Inhalation Devices for Long-Acting [Beta]^Sub 2^-Agonists: Efficiency and Ease of Use of Dry Powder Formoterol Inhalers for Use By Patients With Asthma and COPD

By Molimard, Mathieu Till, Denise; Stenglein, Stephan; Singh, Dilraj; Krummen, Markus

Key words: Aerolizer – Asthma – COPD – Dry-powder inhaler – Foradil – Formoterol ABSTRACT

Background: Since the long-acting beta^sub 2^-agonist bronchodilator, formoterol, first became available for the treatment of subjects with asthma or chronic obstructive pulmonary disease (COPD), generic forms of this agent have been launched in a variety of devices. It is timely to review the characteristics of the original dry powder delivery device, the single-dose Aerolizer*, its In vitro performance and its comparability with other inhaler devices that are now available for delivery of formoterol.

Scope: This review focuses on the performance of the formoterol Aerolizer inhaler in comparison with other inhalers. Publically available data (PubMed) on the device performance characteristics of the Aerolizer were reviewed and summarized, together with the results of comparative studies performed by the authors. Published studies (PubMed) on patient handling and inhaler technique that include the Aerolizer are described and studies comparing the clinical effect of formulerai in the Aerolizer with formoterol delivered via other devices were reviewed and are summarized.

Findings: The Aerolizer performs consistently in dosing efficiency across a range of inspiratory flow rates, suggesting its suitability for use by patients with differing inspiratory flow abilities. The single-dose, capsule-based nature of the device provides patients with obvious feedback on whether the drug has been taken successfully and the Aerolizer has been shown to be one of the more easily used devices in comparative patient handling studies. Studies comparing the clinical effect of formoterol delivered by different inhalation devices show that formoterol via Aerolizer has an equivalent therapeutic effect.

Conclusion: Judged on the basis of dosing efficiency, ease of use and clinical equivalence, formoterol Aerolizer remains a useful option in the management of patients with asthma or COPD.

Introduction

Inhalation pharmacotherapy is a key component in the treatment regimens of patients with asthma and/ or chronic obstructive pulmonary disease (COPD]. The three main categories of inhaler device currently available are nebulizers, pressurized metered-dose inhalers (pMDIs) and dry-powder inhalers (DPIs)1. Nebulizers deliver high doses of bronchodilator quickly and are generally used by patients experiencing acute airflow limitation2.

Pressurized metered-dose inhalers, available since the 1950s, are widely used in both asthma and COPD despite the difficulty in co- ordination that some patients experience with the device34. pMDIs require patients to co-ordinate actuation and inspiration of the dose, which may prove difficult for children, the elderly and patients with chronic conditions such as arthritis56. Although many pMDI treatments are now reformulated with non-chlorofluorocarbon (CFC) propellants such as hydrofluoroalkanes (HFAs)7, the newer HFA pMDIs may still inflict a ‘cold freon’ effect whereby the propellant hits the back of the throat and causes patients to cough or experience a reflex shortness of breath. HFAs also contribute to global warming8.

While breath-actuated pMDIs are now available, breath-actuated dry-powder inhalers are becoming an increasingly popular alternative1,9,10. These inhalation devices deliver either single- unit doses (e.g. Aerolizer[dagger], Rotahaler[double dagger], Spinhaler[section], Inhalator[double dagger][double dagger] or HandiHaler**), or multiple doses from a reservoir (e.g. Turbohaler/ Turbuhaler[double dagger], or Novolizer[double dagger][double dagger]), or blister pack (e.g. Diskhaler[double dagger], Accuhaler/ Diskus[double dagger]). DPIs, like some newer pMDIs, allow patients to monitor the amount of medication remaining1,9,11-13.

The formoterol Aerolizer is a single-dose DPI that delivers 12 [mu]g doses of formoterol, a long-acting beta^sub 2^agonist with a rapid onset of bronchodilatation14 indicated for use in asthma (in patients already receiving inhaled corticosteroids) and in COPD.

This review focuses on the formoterol Aerolizer inhaler in comparison with other inhalers, with respect to dosing efficiency, ease of use and clinical effect of the formoterol Aerolizer. Publically available data on the device performance characteristics of Aerolizer (PubMed search term ‘Aerolizer’ on 18 June 2007, no limits) were reviewed and summarized, together with the results of comparative studies performed by the authors and published in abstract form. For the review of comparative clinical efficacy, a PubMed search (terms formoterol AND Aerolizer, no limits; 18 June 2007) was conducted and studies comparing the clinical effect of formoterol in different devices were included in this review.

Formoterol Aerolizer: design and usage

The formoterol Aerolizer was first introduced in Europe, including the UK and Germany, in 1997: initially for the treatment of patients with asthma and, a few years later, for patients with COPD. The Aerolizer is a single-dose, capsule-based inhaler, with each capsule containing 12 [mu]g of micronized formoterol blended with lactose. To use the Aerolizer, the patient removes the protective case and twists the top of the device away from the mouthpiece, to reveal the capsule-loading/piercing chamber (Figure 1). The capsule is inserted and the mouthpiece is returned to its original position. When the patient depresses the two buttons on either side of the chamber, the capsule is punctured and, on inhalation, air travels through the channels above the capsule- loading chamber. This moves the capsule into the inhalation chamber where it rotates and releases the powder (Figure 1). After inhalation, the patient can open the device to see if the entire dose was inhaled. If so, the empty capsule is removed and the patient replaces the protective cap over the mouthpiece. The device has the advantages that patients know that the device is loaded with the appropriate dose; patients hear the capsule rotating in the inhalation chamber, which signals an adequate inspiratory effort to release the drug during inhalation; and when patients see the empty capsule they know they have taken the full dose.

Dosing efficiency

The main factors influencing the dosing efficiency of a DPI are the patient’s inspiratory flow rate, the device’s internal resistance, uniformity of the emitted dose and the respirable (fine particle) fraction of the dose. Particles > 5 [mu]g in diameter generally deposit in the oropharynx and are not thought to reach the lung15. The respirable fraction of a dose (particles < 5 [mu]m in diameter), therefore, represents the fraction of the dose that is likely to be delivered to the lung. Dosing efficiency is also critically influenced by whether a patient uses the inhaler correctly.

Figure 1. The formaterai Aerolizer: (a) photographic full view and (b) transverse view. When a subject inhales through the device, air travels through the channels above the capsule-loading chamber in the direction shown by the arrows in the transverse view. The air flow moves the capsule into the inhalation chamber where it rotates and releases the powder

Because DPIs are breath-actuated, low inspiratory flow rates can adversely affect drug delivery. In addition to reducing the dose emitted, a low inspiratory flow rate also prevents adequate dispersal of the drug powder. This lowers the respirable fraction of the emitted dose and consequently reduces deposition of particles into the lungs16. Inspiratory flow rate through an inhalation device depends on both the inspiratory effort of the individual patient and the internal resistance of the inhaler17. Internal resistance is the drop in pressure across the device that occurs as a patient inspires through it17 (e.g. the lower the resistance, the easier it is to inhale through the device)18,19. Internal resistance is also related to the respirable fraction, in that higher internal resistance is associated with a greater proportion of small respirable particles, which, provided the patient can generate the necessary inspiratory flow and applies the correct inhalation technique, results in better lung deposition10,19. Many patients using inhaled medications experience reduced inspiratory flow rates: patients with severe airway obstruction (i.e. acute asthma or COPD), children and the elderly1,19,20,22. As such, devices should have a low internal resistance so that these patients receive the most drug benefit available. An ideal DPI, therefore, would have a low internal resistance and yet deliver a high respirable fraction, even at low inspiratory flow rates9.

Device airflow resistance studies

The relationship between the airflow through a device and the patient’s inspiratory effort is known as specific airflow resistance (R^sub D^). In most devices, R^sub D^ ranges from 0.04 to 0.18 cmH^sub 2^0^sup 1/2^/L/min17,23,26. If the R^sub D^ is greater than 0.1 cmH^sub 2^0^sup 1/2^/L/min, patients may find that inhalation through the device is uncomfortable in terms of the need for a longer sustained inspiratory effort17. Reported R^sub D^ values are 0.07 cmH^sub 2^0^sup 1/2^/L/min for the Aerolizer, 0.13 cmH^sub 2^0^sup 1/2^/L/min for the Turbuhaler27 and 0.08 cmH^sub 2^0^sup 1/ 2^/L/min for the Novolizer28. Similar data have been reported in other studies23,29,30. The combination of lower R^sub D^ and a relatively higher inspiratory flow rate for a given inspiratory effort (Figure 2) is likely to allow patients with a wide range of airflow obstruction (e.g. including children and the elderly) to generate sufficient inspiratory flow rates through the Aerolizer for adequate drug delivery. Inspiratory flow rate is closely linked to the dose emitted from a DPI. In a study using a laboratory simulation of inspiration airflow, emitted doses were measured from the formoterol Aerolizer (100 L/min), the salmeterol Accuhaler (80 L/ min) and the terbutaline Turbuhaler (60 L/min]. Emitted doses were 85%, 93% and 76% of label claim, respectively. If the flow rate decreased by 50% (to a flow rate that might occur in a child or patient with COPD) the emitted dose from the Turbuhaler and Accuhaler reduced by 17% and 5%, respectively, whereas no decrease in dose was evident with the Aerolizer31. In a study evaluating the Diskus and Turbuhaler, 7% and 19%, respectively, of patients with severe COPD were unable to generate the inspiratory flow rates of > 60 L/min considered optimal for these devices5. In a study in adults (aged 12-74 years) and children (aged 7-11 years) with mild, moderate or severe asthma, > 90% of patients achieved an inspiratory flow rate of > 60 L/min through the Aerolizer device32.

Studies assessing respirable fraction as a function of airflow

An in vitro study was conducted to compare the respirable (fine particle) fraction of the aerosols generated by the formoterol Aerolizer, formoterol Turbuhaler and formoterol Novolizer at different airflow rates, using the Next Generation Impactor according to USP <601>, apparatus 533. The results showed that the Aerolizer exhibited more consistent respirable dose delivery characteristics at flow rates corresponding to low inspiratory efforts compared with the Turbuhaler and the Novolizer. The respirable fractions obtained with the Novolizer and the Turbuhaler as such were higher compared with the Aerolizer but were significantly influenced by the inspiratory effort and showed greater variability than the Aerolizer. The Turbuhaler showed a significantly (p < 0.05) greater decrease of the respirable fraction compared with the Aerolizer at flow rates lower than 60 L/min (Table 1), which are relevant from a clinical perspective for asthmatic patients34. The mass median aerodynamic diameter (MMAD) results obtained indicate that the delivered respirable fraction from the Aerolizer would, in general, be better distributed in the airways for optimum bronchodilator response35.

Figure 2. Device resistance and inspiratory flow rates of three inhaler devices for delivering long-acting beta^sub 2^agonists23,29,30. R^sub D^ = specific airflow resistance (the inherent resistance of the device); PIF = peak inspiratory flow. The different resistances of the various DPIs means that different inspiratory flows will be needed to create the pressure-drop necessary for optimal drug delivery

Table 1. In vitro performance (fine particle dose, delivered dose) of formaterol delivery devices: the Aerolizer, the Novolizer and the Turbuhaler33

The findings of this study were consistent with previous investigations comparing dose delivery performance of the Aerolizer and Turbuhaler27,36.

Dose uniformity

Maintaining dose consistency is important to maintaining disease control and can vary considerably between dry powder inhalers37. The United States Food and Drug Administration (FDA) draft guideline defines stringent requirements on delivered dose38. An in vitro evaluation according to USP <601> showed that the mean delivered dose from the Aerolizer ranged from 83% to 94% of label claim at patient-relevant flow rates of 30-90 L/min33. The mean delivered doses from the Novolizer and the Turbuhaler were found to be in a broader range of 87-124% and 74-96% of label claim, respectively, over a similar flow rate range. The variability of dose delivery as indicated by the relative standard deviations was higher in the case of the Novolizer and the Turbuhaler (Table 1). Another laboratory study compared the dose of formoterol delivered from the Aerolizer with that delivered from the Turbuhaler27. The results of this study indicated that the delivered dose from the Aerolizer was higher at all flow rates than that from the Turbuhaler, which delivered 16% less of the nominal dose than the Aerolizer at a flow rate of 60 L/ min.

A recent study compared in vitro the aerodynamic particle size distribution and emitted dose of formoterol delivered via the Aerolizer and a non-proprietary single-dose capsule inhaler (ratiopharm), using an 8stage Andersen Cascade Impactor set at a single flow of 60 L/min39. Of the two devices, the formoterol Aerolizer produced particles with a smaller mass median aerodynamic diameter (3.5 [mu]m vs. 4.1 [mu]m, p = 0.018) and a smaller measured particle diameter distribution (geometric standard deviation 2.2 vs. 2.5, p = 0.048]. The formoterol Aerolizer produced a 44% higher fine particle dose than the non-proprietary device (2.6 vs. 1.8 [mu]g p = 0.0001). Although the nonproprietary single-dose capsule inhaler produced a higher total emitted dose than that from the formoterol Aerolizer (11.2 vs. 10.0 [mu]g, p = 0.155, not significant), the respirable fraction (calculated relative to delivered dose) from the formoterol Aerolizer was 58% higher (25.7 vs. 16.3%, p = 2 x 10^sup -8^). Despite the ostensible similarity between the proprietary and non-proprietary devices, the Aerolizer produced the superior profile of formoterol drug delivery.

Ease of use, patient compliance and preference

If a device is easy to use and the inhaled medication delivers prompt bronchodilatation, patients are more likely to adhere to treatment10 and should benefit from better disease control40,41. Difficult-to-use devices are frequently used incorrectly, which can result in under-dosing and reduced efficacy41,42. This may lead to patient dissatisfaction and poor adherence to treatment regimens.

Table 2. Patients’ opinions of the ease of use of formaterol Aerolizer45

pMDIs are often difficult to use correctly, which leaves patients at high risk of receiving incomplete doses42,43. Giraud and Roche44 assessed inhaler technique and asthma control among approximately 4000 patients with asthma treated with inhaled corticosteroids delivered by pMDIs. They found not only that misuse was common, in 71 % of patients, but also that asthma stability (based on level of symptoms, exerciseinduced dyspnoea, beta^sub 2^-agonist use, emergency visits and perception of asthma control) was significantly worse among those who misused their pMDI, notably in those who were poor in their ability to co-ordinate when using the pMDI.

Results from a study of 1380 adult patients with moderate-to- severe asthma who were observed for their ease of use of the Aerolizer and adherence to treatment illustrate the association between these two variables. Approximately 91% of patients used the device correctly by the end of the study. This was mainly due to the fact that nearly 93% of patients found the Aerolizer very easy, or easy to use throughout the study (Table 2), which resulted in high treatment adherence (> 90%).

In another study, 3811 adult patients with COPD or asthma were observed for their ability to correctly use their usual inhaler; the devices assessed included the Aerolizer (formoterol) or the Turbuhaler (terbutaline, budesonide or budesonide/formoterol combination)6. In this study, fewer patients made critical device handling errors (errors affecting drug efficacy) with the Aerolizer than with the Turbuhaler. With the Turbuhaler, 32% (95% CI: 29, 35%) of 868 patients made critical errors, such as incorrect loading of the dose and blowing into the Turbuhaler, compared with 12% (95% CI: 10, 14%) of 769 patients using the Aerolizer. In addition, older patients made more critical errors than younger patients; this effect was more pronounced with the Turbuhaler (approximately 30% of patients aged 31-64 years, 40% of patients > 65 years) than with the Aerolizer (approximately 10% of patients 31-64 years, 15% of patients > 65 years). Similar results were observed in a survey of 984 patients with COPD whose inhalation technique using various devices (containing various drugs) was assessed against a previously established checklist. Critical errors were made by 12-15% of patients when using the Aerolizer, Autohaler or Diskus, compared with 37% and 38% of patients using the pMDI and Turbuhaler, respectively46. Other studies have shown similar results in both adults and children4749. A survey of inhalation technique among patients with asthma or COPD who were experienced users of various dry powder inhalers (Aerolizer, Turbuhaler and Diskus containing various drugs) found that a significantly lower percentage of patients using the Aerolizer failed to correctly perform essential steps for reliable drug delivery (17% with the Aerolizer vs. 23% and 24% with the Turbuhaler and Diskus, respectively; p < 0.05)50.

Clinical efficacy

The clinical efficacy of the formoterol Aerolizer in asthma and COPD has been reported in numerous publications45,49,51-58. In patients with asthma, the formoterol Aerolizer has been shown to provide better long-term (24-h) symptom control than salbutamol (albuterol)51,53,59-60 and has similar benefits to salmeterol52. Likewise, studies in patients with COPD have shown formoterol via the Aerolizer to have a similar onset of action to salbutamol61 and a superior early bronchodilator effect compared with tiotropium62, with a duration of action and efficacy comparable to salmeterol52.

Use of the formoterol Aerolizer was shown to improve symptoms while reducing the need for rescue medication in patients with asthma49,53,54,59,60,63 and with COPD57,58. Sustained improvements in wellbeing or health-related quality of life (HRQoL)56-58 were also demonstrated with formoterol treatment via the Aerolizer. In patients with asthma, treatment with the formoterol Aerolizer was associated with significant improvements in total HRQoL score (p < 0.0001 compared with baseline)64,65. Similarly, patients with COPD treated with the formoterol Aerolizer experienced significant improvements in total HRQoL score (p < 0.03 vs. placebo)57,58. Comparisons of clinical efficacy between the formoterol Aerolizer and other formoterol delivery devices

(i) Turbuhaler

Several studies have compared the efficacy of formoterol delivered via the Aerolizer with formoterol delivered via the Turbuhaler. Lotvall et al.66 compared the efficacy of single doses of formoterol (12 [mu]g) in 19 adult patients with moderate asthma. No statistical difference in the primary efficacy variable (FEV^sub 1^ area under the curve [AUC] over 12 h) was detected between active treatment groups: Aerolizer versus Turbuhaler, p = 0.36; Aerolizer versus placebo, p = 0.0001; Turbuhaler versus placebo, p = 0.0001. The authors concluded that the onset of action, maximal effect and the duration of action of formoterol 12 [mu]g are similar when delivered by either device. In a subsequent study of 200 adults with asthma67 that compared formoterol treatment delivered via the Aerolizer or the Turbuhaler, both treatments had similar clinical efficacy after 4 weeks of treatment (estimated difference in mean morning pre-medication peak expiratory flow, 13.86 L/min, 90% confidence interval [CI] 2.50, 25.21 L/min). Additionally, no significant differences in patients’ symptom scores and rescue medication use between the two treatment groups were detected67. Formoterol via Turbuhaler is also available in a metered dose of 6 [mu]g per puff. Schlimmer68 compared this dose with 12 pg delivered via Aerolizer in a singledose crossover study in 16 subjects with asthma and reported comparable bronchodilator efficacy in terms of onset and duration of bronchodilator effect, although duration was only assessed up to 8 h post-dose.

Eliraz and colleagues also investigated inhalation technique and patient device preference67. Patients were assessed for device- handling capabilities using inhaler-specific checklists following a hierarchical testing procedure. Essential inhalation manoeuvres were performed correctly by 98% of Aerolizer users, compared with 86% of the Turbuhaler group (odds ratio of 7.386; p = 0.0112). More patients using formoterol Aerolizer completed all inhalation steps correctly (80% vs. 70% of the Turbuhaler group), suggesting that the ‘hear-see-feel’ principle of the Aerolizer device has a positive influence on patient handling.

(ii) Novolizer (MEDA Pharma)

In a double-blind study reported by Otto-Knapp and colleagues69, 392 patients with asthma received formoterol 12 [mu]g twice daily via either the Aerolizer or Novolizer (MEDA Pharma). The primary efficacy variable was trough FEV^sub 1^ (i.e. pre-dose) after 4 weeks of treatment. Absolute mean (95% CI) changes from baseline were 0.32 L (0.26-0.38) for the Aerolizer and 0.29 L (0.23-0.35) for the Novolizer, a difference that was within the limits pre-set in this study to demonstrate non-inferiority of the Novolizer device.

(iii) Easyhaler (Orion Pharma)

Two clinical studies have been performed. A singledose crossover study compared formoterol 12 [mu]g delivered via Aerolizer or Easyhaler (Orion Pharma) in 67 subjects with asthma70. The ratio of effect (Easyhaler : Aerolizer) on the primary efficacy variable, the 24-h area under the FEV^sub 1^ curve, was 0.991 (95% CI 0.969- 1.013), within the pre-set limits to establish non-inferiority of the Easyhaler device. A second crossover study compared cumulative 96 [mu]g doses inhaled via the two devices in 33 subjects with asthma and reported non-inferiority of the Easyhaler in terms of adverse events and systemic safety variables such as serum potassium, serum glucose and ECG findings71.

(iv) HFA-pMDI (Modulite; Chiesi)

Houghton and colleagues72 compared the effects of 12 [mu]g formoterol via Aerolizer, an HFA-driven pMDI (Modulite; Chiesi), and a conventional CFC-propelled pMDI, in a single-dose crossover study in 38 subjects with asthma. For the primary efficacy variable, PD20 (the dose of methacholine required to provoke a 20% fall in FEV^sub 1^), they reported non-inferiority of the HFA pMDI (0.51 mg) compared with the Aerolizer and the CFC-pMDI (both 0.62 mg). Clinical equivalence was also shown in two similar crossover studies by Bousquet and colleagues73,74, where single 12 or 24 [mu]g formoterol doses had the same effect on average FEV^sub 1^ in the 12 h post-dose whether delivered by Aerolizer or the HFApMDI device.

(v) Clickhaler (Innovata plc)

Lipworth and colleagues75 compared formoterol 12 [mu]g delivered by Aerolizer, Clickhaler (Innovata plc) or pMDI in two crossover studies in subjects with asthma, aimed at establishing equivalence of the two DPIs in their bronchoprotective effect (methacholine PD20) at 30 min and 8 h post-dose. While both DPIs were equivalent with the pMDI for their effect at 30 min, the difference between Aerolizer and Clickhaler was just outside the equivalence limit, with results in favour of Aerolizer, although the difference was not statistically significant. The effect at 8 h was within equivalence limits for the Aerolizer/Clickhaler difference.

(vi) Certihaler (Novartis Pharma AG, Basel)

Studies in adults76 and children77 with asthma, investigating the efficacy of a range of formoterol doses (5-30 [mu]g) delivered via the multi-dose DPI, Certihaler (Novartis; also known as SkyeHaler and developed by SkyePharma AG, Switzerland) with 12 [mu]g via the Aerolizer, showed no statistically significant difference in effect on the primary efficacy variable, the 24-h area under the FEV^sub 1^ curve, although the magnitude and overall clinical effect suggested similarity between the Aerolizer 12 [mu]g dose and the Certihaler 5 [mu]g dose in children, and the 10 and 15 [mu]g doses in adults.

Conclusions

Formoterol delivery via the Aerolizer is characterized by low internal airflow resistance, together with delivery of a uniform dose with a high respirable fraction. The studies reviewed here show that dose delivery from the Aerolizer varies relatively little over a range of inspiratory flow rates and provides consistently accurate drug delivery to patients at lower inspiratory flow rates. Device handling studies have demonstrated that fewer patients make errors with the Aerolizer than with other dry powder inhalers or the pMDI. Numerous clinical studies have shown that formoterol delivered via the Aerolizer is an effective bronchodilator in both asthma and COPD, providing a rapid onset of effect and a long duration of action, as well as improving other variables reflecting disease control. Comparisons of Aerolizer with multi-dose dry powder inhalers and with newer, HFA-driven inhaler devices have demonstrated equivalence of clinical effect. These results demonstrate that formoterol via Aerolizer has a combination of reliable in vitro performance, ease of use by patients and clinical efficacy that is at least comparable to many of the newer devices available. Formoterol Aerolizer remains a useful option in the management of patients with asthma or COPD.

Acknowledgements

This work was supported by Novartis Pharma AG, Basel, Switzerland. The authors were assisted by S. Filcek in the preparation of the paper; this assistance was funded by Novartis.

* Aerolizer is a registered trade mark of Novartis Pharma AG, Basel, Switzerland

[dagger] Aerolizer is a registered trade mark of Novartis Pharma AG, Basel, Switzerland; [dagger] Rotahaler, Diskus and Accuhaler/ Diskus are registered trade names of Glaxo Wellcome, Greenford, UK; [section] Spinhaler is a registered trade name of Rhone-Poulenc- Rorer, Courbevoie Cedex, France; “” Inhalator and HandiHaler are registered trade names of Boehringer-Ingelheim, Ingelheim, Germany; [double dagger][double dagger] Turbuhaler [known as Turbohaler in the UK) is a registered trade name of the AstraZeneca Group of companies; [double dagger][double dagger]Novolizer is a registered trade name of Meda AB, Solna, Sweden

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CrossRef links are available in the online published version of this paper: http://www.crarojournal.com

Paper CMRO-3712_3, Accepted for publication: 13 July 2007

Published Online: 05 September 2007

doi: 10.1185/030079907X219698

Mathieu Molimard(a), Denise Till(b), Stephan Stenglein(c), Dilraj Singh(d), Markus Krummen(d)

a Departement de Pharmacologie, CHU Pellegrin-Carreire, Bordeaux, France

b Novartis Horsham Research Centre, Horsham, UK

c Novartis Pharma GmbH, Nuernberg, Germany

d Novartis Pharma AG, Basel, Switzerland

Address for correspondence: Professor Mathieu Molimard, MD, PhD, Departement de Pharmacologie, CHU Pellegrin-Carreire, 33076 Bordeaux cedex, France. Tel.: +33 5 57 57 10 60; Fax: +33 5 57 57 46 71; Mathieu.Molimard@pharmaco.u-bordeaux2.fr

Copyright Librapharm Oct 2007

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