Maria Gabriella Matera

Salmeterol and formoterol in partially reversible severe chronic obstructive pulmonary disease: a dose-response study

When testing the response to beta 2-agonist drugs in severe chronic obstructive pulmonary disease (COPD), a dose-response assessment should be undertaken. This study compares the time course of inhaled salmeterol (25, 50 and 75 micrograms) and formoterol (12, 24 and 36 micrograms) at different doses in a group of 12 patients with partially reversible, but severe COPD (FEV1 of 12-32% of predicted values after beta 2-agonist drugs had been withheld for 24 h). All doses of salmeterol and formoterol induced a significant (P < 0.01) spirometric improvement over the 12-h monitoring period, when compared to the spirometric improvement after placebo, but while formoterol induced a dose-dependent increase of the FVC, FEV1 and FEF50, this was not the case for salmeterol. In fact, 75 micrograms salmeterol did not produce a further improvement of these parameters. Mean peak bronchodilation, expressed as the increase in FEV1 over baseline values, occurred 2 h after inhalation of the three doses of salmeterol, and 1 h after inhalation of the three doses of formoterol. A comparison of 50 micrograms salmeterol with 12 micrograms or 24 micrograms formoterol (clinically recommended doses), showed that improvement of FEV1 after salmeterol was statistically (P < 0.05) higher than that after the two doses of formoterol, although the mean peak bronchodilations were similar. This was because salmeterol has a longer duration of action than formoterol. These data demonstrate that salmeterol is equally effective as, but longer-acting than, formoterol at clinically recommended doses in patients suffering from COPD, with severe airway obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Novel long-acting bronchodilators for COPD and asthma

An important step in simplifying asthma and chronic obstructive pulmonary disease (COPD) management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Therefore, the incorporation of once‐daily dose administration is an important strategy to improve adherence and is a regimen preferred by most patients, which may also lead to enhancement of compliance, and may have advantages leading to improved overall clinical outcomes. Once‐daily β2‐agonists or ultra long‐acting β2‐agonists (LABAs) such as carmoterol, indacaterol, GSK‐159797, GSK‐597901, GSK‐159802, GSK‐642444 and GSK‐678007 are under development for the treatment of asthma and COPD. Also some new long‐acting antimuscarinic agents (LAMAs) such as aclidinium, LAS‐35201, GSK656398, GSK233705, NVA‐237 (glycopyrrolate) and OrM3 are under development. In any case, the current opinion is that it will be advantageous to develop inhalers containing combination of several classes of long‐acting bronchodilator drugs in an attempt to simplify treatment regimens as much as possible. Consequently, several options for once‐daily dual‐action ultra LABA+LAMA combination products are currently being evaluated. A different approach is to have a dimer molecule in which both pharmacologies are present (these molecules are known as M3 antagonist‐β2 agonist (MABA) bronchodilators). The advent of a successful MABA product will revolutionize the field and open the door for a new range of combination products.

β2‐adrenoceptor agonists: current and future direction

Despite the passionate debate over the use of β2‐adrenoceptor agonists in the treatment of airway disorders, these agents are still central in the symptomatic management of asthma and COPD. A variety of β2‐adrenoceptor agonists with long half‐lives, also called ultra long‐acting β2‐adrenoceptor agonists (ultra‐LABAs; indacaterol, olodaterol, vilanterol, carmoterol, LAS100977 and PF‐610355) are currently under development with the hopes of achieving once‐daily dosing. It is likely that the once‐daily dosing of a bronchodilator would be a significant convenience and probably a compliance‐enhancing advantage, leading to improved overall clinical outcomes. As combination therapy with an inhaled corticosteroid (ICS) and a LABA is important for treating patients suffering from asthma, and a combination with an inhaled long‐acting antimuscarinic agent (LAMA) is important for treating COPD patients whose conditions are not sufficiently controlled by monotherapy with a β2‐adrenoceptor agonist, some novel once‐daily combinations of LABAs and ICSs or LAMAs are under development.

Ultra long-acting beta 2-agonists in development for asthma and chronic obstructive pulmonary disease

After the discovery of formoterol and salmeterol, new candidates for long-acting β2-adrenoceptor agonists (LABAs) have emerged from various companies. In particular, once-daily β2-adrenoceptor agonists such as arformoterol, carmoterol, indacaterol, GSK-159797, GSK-597901, 159802, 642444 and 678007 are under development for the treatment of asthma and chronic obstructive pulmonary disease. The majority of these compounds are (R,R)-isomers in order to control desensitisation and accumulation. Several options for combination products are currently being evaluated in parallel with the development of these ultra LABAs. Once-daily dosing of an ultra LABA would be a significant convenience and probably a compliance-enhancing advantage leading to improved overall clinical outcomes in patients with asthma and chronic obstructive pulmonary disease. The only limits set for the development of a LABA with a new product profile are medical needs and marketing opportunities.

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

Tumor necrosis factor (TNF)-alpha, a pleiotropic cytokine that exerts a variety of effects, such as growth promotion, growth inhibition, angiogenesis, cytotoxicity, inflammation, and immunomodulation, has been implicated in several inflammatory conditions. It plays a significant role in many inflammatory diseases of lungs. Given that there is significant literature supporting the pathobiologic role of TNF-alpha in asthma, mainly in severe refractory asthma, and COPD, TNF-alpha inhibitors (infliximab, golimumab and etanercept) are now regarded as the potential new medications in asthma and COPD management. The studies reported in literature indicate that TNF-alpha inhibitors are effective in a relatively small subgroup of patients with severe asthma, possibly defined by an increased TNF axis, but they seem to be ineffective in COPD, although an observational study demonstrated that TNF-alpha inhibitors were associated with a reduction in the rate of COPD hospitalisation among patients with COPD receiving these agents to treat their rheumatoid arthritis. These findings require a smart approach because there is still good reason to target TNF-alpha, perhaps in a more carefully selected patient group. TNF-alpha treatment should, therefore, not be thrown out, or abandoned. Indeed, since severe asthma and COPD are heterogeneous diseases that have characteristics that occur with different phenotypes that remained poorly characterized and little known about the underlying pathobiology contributing to them, it is likely that definition of these phenotypes and choice of the right outcome measure will allow us to understand which kind of patients can benefit from TNF-alpha inhibitors.

5-HT modifiers as a potential treatment of asthma

Increased levels of free 5-HT have been shown to be present in the plasma of symptomatic asthmatic patients compared with levels in asymptomatic patients. In addition, free 5-HT has been shown to correlate positively with clinical status and negatively with pulmonary function. These findings suggest that 5-HT might play a role in the pathophysiology of acute asthma. Accordingly, modifiers of the 5-HT transmitter system such as compounds that affect the 5-HT transporter, prejunctional 5-HT receptors or postsynaptic 5-HT receptors might represent a novel treatment of asthma.

Inhaled beta2-adrenoceptor agonists: cardiovascular safety in patients with obstructive lung disease.

Although large surveys have documented the favourable safety profile of β2-adrenoceptor agonists (β2-agonists) and, above all, that of the long-acting agents, the presence in the literature of reports of adverse cardiovascular events in patients with obstructive airway disease must induce physicians to consider this eventuality. The coexistence of β1- and β2-adrenoceptors in the heart clearly indicates that β2-agonists do have some effect on the heart, even when they are highly selective. It should also be taken into account that the β2-agonists utilised in clinical practice have differing selectivities and potencies. β2-agonist use has, in effect, been associated with an increased risk of myocardial infarction, congestive heart failure, cardiac arrest and sudden cardiac death. Moreover, patients who have either asthma or chronic obstructive pulmonary disease may be at increased risk of cardiovascular complications because these diseases amplify the impact of these agents on the heart and, unfortunately, are a confounding factor when the impact of β2-agonists on the heart is evaluated. Whatever the case may be, this effect is of particular concern for those patients with underlying cardiac conditions. Therefore, β2-agonists must always be used with caution in patients with cardiopathies because these agents may precipitate the concomitant cardiac disease.Although large surveys have documented the favourable safety profile of beta(2)-adrenoceptor agonists (beta(2)-agonists) and, above all, that of the long-acting agents, the presence in the literature of reports of adverse cardiovascular events in patients with obstructive airway disease must induce physicians to consider this eventuality. The coexistence of beta(1)- and beta(2)-adrenoceptors in the heart clearly indicates that beta(2)-agonists do have some effect on the heart, even when they are highly selective. It should also be taken into account that the beta(2)-agonists utilised in clinical practice have differing selectivities and potencies. beta(2)-agonist use has, in effect, been associated with an increased risk of myocardial infarction, congestive heart failure, cardiac arrest and sudden cardiac death. Moreover, patients who have either asthma or chronic obstructive pulmonary disease may be at increased risk of cardiovascular complications because these diseases amplify the impact of these agents on the heart and, unfortunately, are a confounding factor when the impact of beta(2)-agonists on the heart is evaluated. Whatever the case may be, this effect is of particular concern for those patients with underlying cardiac conditions. Therefore, beta(2)-agonists must always be used with caution in patients with cardiopathies because these agents may precipitate the concomitant cardiac disease.

Characterization of adenosine receptors involved in adenosine‐induced bronchoconstriction in allergic rabbits

1 Recent work has suggested that adenosine may be involved in asthma via the activation of A1 receptors. However, the role of the recently cloned A3 receptor in airways is largely unknown. In the present study, we have investigated the role of the A3 receptor in adenosine‐induced bronchoconstriction in allergic rabbits. 2 Aerosol challenge of antigen (Ag) immunized rabbits with the adenosine precursor, adenosine 5′‐monophosphate (AMP), resulted in a dose‐dependent fall in dynamic compliance (Cdyn). The maximum fall in Cdyn in these rabbits was significantly greater than that in litter matched, sham immunized animals (P < 0.05). However, there was no significant difference in the maximum increase in airways resistance (RL) between Ag and sham immunized rabbits (P > 0.05). 3 Aerosol challenge of Ag immunized rabbits with cyclopentyl‐adenosine (CPA) (A1‐receptor agonist) elicited a dose‐dependent fall in Cdyn in Ag immunized rabbits and the maximum fall in Cdyn in these rabbits was significantly greater than that observed in sham immunized rabbits (P < 0.05). Similarly, CPA induced dose‐dependent increases in RL in Ag immunized rabbits whereas sham immunized rabbits failed to respond to CPA within the same dose range. The maximum increase in RL in Ag immunized rabbits was significantly greater than that of sham immunized rabbits (P < 0.05). 4 Aerosol challenge of either Ag or sham immunized rabbits with the A3 agonist aminophenylethy‐ladenosine (APNEA) did not elicit dose‐dependent changes in either RL or Cdyn. Moreover, there was no significant difference in the maximum response, measured by either parameter, between the two animal groups (P > 0.05). 5 These data provide further evidence for a role of the A1 receptor in the airways, but do not support a role for the A3 receptor in adenosine‐induced bronchoconstriction in the allergic rabbit.

Clinical pharmacokinetics of salmeterol

Salmeterol is an inhaled long-acting selective β2-adrenoceptor agonist that is commercially available as the xinafoate (1-hydroxy-2-naphthoic acid) salt of the racemic mixture of the two optical isomers, (R)- and (S)-, of salmeterol. It acts locally in the lung through action on β2 receptors.Limited data have been published on the pharmacokinetics of salmeterol. Moreover, there are no data on the extent to which inhaled salmeterol undergoes first-pass metabolism. This lack of information is most likely due to the very low plasma concentrations reached after inhalation of therapeutic doses of salmeterol and the problems in developing an analytical method that is sensitive enough to determine these concentrations.When salmeterol is inhaled, plasma concentrations of the drug often cannot be detected, even at 30 minutes after administration of therapeutic doses. Larger inhaled doses give approximately proportionally increased blood concentrations. Plasma salmeterol concentrations of 0.1 to 0.2 and 1 to 2 µg/L have been attained in healthy volunteers about 5 to 15 minutes after inhalation of a single dose of 50 and 400 µg, respectively. In patients who inhaled salmeterol 50µg twice daily for 10 months, a second peak concentration of 0.07 to 0.2 µg/L occurred 45 to 90 minutes after inhalation, probably because of the gastrointestinal absorption of the swallowed drug.Salmeterol xinafoate dissociates in solution to salmeterol and 1-hydroxy-2-naphthoic acid. These two compounds are then absorbed, distributed, metabolised and excreted independently. The xinafoate moiety has no apparent pharmacological activity, is highly protein bound (>99%), largely to albumin, and has a long elimination half-life of about 12 to 15 days in healthy individuals. For this reason, it accumulates in plasma during repeated administration, with steady-state concentrations reaching about 80 to 90 µg/L in patients treated with salmeterol 50µg twice daily for several months.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 α-hydroxysalmeterol, with subsequent elimination predominantly in the faeces. It has been demonstrated that 57.4% of administered radioactivity is recovered in the faeces and 23% in the urine; most is recovered between 24 and 72 hours after administration. Unchanged salmeterol accounts for <5% of the excreted dose in the urine.Since the therapeutic dose of salmeterol is very low, it is unlikely that any clinically relevant interactions will be observed as a consequence of the coadministration of salmeterol and other drugs, such as fluticasone Propionate, that are metabolised by CYP3A.All the available data clearly show that at the recommended doses of salmeterol, systemic concentrations are low or even undetectable. This is an important point, because it has been demonstrated that the systemic effects of salmeterol are more likely to occur with higher doses, which lead to approximately proportionally increased blood concentrations.

Inhaled β2-Adrenoceptor Agonists

Although large surveys have documented the favourable safety profile of β2-adrenoceptor agonists (β2-agonists) and, above all, that of the long-acting agents, the presence in the literature of reports of adverse cardiovascular events in patients with obstructive airway disease must induce physicians to consider this eventuality. The coexistence of β1- and β2-adrenoceptors in the heart clearly indicates that β2-agonists do have some effect on the heart, even when they are highly selective. It should also be taken into account that the β2-agonists utilised in clinical practice have differing selectivities and potencies. β2-agonist use has, in effect, been associated with an increased risk of myocardial infarction, congestive heart failure, cardiac arrest and sudden cardiac death. Moreover, patients who have either asthma or chronic obstructive pulmonary disease may be at increased risk of cardiovascular complications because these diseases amplify the impact of these agents on the heart and, unfortunately, are a confounding factor when the impact of β2-agonists on the heart is evaluated. Whatever the case may be, this effect is of particular concern for those patients with underlying cardiac conditions. Therefore, β2-agonists must always be used with caution in patients with cardiopathies because these agents may precipitate the concomitant cardiac disease.Although large surveys have documented the favourable safety profile of beta(2)-adrenoceptor agonists (beta(2)-agonists) and, above all, that of the long-acting agents, the presence in the literature of reports of adverse cardiovascular events in patients with obstructive airway disease must induce physicians to consider this eventuality. The coexistence of beta(1)- and beta(2)-adrenoceptors in the heart clearly indicates that beta(2)-agonists do have some effect on the heart, even when they are highly selective. It should also be taken into account that the beta(2)-agonists utilised in clinical practice have differing selectivities and potencies. beta(2)-agonist use has, in effect, been associated with an increased risk of myocardial infarction, congestive heart failure, cardiac arrest and sudden cardiac death. Moreover, patients who have either asthma or chronic obstructive pulmonary disease may be at increased risk of cardiovascular complications because these diseases amplify the impact of these agents on the heart and, unfortunately, are a confounding factor when the impact of beta(2)-agonists on the heart is evaluated. Whatever the case may be, this effect is of particular concern for those patients with underlying cardiac conditions. Therefore, beta(2)-agonists must always be used with caution in patients with cardiopathies because these agents may precipitate the concomitant cardiac disease.