Evidence based review on levosalbutamol
http://www.100md.com
《美国医学杂志》
Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Salbutamol, the most commonly used bronchodilator, is a chiral drug with R (levosalbutamol) and S - isomers (also known as enantiomer). The commonly used formulation is a racemic mixture that contains equal amounts of both R and S isomers. Levosalbutamol is the therapeutically active isomer and has all the β 2 agonist activity. Until recently S- salbutamol was considered inert filler in the racemic mixture but animal as well as human studies have shown that S-salbutamol is not inert rather it may have some deleterious effects. Enantioselective metabolism of salbutamol leads to higher and sustained plasma levels of S-salbutamol with repeated dosing. There has been concern that chronic use of racemic salbutamol may lead to loss of effectiveness and clinical deterioration. Formulation of salbutamol containing only R- isomer (levosalbutamol) has been available in international market since last few years. Clinical trials in acute as well as chronic asthma in adults as well as children have shown that it has therapeutic advantage over racemic salbutamol and also is more cost effective. But, large multicenter trials are needed to prove its therapeutic superiority and cost-effectiveness in long term.
Keywords: Salbutamol; Levosalbutamol or levalbuterol; Asthma
Asthma is a wide spread chronic disease of childhood causing a lot of economic burden and use of health care services. β 2 agonist drugs are the most commonly used bronchodilators used in the treatment of asthma to relive bronchospasm. Salbutamol was approved in 1982 and since then with its potent bronchodilator activity and rapid onset of action it has remained the drug of choice for treatment of acute bronchospasm associated with asthma.
Chiral chemistry and β 2 agonist drugs: Synthetic β 2 agonist bronchodilators including salbutamol are developed based on the structure of the epinephrine and thus are supposed to mimic their bronchodilating action. However endogenous epinephrine produced in our body is a pure single isomer R- epinephrine whereas most of the β 2 agonist drugs including salbutamol are racemic drugs containing mixture of 50%-50% of 'R' (Levo) and 'S' (Dextro) optical isomers (also known as enantiomer). Only R-isomers fit to three-dimensional conformation of β 2 adrenoceptor proteins .[1]
Mechanism of action: Levosalbutamol (LEV) has approximately 2 fold greater affinity than racemic salbutamol (RAC) for the β 2 adrenergic receptor and approximately 100 fold greater binding affinity than S-salbutamol.[1],[2] LEV elevate intracellular concentration of 3'5'-cyclic AMP (cAMP) by activating adenyl cyclase. In the airways, increased concentration of cAMP relaxes bronchial smooth muscle by reducing intracellular calcium and prevents contraction of hyperresponsive airways. Increased concentration of cAMP also inhibits the release of inflammatory mediators from mast cells and eosinophils.[2],[3] Thus, by interacting with b 2 adrenoceptors LEV has bronchodilator, bronchoprotective and anti-edematous properties and inhibits activation of mast cell and eosinophils.
Concern regarding use of racemic salbutamol
S-Salbutamol does not activate β 2 adrenoceptors and do not have any clinically meaningful ability to relax airway smooth muscle and also does not modify activation of b 2 adrenoceptors by LEV so that for many years it was thought to be biologically inert. Technology to separate stereoisomers became available only since the last decade and thus the biologic activities of the salbutamol stereoisomers have been studied. Recently, it has been established that regular and excessive use of RAC induces paradoxical reactions in some subjects with asthma.[4] This has led to development of safer and therapeutically active agents of the available β 2 agonists. Consequently, "Levosalbutamol" was approved by FDA (Food and Drug Administration) in 1999 as a purified single-isomer for clinical use in asthma patients.
S-Salbutamol causes increased airway hyper responsiveness: Bronchoconstriction leading to airway obstruction and development of airway hyperresponsivenes are major hallmarks of asthma and a number of studies have suggested that chronic dosing with RAC for many months may results in increased bronchial hyper-responsiveness in some if not all asthmatics.[4],[5] The exact mechanism underlying this effect is unknown but it appears to be the class effect of β 2-agonists since it also occurs with terbutaline, fenoterol and the long acting β 2-agonist salmeterol.[6]
Animal studies have suggested that bronchial hyperresponsivenes can occur with 'S' isomer but not with 'R' isomer (LEV) or (R, S) - salbutamol (RAC). In bovine trachea S-salbutamol increased and LEV decreased intracellular calcium ions, consistent with what would occur with bronchoconstriction or bronchodilation, respectively. In the animal model the S-salbutamol induced bronchial hyperresponsivenes is not blocked by pretreatment with propranolol but is prevented by vagal nerve resection suggesting that " S-salbutamol causes bronchial hyperresponsivenes by a cholinergic dependent b 2 adrenergic independent mechanism" .[7],[8] This is further suggested when S-salbutamol or LEV is exposed to isolated human bronchus.[9] S-salbutamol enhances and LEV inhibits the contractile response of histamine and leucotriene C4.[10] These pharmacologic actions, if translated clinically, suggest that in the absence of LEV induced smooth muscle relaxation, S-salbutamol has the potential to induce bronchoconstriction in asthmatic patients. But human studies of acute dosing of S- salbutamol, LEV, and RAC and the determination of bronchial hyper responsiveness using methacholine show no consistent convincing evidence that single inhalation dose of S-salbutamol increases bronchial hyperresponsivenes.[11], [12]
S-Salbutamol may contribute to airway obstruction : S-Salbutamol may promote airway obstruction by increasing mucus secretion by airway epithelial cells and interfering with mucociliary clearance.[13] In animal models it has been shown to increase permeability of lung microvasculature resulting in higher number of immune cells in lung tissue by enhancing diapedesis.[14] Airway mucus plugging and increased number neutrophils and cytotoxic T cells in the lung have been associated with fatal exacerbation in asthma patients.[15]
S-Salbutamol has proinflammatory properties : Airway inflammation is important feature of asthma and S - salbutamol has been shown to promote the synthesis and /or release of numerous inflammatory mediators from eosinophils, mast cells, T-lymphocytes and airway epithelial cells. It also induces morphological changes in neutrophils and granulocytes that are associated with recruitment of activation of these cells.[16],[17],[18],[19] It is important to note that effects of S-salbutamol on inflammatory cells and mediators are generally more pronounced in activated versus resting cells, suggesting that agent might be specially detrimental in individuals with asthma who have exaggerated immune response or in the presence of allergen.[18]
The question that remains to be further defined is to what extent all these effects can contribute to bronchial inflammation in vivo.
Pharmacokinetics of salbutamol
Salbutamol is metabolized in human tissues by sulfation mainly in liver, and inactive metabolites produced are rapidly excreted in urine. Rates of metabolism for two isomers are different; LEV is metabolized about 8 times faster than S-salbutamol, leading to a longer half-life and increased accumulation of S- salbutamol in tissues.[20] Accordingly, markedly elevated plasma levels of S- isomer are seen after repeated oral or inhaled dosing with RAC and with time, RAC becomes predominantly S-salbutamol secondary to stereoselective metabolism.[21],[22] Previous studies have demonstrated that S-salbutamol does not appear to have an impact on the pharmacokinetic profile of LEV and administration of RAC results in high and persistent levels of S- salbutamol only.[23]
It is unknown, whether this transformation to predominantly S-salbutamol over time might be the cause for a lot of the paradoxical bronchospasm seen with salbutamol and other racemic β 2-agonist drugs present in the market currently. The alternative to this combination racemic drug is the use of the pure active enantiomer of salbutamol; only if clinical benefits of LEV could be proved.
Clinical studies comparing racemic salbutamol versus levosalbutamol
Clinical studies addressing the activity of LEV, which formed the basis for the US FDA's approval of the product, were designed to investigate its safety and efficacy compared with placebo and included RAC as an active control. Now many studies have been published [Table - 1] and [Table - 2] including pediatric patients hence, it is important that physicians caring patients with asthma are aware of recent data regarding RAC and the therapeutic alternative LEV.
Safety and Efficacy
In long term management of asthma, the Nelson study [Table - 1] was the first major study, which compared LEV with RAC and placebo and evaluated the safety and efficacy of LEV in patients 12 years or above with moderate to severe asthma.[24] In pediatric age group, the safety and efficacy of LEV was first studied by Gawchik et al in 43 children aged 3-11 years.[25] This study was followed by a large trial by Milgrom et al (n=338) among the children of the same age with mild-moderate persistent asthma.[26] In the later study, 0.31 mg LEV produced bronchodilation equal to that associated with RAC 2.5 mg in children which is the half the dose of LEV required to produce the same bronchodilation in adults (LEV 0.63 mg). Gawchik et al also found that LEV 0.31 mg resulted in mean peak percent change in FEV 1 (Forced expiratory volume in 1 second) and area under curve greater than or equal to RAC 2.5 mg. These results suggest that 0.31 mg LEV should be the starting dose in children 4-11 years as compared to adults where 0.63 mg is the starting dose and produce same effect. Safety and efficacy of LEV has been proved in children aged 2-5 years also by Skoner et al recently and it has also been used in infants as young as few months of age.[27] Edell et al (Unpublished) treated reactive airway disease in nine infants aged 6-9 months with levosalbutamol 0.63 mg. Results were clinically comparable or better than those obtained with racemic salbutamol 2.5 mg.
LEV/RAC potency ratios for local and systemic effects were similar in a small dose ranging study by Lotvall suggesting a comparable therapeutic ratio in asthmatic patients.[28] The investigator confirmed that all bronchodilation was achieved by LEV, whether delivered as an isomer or as a mixture (RAC) and did not observe any effect on airway function from S- salbutamol. But, this study has been criticized because this cumulative dose model confounds effects of time and dosing and the results projected seemed to be author's conclusion and it is hard to come up with alternative conclusions.
LEV has also been studied in patients with acute asthma in adults as well as in children [Table - 2] and is found to be safe and effective at least equally if not more than RAC in the management of acute asthma.[29],[30],[31],[32],[33],[34] J C Carl found that substituting LEV for RAC in the emergency department (ED) management of acute asthma in children aged 1-18 years significantly reduced the number of hospitalizations.[30] Ralston et al did not find any advantage of using LEV over RAC but, there are several shortcomings in the conclusion drawn by authors.[31] First, the efficacy of LEV 1.25 mg was compared with RAC 5 mg + Ipratropium Bromide (IB) 0.25 mg rather than RAC alone. Second, instead of using FEV 1 , PEF was used as a measure of improvement in lung function which is not as reliable as FEV 1 for the purpose. Third, the important observations like significantly less tachycardia and lesser use of oral steroids associated with LEV were not considered in drawing the conclusion, which again highlights the clinical benefit of LEV over RAC.
Haider compared LEV with RAC in adults for the treatment of acute asthma and found that LEV was clinically superior bronchodilator, was associated with decreased β 2 mediated side effects, improved clinical outcome, reduced hospital length of stay (LOS) and ultimately cost efficient asthma management.[32]
Overall, these as well as other studies have suggested that LEV has better side effect profile and comparative efficacy of LEV and RAC is as follows: LEV 1.25mg > LEV 0.63mg = RAC 2.5 mg, and children may have even better bronchodilator response (i.e. LEV 0.31 mg=RAC 2.5 mg).
Cost effectiveness
The literature directly comparing LEV and RAC in terms of cost effectiveness is limited especially in pediatric age group. In a retrospective chart review of the adult patients hospitalized with asthma and COPD, Truitt looked at salbutamol use during the two six month periods, during the first time period only RAC was used while in second time period, the hospital had switched over to LEV for nebulization.[33] After controlling for the diagnosis, baseline FEV1, and ipratropium use patients treated with LEV had reduced hospital LOS (almost one day), decreased likelihood of readmission and thus total cost savings. The mean total cost of nebulized therapy was significantly greater for patients receiving RAC than for those receiving LEV. JC Carl also found that substituting LEV for RAC in the ED in acute asthma significantly reduced the number of hospitalization (9%) but hospital LOS was not significantly shorter in LEV group.[30] Nowalk RM also found that among patients not on steroids, fewer LEV than RAC treated patients required admission (3.8% vs. 9.3%, P =.03).[34]
RAC is marketed by several pharmaceutical companies in India but only Cipla is marketing LEV to best of our knowledge. The costs of different doses forms of RAC marketed by various companies are comparable and almost equal. The maximum retail prices of various formulations of LEV are about 10% costlier than equimolar doses of RAC marketed by Cipla. But, LEV may prove to be more cost effective if the cost effectiveness reported in previous studies can be replicated in other large studies. The cost effectiveness of LEV is claimed to be due to several reasons like fewer nebulizer treatments, less need for concomitant inhaled medication, decreased LOS and decrease in hospital readmissions.
Patient satisfaction and quality of life
A 20-minute telephone survey evaluating the treatment satisfaction by caregivers of children with asthma who had used either LEV or RAC, has shown that significantly more caregivers administering LEV (92%) were "extremely" or "very satisfied" with therapy versus those who currently administered RAC (51%; p = 0.001).[35] Although, the study had some limitations (e.g., open-label, non-placebo-controlled and nonrandomized design, and caregiver recall bias), the results consistently favored LEV. The efficacy, dosing flexibility, and improved side effect profile of LEV were the sources of greatest satisfaction for parents/caregivers in the LEV. Skoner also noticed significant improvement in Pediatric Asthma Caregiver's Quality of Life Questionnaire measurements in children aged 2-5 years.[27]
In conclusion, available published studies indicate that levosalbutamol has better side effect profile and more efficacious than racemic salbutamol in the management of acute as well as chronic asthma. It may be more cost effective also. But, most of the published studies were supported by pharmaceutical companies involved in production or marketing of the levosalbutamol, hence, further large multicenter trials and meta-analysis of the available data are needed to prove its therapeutic superiority and cost-effectiveness in long term.
Funding: None
Conflicts of interests: None
Contribution: MKG has conceptualized and drafted the article and MS has revised it critically.β
References
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2.Penn RB, Friele T, McCullough JR, Aberg G, BenovieJL. Comparision of R-, S-, RS-albuterol, interaction with human β 2 adrenergic receptors . Clin Rev Allergy Immunol 1996; 14 : 37-45.
3.Canning B. Pharmacological properties of S -albuterol in human airway smooth muscle preparations. Am J Resp Crit Care Med 2002; 165 : A770.
4.Van Essen-Zandvliet EE, Hughes MD et al. Effects of 22 months of treatment with inhaled salbutamol lung function, airway responsiveness, and symptom in children with asthma. Am Rev Resp Dis 1992; 146: 547-554.
5.Waheda I, Wong CS, Wisniewski Afz et al. Asthma control during and after cessation of regular β 2 agonist treatment. Am Rev Resp Dis 1993; 148 : 707-712.
6.Taylor DR, Sears MR. Bronchodilators and bronchial hyperresponsiveness. Thorax 1994; 49(2) : 190-191.
7.Mazzoni L, Naef R, Chapman ID, Morley J. Hyper-responsiveness of the airways to histamine following exposure of guinea pigs to racemic mixtures and distomers of β 2 -selective sympathomimetics. Pulm Pharmacol 1994; 7 : 367-376.
8.Keir S, Page C, Spina D. Bronchial hyper-responsiveness induced by chronic treatment with albuterol: role of sensory nerves. J Allergy Clin Immunol 2002; 110: 388 - 394.
9.Templeton AGB, Chapman ID, Chilvers E, Morley J, Handley DA. Effects of (S)-albuterol on isolated human bronchus. Pulm Pharmacol 1998; 11 : 1-6.
10.Mazzoni L, Naef R, Chapman ID, Morley J. Hyperresponsiveness of the airways to histamine following exposure of guinea pigs to racemic mixtures and distomers of β 2 -selective sympathomimetics. Pulm Pharmacol 1994; 7 : 367-376.
11.Cockcroft DW, Swystun VA. Effect of single doses of S-salbutamol, R-salbutamol, racemic salbutamol, and placebo on the airway response to methacholine. Thorax 1997; 52 : 845-848.
12.Ramsay CM, Cowan J, Flannery E, McLachlan C, Taylor DR. Bronchoprotective and bronchodilator effects of single doses of (S)-salbutamol, (R)-salbutamol and racemic salbutamol in patients with bronchial asthma. Eur J Clin Pharmacol 1999; 55 : 353-359.
13.Chang MM, Zhao YH, Chen Y et al. S-albuterol but not other b2 agonist isomers, has stimulatory effects on mucin secretion and changes in gene expression on airway epithelium. Am J Resp Crit Care Med 2001; 161:A 144.
14.Perterson BT, Miller EJ, Effect of enatiomers of albuterol on lung epithelial permeability. Am J Resp Crit Care Med 2000; 161: A 416.
15.O'Sullivan S, Cormican L, Faul JL, Ichinohe S, Johnston SL et al. Activated, cytotoxic CD8 + T lymphocytes contribute to the pathology of asthma death. Am J Resp Crit Care Med 2001; 164 : 560-564.
16.Volcheck GW, Gleich GJ, Kita H. Pro-and anti-inflammatory effects of b2 adrenergic agonists on eosinophil response to IL-5. J Allergy Clin Immunolo 1998; 111 : S35.
17.Cho SH, Haartleroad JY, Oh CK. S-albuterol increases the production of histamine and IL-4 in mast cells. Int Arch Allergy Imunolo 2001; 124 : 478-484.
18.Friere M, Pergolizzi R, Millon C, Dominguez PJ. Cytokine, chemokine, and nitric oxide release in stimulated small airway epithelial cells treated with b2 agonist enantiomers of salbutamol. J Allergy Clin Immunolo 2000; 105 : S 292-293.
19.Kwong CC, Chung QN, Choi SS et al. Effects of isomers of albuterol, R-albuterol, and S- albuterol, on human granulocytic function. J Invest Med 2002; 50: 72 A.
20.Walle T, Walle UK, Thornburg KR, Schey KL. Stereoselective sulfation of albuterol in humans. Drug Meabo Dispos 1993; 21 : 76-80.
21.Boulton DW, Fawcett JP. Enantioselective disposition of salbutamol in man following oral and inhaled administration. J Clin Pharmocol 1996; 41: 35-40.
22.Schmekel B, Rydberg I, Norlandar B, Sjosward KN. Stereoselective pharmacokinetics of S-salbutamol after administration of the racemate in healthy volunteers. Eur Respir J 1999; 13 : 1230-1235.
23.Maier G, Henry A, Baumbgartner R et al. The effects of (S)-albuterol, is not through the alteration of the pharmacokinetics of (R)-albuterol: a population PK analysis. J Allergy Clin Immunol 2002; 109 : S 237-239.
24.Nelson HS, Bensch G, Pleskow WW, DiSantostefano R, DeGraw S, Reasner DS, Rollins TE, Rubin PD. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. J Allergy Clin Immunol 1998; 102 : 943-952.
25.Gawchik SM, Saccar CL, Noonan M, Reasner DS, DeGraw SS. The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients. J Allergy Clin Immunol 1999; 103 (4) : 615-621.
26.Milgrom H, Skoner DP, Bensch G, Kim KT, Claus R, Baumgartner RA for the Levalbuterol Pediatric Study Group. Low- dose levalbuterol in children with asthma: safety and efficacy in comparison with placebo and racemic albuterol. J Allergy Clin Immunol 2001; 108 : 938-945.
27.Skoner DP, Greos LS, Kim KT, Roach JM, Parsey M, Baumgartner RA. Evaluation of the safety and efficacy of levalbuterol in 2-5-year-old patients with asthma. Pediatr Pulmonol 2005; 40 : 477-486.
28.Lotvall J, Palmqvist M, Arvidsson P, Maloney A, Ventresca GP, Ward J. The therapeutic ratio of R-albuterol is comparable with that of RS-albuterol in asthmatic patients. J Allergy Clin Immunol 2001; 108 : 726-731.
29.Handley DA, Tinkelman D, Noonan M, Rollins TE, Snider ME, Caron J. Dose-response evaluation of levalbuterol versus racemic albuterol in patients with asthma. J Asthma 2000; 37 : 319-327.
30.Carl JC, Myers TR, Kirchner HL, Kercsmar CM. Comparison of racemic albuterol and levalbuterol for treatment of acute asthma. J Pediatr 2003; 143 : 731-736.
31.Ralston ME, Euwema MS, Knecht KR, Ziolkowski TJ, Coakley TA, Cline SM. Comparison of levalbuterol and racemic albuterol combined with ipratropium bromide in acute pediatric asthma: a randomized controlled trial. J Emerg Med 2005; 29 : 29-35.
32.Haider D. Levalbuterol affords superior health and cost benefit over racemic albuterol in the emergency department. Resp Care 2001; 46 : 1081.
33.Truitt T, Witko J, Halpern M. Levalbuterol compared to racemic albuterol : efficacy and outcomes in patients hospitalized with COPD or asthma. Chest 2003; 123 : 128-135.
34.Nowak RM, Emerman CL, Schaefer K, Disantostefano RL, Vaickus L, Roach JM. Levalbuterol compared with racemic albuterol in the treatment of acute asthma: results of a pilot study. Am J Emerg Med 2004; 22 : 29-36.
35.Berger We, Ames DE, Harrison D. A patient satisfaction survey comparing Levalbuterol with racemic salbutamol in children. Allergy Asthma Proc 2004; 25 : 437-444.(Gupta Mukesh Kumar, Singh Meenu)
Salbutamol, the most commonly used bronchodilator, is a chiral drug with R (levosalbutamol) and S - isomers (also known as enantiomer). The commonly used formulation is a racemic mixture that contains equal amounts of both R and S isomers. Levosalbutamol is the therapeutically active isomer and has all the β 2 agonist activity. Until recently S- salbutamol was considered inert filler in the racemic mixture but animal as well as human studies have shown that S-salbutamol is not inert rather it may have some deleterious effects. Enantioselective metabolism of salbutamol leads to higher and sustained plasma levels of S-salbutamol with repeated dosing. There has been concern that chronic use of racemic salbutamol may lead to loss of effectiveness and clinical deterioration. Formulation of salbutamol containing only R- isomer (levosalbutamol) has been available in international market since last few years. Clinical trials in acute as well as chronic asthma in adults as well as children have shown that it has therapeutic advantage over racemic salbutamol and also is more cost effective. But, large multicenter trials are needed to prove its therapeutic superiority and cost-effectiveness in long term.
Keywords: Salbutamol; Levosalbutamol or levalbuterol; Asthma
Asthma is a wide spread chronic disease of childhood causing a lot of economic burden and use of health care services. β 2 agonist drugs are the most commonly used bronchodilators used in the treatment of asthma to relive bronchospasm. Salbutamol was approved in 1982 and since then with its potent bronchodilator activity and rapid onset of action it has remained the drug of choice for treatment of acute bronchospasm associated with asthma.
Chiral chemistry and β 2 agonist drugs: Synthetic β 2 agonist bronchodilators including salbutamol are developed based on the structure of the epinephrine and thus are supposed to mimic their bronchodilating action. However endogenous epinephrine produced in our body is a pure single isomer R- epinephrine whereas most of the β 2 agonist drugs including salbutamol are racemic drugs containing mixture of 50%-50% of 'R' (Levo) and 'S' (Dextro) optical isomers (also known as enantiomer). Only R-isomers fit to three-dimensional conformation of β 2 adrenoceptor proteins .[1]
Mechanism of action: Levosalbutamol (LEV) has approximately 2 fold greater affinity than racemic salbutamol (RAC) for the β 2 adrenergic receptor and approximately 100 fold greater binding affinity than S-salbutamol.[1],[2] LEV elevate intracellular concentration of 3'5'-cyclic AMP (cAMP) by activating adenyl cyclase. In the airways, increased concentration of cAMP relaxes bronchial smooth muscle by reducing intracellular calcium and prevents contraction of hyperresponsive airways. Increased concentration of cAMP also inhibits the release of inflammatory mediators from mast cells and eosinophils.[2],[3] Thus, by interacting with b 2 adrenoceptors LEV has bronchodilator, bronchoprotective and anti-edematous properties and inhibits activation of mast cell and eosinophils.
Concern regarding use of racemic salbutamol
S-Salbutamol does not activate β 2 adrenoceptors and do not have any clinically meaningful ability to relax airway smooth muscle and also does not modify activation of b 2 adrenoceptors by LEV so that for many years it was thought to be biologically inert. Technology to separate stereoisomers became available only since the last decade and thus the biologic activities of the salbutamol stereoisomers have been studied. Recently, it has been established that regular and excessive use of RAC induces paradoxical reactions in some subjects with asthma.[4] This has led to development of safer and therapeutically active agents of the available β 2 agonists. Consequently, "Levosalbutamol" was approved by FDA (Food and Drug Administration) in 1999 as a purified single-isomer for clinical use in asthma patients.
S-Salbutamol causes increased airway hyper responsiveness: Bronchoconstriction leading to airway obstruction and development of airway hyperresponsivenes are major hallmarks of asthma and a number of studies have suggested that chronic dosing with RAC for many months may results in increased bronchial hyper-responsiveness in some if not all asthmatics.[4],[5] The exact mechanism underlying this effect is unknown but it appears to be the class effect of β 2-agonists since it also occurs with terbutaline, fenoterol and the long acting β 2-agonist salmeterol.[6]
Animal studies have suggested that bronchial hyperresponsivenes can occur with 'S' isomer but not with 'R' isomer (LEV) or (R, S) - salbutamol (RAC). In bovine trachea S-salbutamol increased and LEV decreased intracellular calcium ions, consistent with what would occur with bronchoconstriction or bronchodilation, respectively. In the animal model the S-salbutamol induced bronchial hyperresponsivenes is not blocked by pretreatment with propranolol but is prevented by vagal nerve resection suggesting that " S-salbutamol causes bronchial hyperresponsivenes by a cholinergic dependent b 2 adrenergic independent mechanism" .[7],[8] This is further suggested when S-salbutamol or LEV is exposed to isolated human bronchus.[9] S-salbutamol enhances and LEV inhibits the contractile response of histamine and leucotriene C4.[10] These pharmacologic actions, if translated clinically, suggest that in the absence of LEV induced smooth muscle relaxation, S-salbutamol has the potential to induce bronchoconstriction in asthmatic patients. But human studies of acute dosing of S- salbutamol, LEV, and RAC and the determination of bronchial hyper responsiveness using methacholine show no consistent convincing evidence that single inhalation dose of S-salbutamol increases bronchial hyperresponsivenes.[11], [12]
S-Salbutamol may contribute to airway obstruction : S-Salbutamol may promote airway obstruction by increasing mucus secretion by airway epithelial cells and interfering with mucociliary clearance.[13] In animal models it has been shown to increase permeability of lung microvasculature resulting in higher number of immune cells in lung tissue by enhancing diapedesis.[14] Airway mucus plugging and increased number neutrophils and cytotoxic T cells in the lung have been associated with fatal exacerbation in asthma patients.[15]
S-Salbutamol has proinflammatory properties : Airway inflammation is important feature of asthma and S - salbutamol has been shown to promote the synthesis and /or release of numerous inflammatory mediators from eosinophils, mast cells, T-lymphocytes and airway epithelial cells. It also induces morphological changes in neutrophils and granulocytes that are associated with recruitment of activation of these cells.[16],[17],[18],[19] It is important to note that effects of S-salbutamol on inflammatory cells and mediators are generally more pronounced in activated versus resting cells, suggesting that agent might be specially detrimental in individuals with asthma who have exaggerated immune response or in the presence of allergen.[18]
The question that remains to be further defined is to what extent all these effects can contribute to bronchial inflammation in vivo.
Pharmacokinetics of salbutamol
Salbutamol is metabolized in human tissues by sulfation mainly in liver, and inactive metabolites produced are rapidly excreted in urine. Rates of metabolism for two isomers are different; LEV is metabolized about 8 times faster than S-salbutamol, leading to a longer half-life and increased accumulation of S- salbutamol in tissues.[20] Accordingly, markedly elevated plasma levels of S- isomer are seen after repeated oral or inhaled dosing with RAC and with time, RAC becomes predominantly S-salbutamol secondary to stereoselective metabolism.[21],[22] Previous studies have demonstrated that S-salbutamol does not appear to have an impact on the pharmacokinetic profile of LEV and administration of RAC results in high and persistent levels of S- salbutamol only.[23]
It is unknown, whether this transformation to predominantly S-salbutamol over time might be the cause for a lot of the paradoxical bronchospasm seen with salbutamol and other racemic β 2-agonist drugs present in the market currently. The alternative to this combination racemic drug is the use of the pure active enantiomer of salbutamol; only if clinical benefits of LEV could be proved.
Clinical studies comparing racemic salbutamol versus levosalbutamol
Clinical studies addressing the activity of LEV, which formed the basis for the US FDA's approval of the product, were designed to investigate its safety and efficacy compared with placebo and included RAC as an active control. Now many studies have been published [Table - 1] and [Table - 2] including pediatric patients hence, it is important that physicians caring patients with asthma are aware of recent data regarding RAC and the therapeutic alternative LEV.
Safety and Efficacy
In long term management of asthma, the Nelson study [Table - 1] was the first major study, which compared LEV with RAC and placebo and evaluated the safety and efficacy of LEV in patients 12 years or above with moderate to severe asthma.[24] In pediatric age group, the safety and efficacy of LEV was first studied by Gawchik et al in 43 children aged 3-11 years.[25] This study was followed by a large trial by Milgrom et al (n=338) among the children of the same age with mild-moderate persistent asthma.[26] In the later study, 0.31 mg LEV produced bronchodilation equal to that associated with RAC 2.5 mg in children which is the half the dose of LEV required to produce the same bronchodilation in adults (LEV 0.63 mg). Gawchik et al also found that LEV 0.31 mg resulted in mean peak percent change in FEV 1 (Forced expiratory volume in 1 second) and area under curve greater than or equal to RAC 2.5 mg. These results suggest that 0.31 mg LEV should be the starting dose in children 4-11 years as compared to adults where 0.63 mg is the starting dose and produce same effect. Safety and efficacy of LEV has been proved in children aged 2-5 years also by Skoner et al recently and it has also been used in infants as young as few months of age.[27] Edell et al (Unpublished) treated reactive airway disease in nine infants aged 6-9 months with levosalbutamol 0.63 mg. Results were clinically comparable or better than those obtained with racemic salbutamol 2.5 mg.
LEV/RAC potency ratios for local and systemic effects were similar in a small dose ranging study by Lotvall suggesting a comparable therapeutic ratio in asthmatic patients.[28] The investigator confirmed that all bronchodilation was achieved by LEV, whether delivered as an isomer or as a mixture (RAC) and did not observe any effect on airway function from S- salbutamol. But, this study has been criticized because this cumulative dose model confounds effects of time and dosing and the results projected seemed to be author's conclusion and it is hard to come up with alternative conclusions.
LEV has also been studied in patients with acute asthma in adults as well as in children [Table - 2] and is found to be safe and effective at least equally if not more than RAC in the management of acute asthma.[29],[30],[31],[32],[33],[34] J C Carl found that substituting LEV for RAC in the emergency department (ED) management of acute asthma in children aged 1-18 years significantly reduced the number of hospitalizations.[30] Ralston et al did not find any advantage of using LEV over RAC but, there are several shortcomings in the conclusion drawn by authors.[31] First, the efficacy of LEV 1.25 mg was compared with RAC 5 mg + Ipratropium Bromide (IB) 0.25 mg rather than RAC alone. Second, instead of using FEV 1 , PEF was used as a measure of improvement in lung function which is not as reliable as FEV 1 for the purpose. Third, the important observations like significantly less tachycardia and lesser use of oral steroids associated with LEV were not considered in drawing the conclusion, which again highlights the clinical benefit of LEV over RAC.
Haider compared LEV with RAC in adults for the treatment of acute asthma and found that LEV was clinically superior bronchodilator, was associated with decreased β 2 mediated side effects, improved clinical outcome, reduced hospital length of stay (LOS) and ultimately cost efficient asthma management.[32]
Overall, these as well as other studies have suggested that LEV has better side effect profile and comparative efficacy of LEV and RAC is as follows: LEV 1.25mg > LEV 0.63mg = RAC 2.5 mg, and children may have even better bronchodilator response (i.e. LEV 0.31 mg=RAC 2.5 mg).
Cost effectiveness
The literature directly comparing LEV and RAC in terms of cost effectiveness is limited especially in pediatric age group. In a retrospective chart review of the adult patients hospitalized with asthma and COPD, Truitt looked at salbutamol use during the two six month periods, during the first time period only RAC was used while in second time period, the hospital had switched over to LEV for nebulization.[33] After controlling for the diagnosis, baseline FEV1, and ipratropium use patients treated with LEV had reduced hospital LOS (almost one day), decreased likelihood of readmission and thus total cost savings. The mean total cost of nebulized therapy was significantly greater for patients receiving RAC than for those receiving LEV. JC Carl also found that substituting LEV for RAC in the ED in acute asthma significantly reduced the number of hospitalization (9%) but hospital LOS was not significantly shorter in LEV group.[30] Nowalk RM also found that among patients not on steroids, fewer LEV than RAC treated patients required admission (3.8% vs. 9.3%, P =.03).[34]
RAC is marketed by several pharmaceutical companies in India but only Cipla is marketing LEV to best of our knowledge. The costs of different doses forms of RAC marketed by various companies are comparable and almost equal. The maximum retail prices of various formulations of LEV are about 10% costlier than equimolar doses of RAC marketed by Cipla. But, LEV may prove to be more cost effective if the cost effectiveness reported in previous studies can be replicated in other large studies. The cost effectiveness of LEV is claimed to be due to several reasons like fewer nebulizer treatments, less need for concomitant inhaled medication, decreased LOS and decrease in hospital readmissions.
Patient satisfaction and quality of life
A 20-minute telephone survey evaluating the treatment satisfaction by caregivers of children with asthma who had used either LEV or RAC, has shown that significantly more caregivers administering LEV (92%) were "extremely" or "very satisfied" with therapy versus those who currently administered RAC (51%; p = 0.001).[35] Although, the study had some limitations (e.g., open-label, non-placebo-controlled and nonrandomized design, and caregiver recall bias), the results consistently favored LEV. The efficacy, dosing flexibility, and improved side effect profile of LEV were the sources of greatest satisfaction for parents/caregivers in the LEV. Skoner also noticed significant improvement in Pediatric Asthma Caregiver's Quality of Life Questionnaire measurements in children aged 2-5 years.[27]
In conclusion, available published studies indicate that levosalbutamol has better side effect profile and more efficacious than racemic salbutamol in the management of acute as well as chronic asthma. It may be more cost effective also. But, most of the published studies were supported by pharmaceutical companies involved in production or marketing of the levosalbutamol, hence, further large multicenter trials and meta-analysis of the available data are needed to prove its therapeutic superiority and cost-effectiveness in long term.
Funding: None
Conflicts of interests: None
Contribution: MKG has conceptualized and drafted the article and MS has revised it critically.β
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