Salmeterol xinafoate

β2-adrenergic receptor agonists are a class of drugs acting on the beta2-adrenergic receptor, thereby causing smooth muscle relaxation, which results in dilation of bronchial passages, vasodilation in muscle/liver, relaxation of uterine muscle and release of insulin. Salmeterol xinafoate, as a long-acting beta2-adrenergic receptor agonist, is clinically prescribed for the treatment of asthma, chronic obstructive pulmonary disease (COPD) and other pulmonary disorders. It was previously marketed as a dry powder inhaler in the US and is still available in the UK market.
In vitro: In a previoius study, it was found that salmeterol could reduce retinal Müller cell death through the inhibition of the phosphorylation of IRS-1(Ser307). In addition, the findings also suggest the importance of IRS-1 in beta-adrenergic receptor signaling in the prevention of cell death in retinal Müller cells [1].
In vivo: A previous animal study showed that salmeterol significantly decreased the production of pro-inflammatory cytokines in a model of allergen-challenged mice, which expressed tumor-necrosis factor-alpha, interleukin-1 and interleukin-6. Moreover, it was found that salmeterol could reduce the inflammation caused by lipopolysaccharide in activated murine bone marrow-derived dendritic cells (DCs). Therefore, this study suggested that salmeterol regulated the inflammation of allergen-induced asthma by modulating DCs, providing evidence that DCs were the target immune cells responsible for the action of salmeterol against asthma [2].
Clinical trial: In an early clinical investigation, it was found that salmeterol was significantly better than disodium cromoglycate in improving both morning and evening PEF [3]. A recent Phase-2 clinical trial, named “Dose-Ranging Study of the Salmeterol Component of Fluticasone/Salmeterol Spiromax Compared to Fluticasone Spiromax and Advair Diskus in Asthma Subjects”, was conducted in the US to evaluate the dose response, efficacy and safety of salmeterol combined with fluticasone for the treatment of persistent asthma.
References:
[1] Walker RJ, Anderson NM, Bahouth S, Steinle JJ. Silencing of insulin receptor substrate-1 increases cell death in retinal Müller cells. Mol Vis. 2012;18:271-9
[2] Hu Z, Chen R, Cai Z, Yu L, Fei Y, Weng L, Wang J, Ge X, Zhu T, Wang J, Bai C. Salmeterol attenuates the inflammatory response in asthma and decreases the pro-inflammatory cytokine secretion of dendritic cells. Cell Mol Immunol. 2012;9:267-75.
[3] Bousquet J, Aubert B, Bons J. Comparison of salmeterol with disodium cromoglycate in the treatment of adult asthma. Ann Allergy Asthma Immunol. 1996;76:189-94.

Salmeterol Xinafoate.[Pubmed:26051688]

Profiles Drug Subst Excip Relat Methodol. 2015;40:321-69.

Salmeterol xinafoate is a potent and a long-acting beta2-adrenoceptor agonist. It is prescribed for the treatment of severe persistent asthma and chronic obstructive pulmonary disease. Different methods were used to prepare (R)-(-)-salmeterol such as: mixing a sample of 4-benzyloxy-3-hydroxymethyl-omega-bromoacetophenone with sodium lauryl sulfate and the mixture was added to the microbial culture of Rhodotorula rubra, treatment of p-hydroxyacetophenone with Eschenmoser's salt and carbonate exchange resin followed by a sequence of supported reagents and scavenging agents or via Rh-catalyzed asymmetric transfer hydrogenation. The enantioselective synthesis of (S)-salmeterol was achieved via asymmetric reduction of the azidoketone 4 by Pichia angusta yeast. Physical characteristics of Salmeterol xinafoate were confirmed via: X-ray powder diffraction pattern, thermal analysis and UV, vibrational, nuclear magnetic resonance, and mass spectroscopical data. Initial improvement in asthma control may occur within 30 min following oral inhalation of salmeterol in fixed combination with fluticasone propionate. Clinically important improvements are maintained for up to 12 h in most patients. It is extensively metabolized in the liver by hydroxylation, thus increased plasma concentrations may occur in patients with hepatic impairment.

Crystallographic Structure, Intermolecular Packing Energetics, Crystal Morphology and Surface Chemistry of Salmeterol Xinafoate (Form I).[Pubmed:27894968]

J Pharm Sci. 2017 Mar;106(3):882-891.

Single crystals of Salmeterol xinafoate (form I), prepared from slow cooled supersaturated propan-2-ol solutions, crystallize in a triclinic P1 symmetry with 2 closely related independent salt pairs within the asymmetric unit, with an approximately double-unit cell volume compared with the previously published crystal structure. Synthonic analysis of the bulk intermolecular packing confirms the similarity in packing energetics between the 2 salt pairs. The strongest synthons, as expected, are dominated by coulombic interactions. Morphologic prediction reveals a plate-like morphology, dominated by the {001}, {010}, and {100} surfaces, consistent with experimentally grown crystals. Although surface chemistry of the slow-growing {001} face comprises large sterically hindering phenyl groups, although weaker coulombic interactions still prevail from the alcohol group present on the phenyl and hydroxymethyl groups. The surface chemistry of the faster growing {010} and {100} faces are dominated by the significantly stronger cation/anion interactions occurring between the carboxylate and protonated secondary ammonium ion groups. The importance of understanding the cohesive and adhesive nature of the crystal surfaces of an active pharmaceutical ingredient, with respect to their interaction with other active pharmaceutical ingredient crystals and how that may affect formulation design, is highlighted.

Step-down therapy in well-controlled asthmatic patients using salmeterol xinafoate/fluticasone propionate combination therapy.[Pubmed:27051309]

J Asthma Allergy. 2016 Mar 18;9:65-70.

PURPOSE: A combination therapy with inhaled corticosteroid (ICS) and a long-acting beta agonist (LABA) is the standard treatment for asthmatic patients, and step-down treatment is recommended once control has been achieved. However, little data exist that evaluate the long-term outcomes after step-down treatment. OBJECTIVE: To compare the long-term outcomes of step-down therapy with ICS/LABA or ICS alone for asthmatic patients who have achieved well-controlled asthma by the ICS (250 microg fluticasone)/LABA (50 microg salmeterol) combination (SFC, two puffs per day). PATIENTS AND METHODS: We randomized 40 well-controlled patients with asthma receiving SFC (250 microg) to two groups; one group of patients received step-down therapy with low-dose SFC (100 microg, two puffs daily) and another group of patients received step-down therapy with high-dose fluticasone propionate (FP) alone (500 microg, daily). The two groups were monitored over 12 months for changes in asthma control test scores, respiratory function (percent forced expiratory volume in 1 second, maximal expiratory flow rate at 50% of the vital capacity [%FEF50], and maximal expiratory flow rate at 25% of the vital capacity [%FEF25]), and the concentration of fractional exhaled nitric oxide. RESULTS: There was no significant difference in the dropout rate between the SFC and FP groups. Low-dose SFC maintained the stability of all parameters over 12 months, whereas the FP group exhibited a rapid 5% decrease in forced expiratory volume in 1 second within 2 months after discontinuation of salmeterol; furthermore, after 10 months, there was a gradual decrease in %FEF50 and %FEF25. CONCLUSION: This study suggests that a balanced step-down protocol, including both ICS and LABA, is essential in providing long-term stability to patients with mild-to-moderate well-controlled asthma.

Formulation of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery.[Pubmed:26220015]

Eur J Pharm Biopharm. 2015 Oct;96:132-42.

Co-administration of an inhaled corticosteroid and long acting beta agonist for chronic obstructive pulmonary disease has reduced mortality compared to either drug alone. This combination reduces exacerbations, hospitalization, emergency department visits and health care costs. A novel fixed-dose combination of the long acting beta-2 agonist Salmeterol xinafoate (SX) and the corticosteroid mometasone furoate (MF) were prepared in a composite particle formulation as brittle matrix powder (BMP) and investigated for suitability as an inhaled combination product. In this study, BMP fixed dose combinations of SX and MF with or without stabilizing excipients (lactose, mannitol, glycine and trehalose) were prepared and characterized with respect to their thermal properties, morphology, aerodynamic performance and physical stability. BMP combination formulations of SX and MF exhibited improved aerodynamic properties when delivered by dry powder inhalation as compared to the micronized blends of the same substances. Aerodynamic evaluation was carried out by next generation pharmaceutical impactor (NGI) with a marketed DPI device. Results demonstrated that co-deposition occurred when SX and MF were formulated together as composite particles in a BMP, while physical blends resulted in inconsistent deposition and dose uniformity. As a result of the bottom-up particle engineering approach, combination BMP formulations allow for dual API composite formulations to be dispersed as aerosolized particles. Aerosolized BMP combination formulations resulted in delivered dose uniformity and co-deposition of each API. Further, an excipient-free formulation, BMP SXMF, delivered approximately 50% of the loaded dose in the respirable range and demonstrated stability at ambient conditions for 6months. Single dose 24-h pharmacokinetic studies in rats demonstrated that lung tissue deposition and blood circulation (AUC0-24h) of two APIs were higher for the BMP combination group exhibiting a significantly higher lung concentration of drugs than for the crystalline physical blend. While high system drug levels are generally undesirable in lung targeted therapies, high blood levels in this rodent study could be indicative of increased pulmonary tissue exposure using BMP formulations.

Effects of salmeterol xinafoate and fluticasone propionate on immunological activation of human cultured mast cells.[Pubmed:17130681]

Allergol Int. 2006 Dec;55(4):387-93.

BACKGROUND: The clinical efficacy of combination therapy comprising a long acting beta(2)-agonist (LABA) and corticosteroid is widely recognized for the treatment of adult asthma. Here we examine the effect of Salmeterol xinafoate (SX) and fluticasone propionate (FP) alone and in combination on the immunological activation of human cultured mast cells (HCMC)in vitro. METHODS: HCMC were passively sensitized with IgE antibody and then activated by challenging with anti-IgE antibody. The effect of drugs on the activation of mast cells was examined by measuring the amount of released chemical mediators (histamine, leukotrienes (LT) and prostaglandin D(2) (PGD(2))) and granulocyte macrophage colony stimulating factor (GM-CSF). RESULTS: The release of each chemical mediator was inhibited by 10-9-10-8M SX but not by 10-10-10-7M FP. The production of GM-CSF was inhibited by a concentration of 10-8M in both drugs and the inhibition was augmented by combined treatment with 10-11M of each drug. CONCLUSIONS: The immunological release of chemical mediators (histamine, LT, PGD(2)) from HCMC was inhibited by SX but not by FP. SX and FP inhibited the production of GM-CSF by HCMC and both drug showed synergistic inhibition in the production of GM-CSF.

Use of a long-acting inhaled beta2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease.[Pubmed:11316640]

Am J Respir Crit Care Med. 2001 Apr;163(5):1087-92.

Chronic obstructive pulmonary disease (COPD) is a condition in which continuous bronchodilation may have clinical advantages. This study evaluated salmeterol, a beta-agonist bronchodilator with a duration of action substantially longer than that of short-acting beta-agonists, compared with ipratropium, an anticholinergic bronchodilator, and placebo in patients with COPD. Four hundred and five patients with COPD received either salmeterol 42 microg twice daily, ipratropium bromide 36 microg four times daily, or placebo for 12 wk in this randomized, double-blind, parallel-group study. Patients were stratified on the basis of bronchodilator response to albuterol (> 12% and > 200-ml improvement) and were randomized within each stratum. Bronchodilator response was measured over 12 h four times during the treatment period. Salmeterol provided similar maximal bronchodilatation to ipratropium but had a longer duration of action and a more constant bronchodilatory effect with no evidence of bronchodilator tolerance. Both active treatments were well tolerated. Salmeterol was an effective bronchodilator with a consistent effect over this 12-wk study in patients with COPD, including those "unresponsive" to albuterol. The long duration of action of salmeterol offers the advantage of twice daily dosing compared with the required four times a day dosing with ipratropium.

The long-acting beta2-agonist salmeterol xinafoate: effects on airway inflammation in asthma.[Pubmed:10515401]

Eur Respir J. 1999 Aug;14(2):275-82.

Salmeterol xinafoate is an inhaled long-acting beta2-adrenoceptor agonist recently introduced for the treatment of asthma. Both in vitro and animal studies suggest that it may have anti-inflammatory activities of benefit in this disease. To assess this directly, the effects of 6 weeks' treatment with salmeterol on indices of clinical activity, airway dysfunction and inflammation in subjects with stable atopic asthma were investigated. In a double blind study, asthmatic patients were randomized to 6 weeks' treatment with either salmeterol 50 microg twice daily (n=14) or placebo (n=12). They underwent bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsy immediately before starting treatment and again after 6 weeks. Treatment with salmeterol improved clinical indices of asthma activity, but there were no changes in BAL differential cell counts or mediator levels, and no change in T-cell numbers or activation status. In the biopsy specimens there were no changes in numbers of inflammatory cells, sub-basement membrane collagen deposition or mast cell degranulation. Regular treatment with salmeterol improves clinical indices of asthma but has no effect on the underlying inflammatory process. These findings strengthen guideline recommendations that long-acting beta2-agonists should not be prescribed as sole antiasthma medication.

Salmeterol xinafoate is a long-acting beta-2 adrenergic receptor (β2AR) agonist, with Ki of 1.5 nM for WT β2AR, and used for asthma treatment.

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