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词条 Long-acting beta-adrenoceptor agonist
释义

  1. Medical uses

  2. Agents

  3. Ultra-LABAs

     Ultra-LABAs under development  Failed agents 

  4. Concerns

  5. References

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Long-acting β adrenoceptor agonists (LABAs, more specifically, long-acting β2 adrenergic receptor agonists) are usually prescribed for moderate-to-severe persistent asthma patients or patients with chronic obstructive pulmonary disease (COPD). They are designed to reduce the need for shorter-acting β2 agonists such as salbutamol (albuterol), as they have a duration of action of approximately 12 hours in comparison with the 4-to-6-hour duration of salbutamol, making them candidates for sparing high doses of corticosteroids{{citation needed|date=February 2011|reason=LABAs don't reduce inflammation and are not usually better tolerated than corticoids, so using a LABA to spare corticoid is questionable.}} or treating nocturnal asthma and providing symptomatic improvement in patients with COPD. With the exception of formoterol, long-acting β2 agonists are not recommended for the treatment of acute asthma exacerbations because of their slower onset of action compared to salbutamol. Their long duration of action is due to the addition of a long, lipophilic side-chain that binds to an exosite on adrenergic receptors. This allows the active portion of the molecule to continuously bind and unbind at β2 receptors in the smooth muscle in the lungs.

Medical uses

When combined with inhaled steroids, β adrenoceptor agonists can improve symptoms.[1][2] In children this benefit is uncertain and they may be potentially harmful.[2] They should not be used without an accompanying steroid due to an increased risk of severe symptoms, including exacerbation in both children and adults.[3] A 2013 meta-analysis was unable to determine whether an increase serious adverse events reported in the previous meta-analysis on regular salmeterol alone is abolished by the additional use of regular inhaled corticosteroid.[4] Large surveillance studies are ongoing to provide more information. There were no asthma-related deaths and few asthma-related serious adverse events when salmeterol is used with an inhaled steroid.[5][6] At least with formoterol, an increased risk appears to be present even when steroids are used[7] and this risk has not been ruled out for salmeterol.[8]

Agents

Some of the currently available long-acting β2 adrenoceptor agonists include:

INN: Trade (brand) name
  • arformoterol: Brovana (some consider it to be an ultra-LABA)[9]
  • bambuterol: Bambec, Oxeol
  • clenbuterol: Dilaterol, Spiropent
  • formoterol: Foradil, Oxis, Perforomist
  • salmeterol: Serevent
  • Protokylol

Ultra-LABAs

Several long-acting β adrenoreceptor agonists have a duration of action of 24 hours, allowing for once-daily dosing. They are considered to be ultra-long-acting β adrenoreceptor agonists (ultra-LABAs)[10] and are now approved.

  • indacaterol: approved by the European Medicines Agency (EMA) on November 30, 2009,[11] and by Russian FDA-equivalent under the trade name Onbrez Breezhaler. In the United States. it was approved by the Food and Drug Administration (FDA) under the trade name Arcapta Neohaler on July 1, 2011)[12]
  • olodaterol: approved in some EU countries and Russia, and by the United States FDA on July 31, 2014 under Striverdi Respimat[13]
  • vilanterol is the ultra-LABA not available by itself but only as a component of combination drugs:
    • with fluticasone furoate: Breo Ellipta (U.S.), Relvar Ellipta (EU, RU). This second medication in this combination is the synthetic inhaled corticosteroid fluticasone furoate. This product was approved by the FDA on May 2013 as once-daily inhaled therapy for the treatment of chronic obstructive pulmonary disease (COPD)
    • with umeclidinium bromide: Anoro Ellipta. Umeclidinium bromide is a long-acting {{w|muscarinic antagonist}}.[14] This combination was approved by the FDA on December 18, 2013[15] for the long-term maintenance treatment of COPD. On March 28, 2014, it was approved in European countries[16] and in Russia[17] under the same trade name

Ultra-LABAs under development

  • abediterol (codenamed LAS100977)[18][19]
  • salmefamol (salbutamol and para-methoxyamphetamine (PMA) hybrid)

Failed agents

  • carmoterol (formerly TA-2005):[19] development terminated[20]
  • PF-610355: development terminated[21]

Concerns

While the use of inhaled LABAs are still recommended in asthma guidelines for the resulting improved symptom control,[22] further concerns have been raised, by a large meta-analysis of the pooled results from 19 trials with 33,826 participants, that salmeterol may increase the small risks of asthma deaths, and this additional risk is not reduced with the additional use of inhaled steroids (e.g., as with the combination product fluticasone/salmeterol).[23]

This seems to occur because although LABAs relieve asthma symptoms, they also promote bronchial inflammation and sensitivity without warning.[24]

On February 18, 2011, the FDA issued a safety alert for long-acting β agonists.[25]

References

1. ^{{cite journal|last=Higashi|first=AS|author2=Zhu S |author3=Stafford RS |author4= Alexander GC |title=National trends in outpatient asthma treatment, 1997-2009.|journal=Journal of General Internal Medicine|volume=26|pages=1465–70|year=2011|pmid=21769507|doi=10.1007/s11606-011-1796-4|issue=12 |pmc=3235617}}
2. ^1 {{cite journal|last1=Ducharme|first1=Francine M|last2=Ni Chroinin|first2=Muireann|last3=Greenstone|first3=Ilana|last4=Lasserson|first4=Toby J|title=Addition of long-acting beta2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children|journal=The Cochrane Database of Systematic Reviews|date=12 May 2010|issue=5|pages=CD005535|doi=10.1002/14651858.CD005535.pub2|pmid=20464739|pmc=4169792}}
3. ^{{cite journal |author=Fanta CH |title=Asthma |journal=New England Journal of Medicine|volume=360|issue=10 |pages=1002–14 |date=March 2009 |pmid=19264689 |doi=10.1056/NEJMra0804579}}
4. ^{{Cite journal|last=Cates|first=Christopher J.|last2=Jaeschke|first2=Roman|last3=Schmidt|first3=Stefanie|last4=Ferrer|first4=Montse|date=2013-03-28|title=Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events|journal=The Cochrane Database of Systematic Reviews|issue=3|pages=CD006922|doi=10.1002/14651858.CD006922.pub3|issn=1469-493X|pmid=23543548}}
5. ^{{cite journal |author=Cates CJ, Cates MJ|title=Regular treatment with salmeterol for chronic asthma: serious adverse events |journal=Cochrane Database Syst Rev |issue=3 |pages=CD006363 |year=2008 |pmid=18646149 |pmc=4015854 |doi=10.1002/14651858.CD006363.pub2|editor1-last=Cates |editor1-first=Christopher J }}
6. ^{{cite web|title=FDA Drug Safety Communication: New safety requirements for long-acting inhaled asthma medications called Long-Acting Beta-Agonists (LABAs)|url=http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm200776.htm|work=FDA|date=Feb 2010|quote=Based on the available information, FDA concludes there is an increased risk for severe exacerbation of asthma symptoms, leading to hospitalizations in pediatric and adult patients as well as death in some patients using LABAs for the treatment of asthma. The agency is requiring the REMS and class-labeling changes to improve the safe use of these products.}}
7. ^{{cite journal|last=Cates|first=CJ|author2=Cates, MJ |title=Regular treatment with formoterol for chronic asthma: serious adverse events|journal=Cochrane Database of Systematic Reviews|date=Apr 18, 2012|volume=4|issue=4|pages=CD006923|pmid=22513944|pmc=4017186|doi=10.1002/14651858.CD006923.pub3}}
8. ^{{cite journal|last=Cates|first=CJ|author2=Cates, MJ |title=Regular treatment with salmeterol for chronic asthma: serious adverse events|journal=Cochrane Database of Systematic Reviews|date=Jul 16, 2008|issue=3|pages=CD006363|pmid=18646149|pmc=4015854|doi=10.1002/14651858.CD006363.pub2}}
9. ^{{cite journal|last1=Matera|first1=MG|last2=Cazzola|first2=M|title=Ultra-Long-Acting β2-Adrenoceptor Agonists: An Emerging Therapeutic Option for Asthma and COPD?|journal=Drugs|date=2007|volume=67|issue=4|pages=503–15|doi=10.2165/00003495-200767040-00002|url=https://www.researchgate.net/publication/6453632_Ultra-Long-Acting_2-Adrenoceptor_Agonists|accessdate=7 March 2016|pmid=17352511}}
10. ^{{cite journal |vauthors=Cazzola M, Matera MG, Lötvall J |title=Ultra long-acting beta 2-agonists in development for asthma and chronic obstructive pulmonary disease |journal=Expert Opin Investig Drugs |volume=14 |issue=7 |pages=775–83 |date=July 2005 |pmid=16022567 |doi=10.1517/13543784.14.7.775 |url=}}
11. ^European Public Assessment Report for Onbrez Breezhaler {{webarchive|url=https://web.archive.org/web/20100116122038/http://www.ema.europa.eu/humandocs/Humans/EPAR/onbrez_breezhaler/onbrez_breezhaler.htm |date=2010-01-16 }}
12. ^{{cite press release |url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm261649.htm |title=FDA approves Arcapta Neohaler to treat chronic obstructive pulmonary disease |publisher=U.S. Food and Drug Administration |date=2011-07-01 |accessdate=2011-07-02}} 
13. ^{{cite news|url=https://www.boehringer-ingelheim.com/news/news_releases/press_releases/2013/18_october_2013_olodaterol.html|title=New once-daily Striverdi (olodaterol) Respimat gains approval in first EU countries|publisher=Boehringer-Ingelheim|date=18 October 2013}}
14. ^{{cite web|title=Incruse Ellipta (umeclidinium inhalation powder) for Oral Inhalation Use. Full Prescribing Information|url=https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Incruse_Ellipta/pdf/INCRUSE-ELLIPTA-PI-PIL.PDF|publisher=GlaxoSmithKline, Research Triangle Park, NC 27709|accessdate=22 February 2016}}
15. ^{{cite web|title=FDA approves Anoro Ellipta to treat chronic obstructive pulmonary disease|url=http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm379057.htm|publisher=U.S. Food and Drug Administration|accessdate=25 March 2016}}
16. ^{{cite web|title=Assessment report: Anoro. INN: umeclidinium bromide/vilanterol|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002751/WC500168425.pdf|website=European Medicines Agency|accessdate=25 March 2016}}
17. ^{{cite web|title=State Register of Nedicines: Anoro Ellipta (vilanterol + umeclidinium bromide)|url=http://grls.rosminzdrav.ru/GRLS.aspx?RegNumber=&MnnR=&lf=&TradeNmR=Аноро+Эллипта&OwnerName=&MnfOrg=&MnfOrgCountry=&isfs=0&isND=-1®type=&order=RegDate&orderType=desc&pageNum=1|website=Russian State Register of Medicinal Products|accessdate=25 March 2016|language=Russian}}
18. ^{{cite journal |last1=Beier |first1=J |last2=Fuhr |first2=R |last3=Massana |first3=E |last4=Jiménez |first4=E |last5=Seoane|first5=B|last6=de Miquel|first6=G|last7=Ruiz|first7=S|title=Abediterol (LAS100977), a novel long-acting β2-agonist: Efficacy, safety and tolerability in persistent asthma|journal=Respiratory Medicine|date=October 2014|volume=108|issue=10|pages=1424–1429|doi=10.1016/j.rmed.2014.08.005|pmid=25256258|url=http://www.resmedjournal.com/article/S0954-6111(14)00287-X/pdf|accessdate=25 March 2016}}
19. ^1 {{cite journal|last=Cazzola|first=Mario|author2=Luigino Calzetta |author3=Maria Gabriella Matera3 |title=β2-adrenoceptor agonists: current and future direction|journal=Br J Pharmacol|date=May 2011|volume=163|issue=1|pages=4–17|doi=10.1111/j.1476-5381.2011.01216.x|pmid=21232045|pmc=3085864}}
20. ^{{cite web|title=Chiesi: Annual Report 2010|url=http://www.chiesi.es/Assets/docs/Annual_report_2010.pdf|publisher=Chiesi Farmaceutici S.p.A.|accessdate=27 March 2016|page=20}}
21. ^{{cite web|title=AdisInsight: PF 610355|url=http://adisinsight.springer.com/drugs/800025582|publisher=Springer International Publishing AG|accessdate=25 March 2016}}
22. ^British Thoracic Society & Scottish Intercollegiate Guidelines Network (SIGN). British Guideline on the Management of Asthma. Guideline No. 63. Edinburgh:SIGN; 2004. (HTML, Full PDF {{webarchive|url=https://web.archive.org/web/20060724153838/http://www.sign.ac.uk/pdf/sign63.pdf |date=2006-07-24 }}, Summary PDF {{webarchive|url=https://web.archive.org/web/20060724154104/http://www.sign.ac.uk/pdf/qrg63.pdf |date=2006-07-24 }})
23. ^{{cite journal |vauthors=Salpeter S, Buckley N, Ormiston T, Salpeter E | title = Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths | journal = Ann Intern Med | volume = 144 | issue = 12 | pages = 904–12 | year = 2006 | pmid=16754916 | doi=10.7326/0003-4819-144-12-200606200-00126}}
24. ^{{cite news | author=Krishna Ramanujan | title=Common asthma inhalers cause up to 80 percent of asthma-related deaths, Cornell and Stanford researchers assert | url=http://www.news.cornell.edu/stories/June06/AsthmaDeaths.kr.html | date=June 9, 2006 | publisher=ChronicalOnline - Cornell University}}
25. ^{{cite web|title=Safety Alerts for Human Medical Products > Long-Acting Beta-Agonists (LABAs): New Safe Use Requirements|url=http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm201003.htm|publisher=U.S. Food and Drug Administration|accessdate=25 March 2016}}
{{Asthma and copd rx}}{{Adrenergic agonists}}

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