Salmeterol asthma treatment

The addition of a long-acting beta2 agonist (e.g. salmeterol) to treatment in patients with chronic asthma inadequately controlled by inhaled corticosteroids and as required short-acting beta2 agonists is beneficial. ... 

Sears MR, Taylor DR. (1993) BronchodUator treatment in asthma. Increase in deaths during salmeterol treatment unexplained. BMJ. 306, 1610-1611. 

Severe cases may, however, require an intensified bronchodilator treatment with systemic jk-mimetics or theophylline (systemic use only low therapeutic index monitoring of plasma levels needed). Salmeterol is a long-acting in-halative P2-mimetic (duration 12 h onset -20 min) that offers the advantage of a lower systemic exposure. It is used prophylactically at bedtime for nocturnal asthma. 

Dr David Graham from the FDA, speaking to the US senate in 2004, controversially raised concerns (refuted by the respective Pharmaceutical Companies) over the safety of the retinoid, isotretinoin (used in the treatment of cancer), the statin, rosuvastatin (used to lower cholesterol), a long-acting p2-receptor antagonist, salmeterol (used in asthma therapy), and a selective serotonin reuptake inhibitor, paroxetine (used as an antidepressant) (21). 

The P2 selective adrenergic agonists are most widely used drugs for the treatment of asthma. They are effective after oral and inhaled administration and have a longer duration of action. Albuterol (salbutamol), salmeterol, bitolterol, pir-buterol are available as aerosol pack in metered dose. 

Treatment with omalizumab, the monoclonal humanized anti-IgE antibody, is reserved for patients with chronic severe asthma inadequately controlled by high-dose inhaled corticosteroid plus long-acting B-agonist combination treatment (eg, fluticasone 500 meg plus salmeterol 50 meg inhaled twice daily). This treatment reduces lymphocytic, eosinophilic bronchial inflammation and effectively reduces the frequency and severity of exacerbations. It is reserved for patients with demonstrated IgE-mediated sensitivity (by positive skin test or radioallergosorbent test [RAST] to common allergens) and an IgE level within a range that can be reduced sufficiently by twice-weekly subcutaneous injections. 

Beclomethasone dipropionate 400 micrograms/day and salmeterol 50 micrograms bd were compared in asthmatic children treated for 12 months. Beclomethasone dipropionate treatment resulted in better overall asthma control. Over 12 months, linear growth was 3.96 cm/year in the children using beclomethasone dipropionate, compared with 5.40 cm/year in those who used salmeterol and 5.04 cm/year in a placebo group (SEDA-22,186). 

Seretide is a combination therapy consisting of fluticasone propionate and salmeterol. It is marketed by GSK for the treatment of asthma. Fluticasone is the chiral component and a steroid derivative. 

A Salmeterol, also a p2 agonist, has a slow onset of action and is not used in acute asthmatic attacks. B, E Cromolyn and nedocromil are used prophylacticlly, but are not effective in acute asthma. C Beclomethasone is an anti-inflamatory agent indicated for moderate to severe asthma. Inhaled beclomethasone reduces airway inflammation but its actions are not immediate the drug is administered chronically, but it is not effective in the treatment of an acute asthmatic attack. 

The reaction of epoxide rings with nucleophiles is important for the synthesis of many biologically active compounds, including albuterol and salmeterol, two bronchodilators used in the treatment of asthma (Figure 9.10). 

Drotar DE, Davis EE, Cockcroft DW. Tolerance to the bronchoprotective effect of salmeterol 12 horns after start-mg twice daily treatment. Ann Allergy Asthma Immunol 1998 80(l) 31-4. 

In a double-blind, multicenter trial in primary care, 911 patients with asthma, who were already receiving maintenance anti-inflammatory therapy, were randomized to treatment with salmeterol (50 micrograms bd) or placebo for six months (6). As expected, the patients treated with salmeterol had higher mean peak expiratory flows, used less rescue salbutamol, and had less disturbed sleep than the patients treated with placebo. The most important result from this study was that the number of severe exacerbations was the same in both groups in other words, salmeterol did not increase the frequency of severe exacerbations. 

Previous studies over periods of up to 8 weeks have established that the bronchoprotective effect of salmeterol abates with regular use, even after only 1 week of regular treatment. The effects of longer-term use of salmeterol on airway hyper-responsiveness have been examined in a randomized, double-blind, placebo-controlled trial in 408 patients with mild asthma (14). These patients were not using inhaled corticosteroids and took salmeterol (42 micrograms bd) or placebo for 24 weeks. Methachohne challenges were performed at 4, 12, and 24 weeks. At 4 weeks... 

There was also an arm treated with inhaled fluticasone alone. Outcome variables were peak flow and asthma symptoms. Both combination and concurrent therapy with fluticasone plus salmeterol resulted in significantly better symptom control and higher peak flows than fluticasone alone. There were no significant differences in the effects of fluticasone plus salmeterol delivered in a combination inhaler versus separate inhalers. Drug-related adverse effects were similar in all three treatment groups most were asthma-related, but hoarseness, dysphonia, and throat irritation were the commonest adverse effects attributed to therapy (1-4%). 

The effects of salmeterol 50 micrograms plus fluticasone 250 micrograms delivered via a combination inhaler and via separate inhalers have been compared in 371 asthmatic patients (18). There were equivalent improvements in peak flows and asthma sjmptoms. Candidiasis, dysphonia, and throat irritation were the commonest adverse effects attributed to treatment and occurred equally in the two groups (35%). Palpitation and tremor, which may have been related to salmeterol, occurred in 2% (for each symptom) of the combination group and in 1% and under 1% of the separate inhaler group. In both of these studies compliance was measured by dose counters on the inhalers and was equivalent in the two groups. 

Experimental studies continue to show that regular treatment with either formoterol or salmeterol in patients with asthma can produce subsensitivity to the bronchodilator effects of salbutamol (19,20). This bronchodilator subsensitivity can be partly reversed by a bolus dose of inhaled or systemic corticosteroids. The clinical relevance of these experimental findings is unclear. 

Taylor DR, Town GI, Herbison GP, Boothman-BurreU D, Flannery EM, Hancox B, Harre E, Laubscher K, Linscott V, Ramsay CM, Richards G, Cowan J, Holbrook N, McLachlan C, Rigby S. Asthma control during long-term treatment with regular inhaled salbutamol and salmeterol. Thorax 1998 53(9) 744-52. 

Aubier M, Pieters WR, Schlosser NJ, Steinmetz KO. Salmeterol/fluticasone propionate (50/500 microg) in combination in a Diskus inhaler (Seretide) is effective and safe in the treatment of steroid-dependent asthma. Respir Med 1999 93(12) 876-84. 

Fig. 8. Asthma exacerbations by ADRB2 genotype. Total asthma exacerbation in patients who had different genotype and one different (F-agonist treatment of either placebo (white), albuterol (blue), or salmeterol (black).

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