salmeterol xinafoate

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salmeterol

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/02/06 20:45:23」(JST)

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Salmeterol

Clinical data
Trade names	Serevent
AHFS/Drugs.com	Monograph
Pregnancy category	C
Routes of administration	Inhalation (MDI, DPI)
ATC code	R03AC12 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only ℞ (Prescription only)
Pharmacokinetic data
Protein binding	96%
Metabolism	Hepatic (CYP3A4)
Biological half-life	5.5 hours
Identifiers
IUPAC name (RS)-2-(hydroxymethyl)-4-{1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl}phenol
CAS Number	89365-50-4 Y
PubChem (CID)	5152
IUPHAR/BPS	559
DrugBank	DB00938 Y
ChemSpider	7987886 Y
UNII	2I4BC502BT Y
KEGG	D05792 N
ChEBI	CHEBI:9011 N
ChEMBL	CHEMBL1263 N
ECHA InfoCard	100.122.879
Chemical and physical data
Formula	C25H37NO4
Molar mass	415.57
3D model (Jmol)	Interactive image
Chirality	Racemic mixture
SMILES OCc1cc(ccc1O)[C@H](O)CNCCCCCCOCCCCc2ccccc2
InChI InChI=1S/C25H37NO4/c27-20-23-18-22(13-14-24(23)28)25(29)19-26-15-7-1-2-8-16-30-17-9-6-12-21-10-4-3-5-11-21/h3-5,10-11,13-14,18,25-29H,1-2,6-9,12,15-17,19-20H2/t25-/m1/s1 Y Key:GIIZNNXWQWCKIB-RUZDIDTESA-N Y
NY (what is this?)  (verify)

Salmeterol is a long-acting β₂ adrenergic receptor agonist (LABA) used in the maintenance and prevention of asthma symptoms and maintenance of chronic obstructive pulmonary disease (COPD) symptoms. Symptoms of bronchospasm include shortness of breath, wheezing, coughing and chest tightness. It is also used to prevent breathing difficulties during exercise (exercise-induced bronchoconstriction). It is marketed as Serevent in the US. It is available as a dry powder inhaler that releases a powdered form of the drug. It was previously available as a metered-dose inhaler (MDI) but was discontinued in the US in 2002. It is still available as an MDI in the UK as of 2013.

Medical uses

Salmeterol is used in moderate-to-severe persistent asthma following previous treatment with a short-acting β₂ adrenoreceptor agonist (SABA) such as salbutamol (albuterol). LABAs should not be used as a monotherapy, instead, they should be used concurrently with an inhaled corticosteroid, such as beclometasone dipropionate or fluticasone propionate in the treatment of asthma to minimize serious reactions such as asthma-related deaths. In chronic obstructive pulmonary disease (COPD), LABAs may be used as monotherapy or in combination with corticosteroids. In exercise-induced bronchospasm monotherapy may be indicated in patients without persistent asthma. LABAs should not be used to treat acute symptoms.

The primary noticeable difference of salmeterol from salbutamol, and other short-acting β₂ adrenoreceptor agonists (SABAs), is its duration of action. Salmeterol lasts approximately 12 hours in comparison with the salbutamol, which last about 4–6 hours.

When used regularly every day as prescribed, inhaled salmeterol decreases the number and severity of asthma attacks. However, like all LABA medications, it is not for use in relieving an asthma attack that has already started.

Inhaled salmeterol works like other β₂ agonists, causing bronchodilation by relaxing the smooth muscle in the airway so as to treat the exacerbation of asthma. The long duration of action occurs by the molecules initially diffusing into the plasma membrane of the lung cells, and then slowly being released back outside the cell where they can come into contact with the β₂ adrenoreceptors, with the long carbon chain forming an anchor in the membrane. Interestingly, salmeterol binding to the β₂ adrenoreceptor does not induce desensitization or internalization of receptors which may also contribute to its long therapeutic duration of action. Formoterol has been demonstrated to have a faster onset of action than salmeterol as a result of a lower lipophilicity, and has also been demonstrated to be more potent—a 12 µg dose of formoterol has been demonstrated to be equivalent to a 50 µg dose of salmeterol.

Pregnancy and lactation

The FDA assigns a Category C to salmeterol in pregnancy. Salmeterol use during pregnancy must be decided based on the risks versus benefits to the mother. There are no well-controlled studies with salmeterol in pregnant women. Some animal studies showed developmental malformation when the mother was given several clinical doses orally. In rats, salmeterol xinafoate is excreted in the milk. However, since there are no data to show excretion of salmeterol in a mother's breast milk, a decision on whether to continue or discontinue therapy should be decided based on the important benefits it provides to the mother. Pregnant and lactating women should consult their doctors before using salmeterol.

Side effects

Due to its vasodilation properties, the common side effects of salmeterol are dizziness, sinus infection, and migraine headaches. In most cases, salmeterol side effects are minor and either don't require treatment or can easily be treated. Certain side effects, however, should be reported to a healthcare provider immediately. Some of these more serious side effects include a very fast heart rate, high blood pressure, and worsening breathing problems.

Structure-activity relationship

Salmeterol has an aryl alkyl group with a chain length of 11 atoms from the amine. This bulkiness makes the compound more lipophilic and it also makes it selective to β₂ adrenergic receptors.

History

Previously Used Metered Dose inhaler of Serevent brand salmeterol

A typical Dry Powder inhaler Salmeterol diskus

Salmeterol, first marketed and manufactured by Glaxo (now GlaxoSmithKline, GSK) in the 1980s, was released as Serevent in 1990. The product is marketed by GSK under the Allen & Hanburys brand in the UK.

In November 2005, the US Food and Drug Administration released a health advisory, alerting the public to findings that show the use of long-acting β₂ agonists could lead to a worsening of symptoms, and in some cases death.

While the use of inhaled LABAs are still recommended in asthma guidelines for the resulting improved symptom control, further concerns have been raised. A large meta-analysis of pooled results from 19 trials with 33,826 participants, suggests that salmeterol may increase the small risks of asthma-related deaths, and this additional risk is not reduced with the additional use of inhaled steroids (e.g., as with the combination product fluticasone/salmeterol). This seems to occur because although LABAs relieve asthma symptoms, they also promote bronchial inflammation and sensitivity without warning.

Long-acting β₂ adrenoceptor agonists (LABAs)

Currently available long-acting β₂ adrenergic receptor agonists include salmeterol (inhaled or sustained-release oral), formoterol, bambuterol and some others. Combinations of inhaled steroids and these long-acting bronchodilators are becoming more widespread; the most common combination currently in use is fluticasone/salmeterol (brand names Seretide (UK) and Advair (U.S.)).

See also

• Vilanterol — an ultra-long-acting β₂ adrenoreceptor agonist with a similar chemical structure.

Footnotes

UpToDate Contents

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• 1. 喘息におけるβ刺激剤：長期使用に関する議論 beta agonists in asthma controversy regarding chronic use
• 2. 思春期および成人における間欠型喘息および軽症持続型喘息の治療 treatment of intermittent and mild persistent asthma in adolescents and adults
• 3. 安定した慢性閉塞性肺疾患（COPD）のマネージメント management of stable chronic obstructive pulmonary disease
• 4. 喘息におけるβ刺激剤：急性期投与および予防的使用 beta agonists in asthma acute administration and prophylactic use
• 5. 思春期および成人における中等度持続型喘息の治療 treatment of moderate persistent asthma in adolescents and adults

English Journal

• Clinical Bioequivalence of OT329 SOLIS and ADVAIR DISKUS in Adults with Asthma.

• Longphre MV1, Getz EB1, Fuller R1.
• Annals of the American Thoracic Society.Ann Am Thorac Soc.2017 Feb;14(2):182-189. doi: 10.1513/AnnalsATS.201606-436OC.
• RATIONALE: OT329 SOLIS is a generic candidate for the branded asthma treatment, ADVAIR DISKUS (fluticasone propionate/salmeterol xinafoate), and, as such, the manufacturer is required to provide evidence of clinical "bioequivalence" as a condition for regulatory approval.OBJECTIVES: The objective of
• PMID 27849125

• Measurement of the Raman spectra and hygroscopicity of four pharmaceutical aerosols as they travel from pressurised metered dose inhalers (pMDI) to a model lung.

• Davidson N1, Tong HJ2, Kalberer M2, Seville PC3, Ward AD4, Kuimova MK5, Pope FD6.
• International journal of pharmaceutics.Int J Pharm.2017 Jan 31. pii: S0378-5173(17)30060-1. doi: 10.1016/j.ijpharm.2017.01.051. [Epub ahead of print]
• Particle inhalation is an effective and rapid delivery method for a variety of pharmaceuticals, particularly bronchodilation drugs used for treating asthma and COPD. Conditions of relative humidity and temperature inside the lungs are generally very different from the outside ambient air, with the l
• PMID 28159683

• Detection and pharmacokinetics of salmeterol in thoroughbred horses following inhaled administration.

• Fenwick SJ1, Hincks PR1, Scarth JP1, Wieder ME1, Hillyer LL2, Paine SW3.
• Journal of veterinary pharmacology and therapeutics.J Vet Pharmacol Ther.2017 Jan 17. doi: 10.1111/jvp.12382. [Epub ahead of print]
• Salmeterol is a man-made beta-2-adrenergic receptor agonist used to relieve bronchospasm associated with inflammatory airway disease in horses. Whilst judicious use is appropriate in horses in training, they cannot race with clinically effective concentrations of medications under the British Horser
• PMID 28097668

Japanese Journal

• 臨床研究・症例報告 小児気管支喘息患者に対するサルメテロールキシナホ酸塩・フルチカゾンプロピオン酸エステル(アドエアドライパウダーインヘラー及びエアゾール)の特定使用成績調査(最終報告)

• 小児科臨床 67(3), 467-479, 2014-03
• NAID 40019984345

• 小児気管支喘息に対する長時間作用性β₂刺激薬(LABA)サルメテロールの安全性

• アレルギー・免疫 20(7), 1054-1062, 2013-07
• NAID 40019711697

• 慢性閉塞性肺疾患(COPD)に対するサルメテロールキシナホ酸塩・フルチカゾンプロピオン酸エステル配合剤(アドエア250ディスカス)の長期特定使用成績調査 : 中間報告

• 呼吸器内科 23(1), 111-122, 2013-01
• NAID 40019578854

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「サルメテロール」

「サルメテロール」

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英

salmeterol

化

キシナホ酸サルメテロール salmeterol xinafoate

商

Serevent、アドエア(サルメテロールキシナホ酸塩、フルチカゾンプロピオン酸エステル)、セレベント

関

長時間作用型β2刺激薬