Combined treatment with salmeterol (0.16 mg/kg) and formoterol (0.32 mg/kg) had a beneficial impact on rats with chronic obstructive pulmonary disease (COPD) [3].

Cell proliferation assay [2]
Cell Types: Human T lymphocytes (THP-1 cells)
Tested Concentrations: 0.001, 0.01, 0.05, 0.2, 1, 5, and salmeterol (0.001-25 μM) inhibit human T floating [2] . 25 µM
Incubation Duration:
Experimental Results: Th2 cell proliferation was inhibited in a concentration-dependent manner.

Animal/Disease Models: Male C57BL/6 mice (6-8 weeks old, body weight: 32-35 g) [3]
Doses: salmeterol (0.16 mg/kg) and/or formoterol (0.32 mg/kg)
Route of Administration: The efficacy of combination therapy was studied in this model for 56 days. The observation period is long.
Experimental Results: COPD mice had Dramatically improved COPD assessment test scores.

Absorption, Distribution and Excretion
In asthmatic patients, a 50µg dose of inhaled salmeterol powder reaches a Cmax of 47.897pg/mL, with a Tmax of 0.240h, and an AUC of 156.041pg/mL/h.
Salmeterol is 57.4% eliminated in the feces and 23% in the urine. Less than 5% of a dose is eliminated in the urine as unchanged salmeterol.
In asthmatic patients, the volume of distribution of the central compartment is 177L and the volume of distribution of the peripheral compartment is 3160L.
The average clearance of salmeterol in a group of asthmatic patients was 392L/h. Further data regarding the clearance of salmeterol is not readily available.
The absorption of salmeterol xinafoate from the respiratory tract following oral inhalation has not been fully characterized. Although it has been suggested that most of an orally inhaled drug actually is swallowed, the bronchodilating action of orally inhaled sympathomimetic agents is believed to result from a local action of the portion of the dose that reaches the bronchial tree. Systemic concentrations of salmeterol are low or undetectable after inhalation of the recommended dosage of the aerosol (42 ug) or powder (50 ug) twice daily and are not predictive of therapeutic effects.
Binding of salmeterol averages 96% in vitro to human plasma proteins over the concentration range of 8-7722 ng/mL, which are concentrations greatly exceeding those achieved following usual doses of the drug. Salmeterol is bound to albumin and alpha 1 acid glycoprotein; the xinafoate moiety also is highly protein bound (greater than 99%) to albumin.
The distribution of salmeterol into various human organs and tissues following oral inhalation has not been fully characterized. Results of studies in rats indicate that salmeterol crosses the blood-brain barrier in trace amounts.
It is not known if salmeterol and/or its metabolites cross the placenta in humans. Following oral administration of 10 mg/kg of salmeterol in mice and rats, placental transfer of salmeterol occurred.
For more Absorption, Distribution and Excretion (Complete) data for SALMETEROL (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Salmeterol is predominantly metabolized by CYP3A4 to alpha-hydroxysalmeterol, and minorly by an unknown mechanism to an O-dealkylated metabolite.
... A minor metabolite is formed by o-dealkylation of the phenylalkyl side chain /of salmeterol/.
... The cytochrome P450 (CYP) isoform 3A4 is responsible for aliphatic oxidation of salmeterol base, which is extensively metabolised by hydroxylation with the major metabolite being alpha-hydroxysalmeterol, with subsequent elimination predominantly in the feces...
Hepatic, metabolized by hydroxylation via CYP3A4
Half Life: 5.5 hours

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Biological Half-Life
The half life of salmeterol is 5.5h.
Following oral administration of salmeterol in healthy individuals, the terminal elimination half-lives of salmeterol and the xinafoate moiety are about 5.5 hours and 11-15 days, respectively.

Toxicity Summary
Salmeterol's long, lipophilic side chain binds to exosites near beta(2)-receptors in the lungs and on bronchiolar smooth muscle, allowing the active portion of the molecule to remain at the receptor site, continually binding and releasing. Beta(2)-receptor stimulation in the lung causes relaxation of bronchial smooth muscle, bronchodilation, and increased bronchial airflow.

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Toxicity Data
By the oral route, no deaths occurred in rats at 1,000 mg/kg (approximately 81,000 times the maximum recommended daily inhalation dose in adults and approximately 38,000 times the maximum recommended daily inhalation dose in children on a mg/m² basis).

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Interactions
Salmeterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol on the vascular system may be potentiated by these agents.
In clinical studies, inhaled corticosteroids and/or inhaled cromolyn sodium did not alter the safety profile of salmeterol oral inhalation when these drugs were administered concurrently.
The systemic pharmacodynamic effects of inhaled salmeterol were not affected by the co-administration of fluticasone propionate.

[1]. The discovery of long-acting saligenin β₂ adrenergic receptor agonists incorporating a urea group. Bioorg Med Chem. 2011 Oct 15;19(20):6026-32.

[2]. Malcolm Johnson. Effects of beta2-agonists on resident and infiltrating inflammatory cells. J Allergy Clin Immunol. 2002 Dec;110(6 Suppl):S282-90.

[3]. Efficacy of salmeterol and formoterol combination treatment in mice with chronic obstructive pulmonary disease. Exp Ther Med. 2018 Feb;15(2):1538-1545.

Therapeutic Uses
Bronchodilator
Salmeterol ... /is/ indicated to prevent bronchospasm and reduce the frequency of acute asthma exacerbations in patients with chronic asthma who require regular treatment with an inhaled shorter-acting beta-adrenergic bronchodilator. ... Salmeterol may be used with or without concurrent inhaled or systemic corticosteroid therapy. During therapy with salmeterol ... , it is important for patients to have a fast-acting inhaled beta-adrenergic bronchodilator available for relief of acute attacks. /Included in US product labeling/
Salmeterol ... /is/ indicated for the prevention of exercise-induced bronchospasm. With use of salmeterol ... , it is important for patients to also have a fast-acting inhaled beta-adrenergic bronchodilator available for relief of acute attacks. ... /Included in US product labeling/
Salmeterol ... /is/ indicated as bronchodilators for the treatment of bronchospasm associated with chronic obstructive airway disease, including bronchitis and pulmonary emphysema. ... /Included in US product labeling/

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Drug Warnings
Data from a large placebo-controlled safety study that was stopped early suggest that salmeterol may be associated with rare serious asthma episodes or asthma-related deaths. Data from this study, called the Salmeterol Multi-center Asthma Research Trial (SMART), further suggest that the risk might be greater in African American patients. These results led to stopping the study prematurely. The data from the SMART study are not adequate to determine whether concurrent use of inhaled corticosteroids provides protection from this risk. Given the similar basic mechanisms of action of beta2-agonists, it is possible that the findings seen in the SMART study may be consistent with a class effect. Findings similar to the SMART study findings were reported in a prior 16-week clinical study performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) study. In the SNS study, the incidence of asthma-related death was numerically, though not statistically, greater in patients with asthma treated with salmeterol (42 ug twice daily) versus albuterol (180 ug 4 times daily) added to usual asthma therapy.
Salmeterol oral inhalation therapy is intended for the maintenance treatment of asthma or chronic obstructive pulmonary disease (COPD) and should not be initiated in patients with substantially worsening or acutely deteriorating asthma or acute symptoms of COPD. ... Serious acute respiratory events, including fatalities, have been reported when salmeterol oral inhalation therapy has been initiated in such situations. In most cases, these adverse events have occurred in patients with severe asthma (e.g., those with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, or previous life-threatening acute asthma exacerbations) and/or in some patients in whom asthma has been acutely deteriorating (e.g., unresponsive to usual medications, increasing need for inhaled short-acting beta-agonists, marked increase in symptoms, recent emergency room visits, sudden or progressive deterioration in pulmonary function). However, such events also have occurred in patients with less severe asthma. Although it has not been determined whether salmeterol oral inhalation therapy contributed to these events or simply failed to relieve the deteriorating asthma, the manufacturer states that use of salmeterol oral inhalation in patients with substantially worsening or acutely deteriorating asthma is inappropriate.
Since salmeterol is cleared predominantly by hepatic metabolism, impaired liver function theoretically may lead to accumulation of the drug in plasma. Therefore, the manufacturer recommends that patients with hepatic disease be monitored closely while receiving salmeterol therapy.
Usual doses of salmeterol oral inhalation generally produce no apparent cardiovascular effects. However, clinically important changes in systolic and/or diastolic blood pressure and heart rate, as well as ECG changes, have occurred infrequently with salmeterol therapy in controlled clinical studies. Adverse cardiovascular effects of salmeterol have in some instances required discontinuance of the drug. Hypertension has been reported with salmeterol inhalation aerosol or powder during postmarketing surveillance.
For more Drug Warnings (Complete) data for SALMETEROL (21 total), please visit the HSDB record page.

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Pharmacodynamics
Salmeterol is a long acting beta-2 adrenergic receptor agonist that binds to both the active and exo sites of the beta-2 adrenergic receptor. Salmeterol has a longer duration of action than other beta-2 agonists like [salbutamol]. Patients should be counselled regarding the risks of long acting beta agonist (LABA) monotherapy, hypokalemia, hypoglycemia, and not to take this drug with another LABA.

C25H37NO4

415.5656

415.272

89365-50-4

Salmeterol xinafoate;94749-08-3

5152

White to off-white solid powder

1.1±0.1 g/cm3

603.0±55.0 °C at 760 mmHg

75.5-76.5 °C
75.7-76.5 °C
75.5 - 76.5 °C

318.5±31.5 °C

0.0±1.8 mmHg at 25°C

1.566

3.07

4

5

16

30

403

0

GIIZNNXWQWCKIB-UHFFFAOYSA-N

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

2-(hydroxymethyl)-4-[1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl]phenol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~240.63 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.02 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.02 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.02 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)