Man or Muppet The song from The Muppets(2011) film "Am I a Man or Am I a Muppet" I don't own anything.This belongs to Walt Disney ,The ...
The Muppets - Man or Muppet song HD
I'm not gonna lie: I cheered when the Muppets won the Oscars for Best Original Song. So here are the lyrics for "Man or Muppet". Lyrics written by Bret McKenzie.
The Muppets-Man or Muppet Lyrics


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The 71st session of the United Nations General Assembly will begin on Monday (19th of September, 2016.)
President Muhammadu Buhari has announced he will be participating at the five0-day event.
The statement was made public by the Special Adviser on Media and Publicity to the President, Mr. Femi Adesina.
Adesina said president Buhari would deliver Nigeria's statement at the opening of the General Debate of the Assembly on "The Sustainable Development Goals: A Universal Push to Transform Our World."
Read Also: The imminent disintegration of Nigeria — President Buhari: Part 4.
The president would also attend another summit on "Large Movements of Refugees and Migrants."
According to Adesina, "The summit is the first of its to be kind organized by the General Assembly at the Heads of State and Government level.
"The meeting is expected to come up with a blueprint for a better international response to enhance protection of migrants and refugees.
"On the margins of the 71st UNGA, President Buhari will sign the Paris Agreement on Climate Change.
"He will also participate in activities venerating the 30th anniversary of the Declaration of the Right to Development.
President Buhari will equally participate in an event hosted by the UN Secretary-General, Ban Ki-Moon, on "Ending Need in the Lake Chad."
Read Also: Like Obama, like Buhari: An Analysis of the Economy – Part 2.
He will present a keynote address on "Taking Climate Action toward Sustainable Development in Nigeria and the Lake Chad Basin."
Recall that the President had once warned that "Unless developed countries make concerted efforts to complete feasibility around Lake Chad, the Lake will dry up.
"The people will go somewhere and they will create problems for those countries," PMB said.
Over nine million people are in need of humanitarian assistance in the Lake Chad Basin.
President Muhammadu Buhari is expected to attend series of meetings as well as other side events, which were of significant interest to Nigeria.