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Spiriva® respimat®

The recommended therapeutic dose is 2 inhalation doses of Respimat® inhaler spray (5 mcg/dose) 1 time/day, at the same time of day.

In elderly patients, patients with impaired liver function and patients with minor impaired renal function (creatinine clearance 50-80 ml/min)

you can use the drug Spiriva® Respimat® at the recommended dose.

However, the use of the drug in patients with moderate or significant renal impairment (creatinine clearance less than 50 ml/min)

should be carefully monitored.

COPD does not usually occur in children. Safety and effectiveness of the drug Spiriva® Respimat® in children

have not been studied.

Rules for using the Spiriva® Respimat® inhaler

Before using the inhaler for the first time, you must carry out the steps listed below under numbers 1-6.

Inserting a cartridge

1. With the green cap closed, press the locking button and remove the transparent sleeve down.

2. Remove the cartridge from the packaging. Insert the thin end into the inhaler until it locks into place. To ensure that the cartridge is fully inserted, gently press the cartridge onto a hard surface. Once the cartridge is inserted into the inhaler, there is no need to remove it.

3. Put the transparent sleeve back on. After this, the sleeve should no longer be removed.

Preparing to use your inhaler for the first time

4. The inhaler should be held vertically with the green cap on. You need to turn the transparent sleeve in the direction of the red arrows indicated on the label until it clicks (half a turn).

5. Remove the green cap.

6. Point the inhaler down. Press the dose button. Close the green cap.

Repeat steps 4, 5 and 6 until an aerosol cloud appears.

Then repeat steps 4, 5 and 6 three more times to ensure the inhaler is ready for use.

The Spiriva® Respimat® inhaler is now ready for use.

The implementation of these steps does not reduce the number of doses of the drug. Once prepared, the Spiriva® Respimat® inhaler delivers 30 doses (60 inhalations).

Using an inhaler

I. Hold the inhaler upright with the green cap on to prevent accidental release of the medication. Turn the transparent sleeve in the direction of the red arrows indicated on the label until it clicks (half a turn).

II. Remove the green cap. Exhale slowly and deeply. Cover the end of the mouthpiece tightly with your lips. The air hole of the inhaler must be free. Point the inhaler towards the back of the throat.

While inhaling slowly and deeply through your mouth, press the dose button and continue inhaling as long as possible. Hold your breath for 10 seconds or as long as comfortable.

III. Repeat steps I-II to obtain the full dose. This inhaler should only be used once a day.

Close the green cap of the inhaler until you use it again.

If the Spiriva® Respimat® inhaler has not been used for more than 7 days, you should point it down before use and press the dose button once. If the inhaler has not been used for more than 21 days, repeat steps 4-6 until an aerosol cloud is obtained. Then repeat steps 4-6 three more times.

Determining when to start using a new inhaler

The Spiriva® Respimat® inhaler contains 30 doses (60 inhalations). The dose indicator shows approximately how much of the drug is left. When the inhaler pointer points to the red area of the scale, this means there is approximately 7 days of medication left (14 inhalations). During this time, you must obtain a prescription for a new Spiriva® Respimat® inhaler.

When the inhaler pointer reaches the end of the red area of the scale (i.e. when 30 doses have been used), this means that the inhaler is empty. The inhaler will be automatically blocked. From this point on, turning the transparent sleeve will not be possible.

After the first use, the Spiriva® Respimat® inhaler must be discarded no later than after 3 months, even if not the entire amount of the medicine has been used.

Caring for your inhaler

The mouthpiece and metal part of the atomizer must be cleaned with a damp, soft cloth at least once a week. Slight discoloration of the mouthpiece does not affect the functioning of the inhaler. If necessary, wipe the outside of the inhaler with a damp cloth.

Spiriva Respimat - a new direction in the treatment of COPD

The role of tiotropium bromide in the treatment of COPD Tiotropium bromide belongs to the group of M-anticholinergics. The drug is characterized by an ultra-long-lasting (more than 24 hours) bronchodilator effect, due to which tiotropium can be prescribed 1 time per day. Today, tiotropium bromide is the most active drug in the range of anticholinergics: in its anticholinergic activity, tiotropium is 12 times superior to atropine and 20–30% more active than ipratropium and aclidinium bromide [1]. All M-anticholinergics are non-selective drugs, i.e. they block M-cholinergic receptors of all subtypes. At the same time, blockade of M1 and M3 receptors promotes dilation of the bronchi and provides a therapeutic effect of the drugs, while blockade of M2 receptors is undesirable, because this subtype of cholinergic receptors is responsible for signal inhibition at synapses. Tiotropium bromide is distinguished by a very short-term blockade of M2 receptors (T½ of communication with M2 receptors for tiotropium is only 3.6 hours), while the blockade of M1 and M3 receptors lasts more than 1 day. [1]. In patients with COPD, the main pathological changes occur at the level of small peripheral airways, which are largely damaged by exposure to tobacco smoke and neutrophilic inflammation. Moreover, these changes are irreversible. But along with this, patients with COPD are distinguished by an increased tone of the parasympathetic system, which leads to a narrowing of the large bronchi (the total resistance of the respiratory tract is determined mainly by the central bronchi, since their total lumen - about 2 cm2 - is significantly less than the total lumen of the peripheral bronchi) and an increase in the total resistance respiratory tract [2]. By acting on the cholinergic receptors of the central bronchi, tiotropium bromide eliminates the influence of the parasympathetic nervous system, large bronchi expand, and the overall resistance of the respiratory tract decreases. As a result, residual lung capacity decreases and tidal volume increases. As a result, shortness of breath decreases in patients, and it is easier for them to perform physical activity [3]. After inhalation of tiotropium bromide, the forced expiratory volume in the first second (FEV1) increases by 150–180 ml (compared to placebo) or by 103 ml compared to the control group receiving therapy with β2-agonists and inhaled corticosteroids [4]. To an even greater extent, tiotropium bromide eliminates the so-called “air trap”, i.e. reduces the volume of air that remains in the patient’s lungs after maximum exhalation [5]. As a result, the drug increases tidal volume, reduces the severity of dyspnea, increases exercise tolerance [6] and reduces exercise-related concentrations of catecholamines in the blood [7]. The positive effect of tiotropium is not limited to the function of external respiration - it significantly (38–44%) reduces the number of exacerbations of COPD [8,9] and mortality from any cause in patients with COPD by 12–16% [4,10]. It is important to emphasize that the beneficial effects of tiotropium last for a long time (the longest study to date of this drug lasted 4 years [4]), while the effects of other bronchodilators (long-acting β2-agonists, for example, salmeterol) can be markedly reduced with constant intake [11] due to a decrease in the number and sensitivity of β-adrenergic receptors [12]. In patients with COPD, tiotropium can be prescribed as monotherapy, which can significantly (27%) reduce the risk of severe exacerbations of COPD compared with monotherapy with salmeterol (a long-acting β2 agonist) [13]. A meta-analysis of studies comparing tiotropium with long-acting β2-agonist therapy showed that tiotropium and β2-agonists provided approximately the same increase in FEV1, but patients receiving tiotropium had a 14% lower risk of exacerbations, and the frequency of adverse events is 12% less than when prescribing β2-agonists (comparative studies of tiotropium with salmeterol, formoterol and indacaterol were included in the analysis) [14]. In severe COPD, when a combination of several drugs is required, tiotropium can be effectively combined with drugs from other pharmaceutical groups. In particular, tiotropium acts as a synergist of long-acting β2-agonists [15], because against the background of its administration, the sensitivity of β-adrenergic receptors increases [16]. Clinical studies have proven the effectiveness of the combination of tiotropium with roflumilast [17] and combination drugs that include β2-agonists and inhaled corticosteroids (budesonide/formoterol) [18]. Respimat® - a new generation inhaler Tiotropium bromide in the form of a new inhalation device Respimat® (Fig. 1) went on sale in our country in 2012. This device combines the best qualities of a metered dose aerosol inhaler (MDI): simplicity, compactness, the ability to quickly perform inhalation and the positive properties of a nebulizer: the inhaler releases an aerosol slowly (about 1.5 s). Thus, during the inhalation process, patients do not have problems with breathing coordination. Aerosol particles generated by conventional MPDs have a high initial velocity – from 2 to 8 m/s [19]. Moving at such a speed, the particles, by inertia, collide with the back wall of the pharynx. As a result, most of the dose (50 to 80%) is deposited in the oropharynx, swallowed with saliva and absorbed into the gastrointestinal tract, causing undesirable systemic effects. During inhalation, Respimat releases an aerosol at a speed of about 1 m/s, which is several times less than the speed of the aerosol created by the MDI. By moving slowly, the aerosol particles avoid collision with the back wall of the pharynx and tongue, which reduces the deposition of the drug in the oral cavity. As a result, the amount of active substance delivered to the respiratory tract increases significantly. It is important to note that Respimat generates an aerosol within 1.5 s, while the drug is released from a MDI in an average of only 0.2 s [19]. When inhaling through a MDI, patients are forced to coordinate their inhalation so that the activation of the inhaler and the start of inhalation coincide perfectly in time: if the patient begins to inhale before activating the inhaler or, conversely, inhales late, the amount of drug delivered to the respiratory tract may decrease by several times [20]. A number of patients find it difficult to achieve good coordination between inspiration and activation of the inhaler; for example, 18% of patients activate their MDI in the second half of inspiration, and 5% - after completion of inspiration [21]. Respimat, providing drug release within 1.5 s, significantly reduces the consequences of errors associated with insufficient coordination of the patient's inhalation. As a result, Respimat is able to increase the deposition of the drug in the lower respiratory tract several times compared to MDI (Fig. 2). For another type of delivery device, powder inhalers, there are also application features that often limit their effectiveness. Thus, patients using powder inhalers must inhale the powder quickly enough. In particular, the minimum inspiratory flow rate through the Turbuhaler, Multidisc and HandiHaler should be 30 l/min. [22]. Most patients with COPD are able to inhale the drug at this rate [23]. But if the patient uses a capsule-type inhaler, the duration of inhalation should be at least 3 s: if the inhalation lasts less time, then the powder does not have time to completely leave the capsule. Taking a long breath at a high rate is generally problematic for COPD patients, especially since some inhalers (Aerolyzer) require inhalation at a rate of more than 60 l/min. (the volume of inspiration lasting 3 seconds at a speed of 60 l/min is 3 l). As a result, when using powder inhalers, part of the dose remains in the capsule, and the patient must check the capsule each time and, if necessary, inhale again. When using powder inhalers, the patient is required to inhale faster and longer, while when using Respimat there are no special requirements for the breathing maneuver that the patient performs. Thus, Respimat is much more convenient to use for patients with COPD compared to MDIs and powder inhalers. Another important advantage of the new inhaler is that 55% of the dose of tiotropium bromide in Respimat is released in the form of particles of optimal aerodynamic diameter, which guarantees a high degree of pulmonary deposition (Table 1). Thus, Respimat today is one of the most advanced means of delivering drugs to the respiratory tract. In addition, Respimat is a universal delivery system. In the future, not only tiotropium, but also short-acting bronchodilators, as well as a new ultra-long-acting β2-agonist (24 hours) - olodaterol - will be produced in the form of Respimat. Due to the high degree of pulmonary deposition, the daily dose of tiotropium in Respimat is only 5 mcg (2 inhalations of 2.5 mcg), but Spiriva Respimat provides a therapeutic effect comparable to the administration of 18 mcg of the drug through the HandiHaler [28]. Respimat from the patient's point of view Respimat is easy to use. In the study, 97.7% of patients surveyed stated that using Respimat was “very easy” or “simple” (Fig. 3) [29]. To the question: “How quickly did you feel confident using Respimat?” the majority (76.6%) of patients responded that they felt confident after the first or second experience of using this inhaler (Fig. 4). Among patients who used both Respimat and MDI for the treatment of COPD, 74% preferred Respimat, 19% preferred MDI, and 9% were undecided [29]. Patients with COPD, for whom Respimat is intended, pose a serious problem for doctors in terms of training in inhalation techniques due to old age and psychological problems associated with the impact of the disease on mental processes (depression, negative attitude towards therapy). In particular, a study conducted by Brand P. et al. [30], showed that additional training in the technique of inhalation using a pMDI is practically unable to improve the degree of drug delivery to the respiratory tract. However, if patients use Respimat, then the amount of drug delivered to the lungs is, on average, significantly higher compared to MDI, and physician supervision and additional training can further increase the level of pulmonary deposition of the drug (Fig. 5). Safety The safety of tiotropium bromide (HandiHaler) has been studied and proven in 30 international comparative studies involving more than 30 thousand patients. In particular, it has been shown that tiotropium bromide is well tolerated by patients and does not have undesirable effects on the cardiovascular system [31], and also does not affect urodynamics in patients with benign prostatic hypertrophy [32]. Spiriva Respimat (unlike HandiHaler): • contains 3.6 times less active ingredient as a daily dose; • less retention in the oral cavity and, as a result, a smaller amount of tiopropium can be swallowed by the patient with saliva and subsequently absorbed into the gastrointestinal tract; • the concentration of the drug in the blood after inhalation through Respimat is quite small and does not differ significantly from the concentration that is created after inhalation through HandiHaler [33–35]. Thus, Spiriva Respimat should provide at least the same high degree of safety for patients as Spiriva HandiHaler. Indeed, in terms of the total number of adverse events, Spiriva Respimat does not differ from placebo [36] - with the exception of complaints of dry mouth, which were 2 times more likely to be noted in the tiotropium group and are naturally explained by the anticholinergic effect of the drug. However, a pooled analysis of 2 tiotropium studies conducted by Bateman E. et al. [37], showed that the number of deaths from any cause, including patients who did not complete the study, was higher in the groups receiving tiotropium Respimat than in the placebo group: 2.4% (tiotropium 5 μg), 2.7% (tiotropium 10 mcg) and 1.6% (placebo). It is important to note that the difference in the incidence of death from any cause between the treatment and placebo groups was not statistically significant. In addition, the increase in the risk of death was not recorded in all studies of Respimat and may be due to errors in the organization of the studies (in particular, the inclusion in the study of patients who were known to suffer from heart rhythm disturbances [38]). The supposed increase in the risk of deaths reported by Bateman E. and Singh S. did not affect the position of regulatory authorities responsible for the safety of medicines in more than 55 countries, including Western Europe and Russia. The US registration application for SpirivaRespimat has been submitted to the FDA. However, in order to finally confirm the safety of Spiriva Respimat, a special TIOSPIR study was launched with the participation of more than 17 thousand COPD patients. In this study, patients were randomized to receive Spiriva Respimat (5 mcg/day) and Spiriva HandiHaler (18 mcg/day). The main conclusion of TIOSPIR should be that tiotropium delivered through Respimat is safe. The study will also provide additional information about the effectiveness of Spiriva Respimat in the treatment of COPD. The completion of the study is expected in 2013, but at this time it can be assumed that no unexpected results will be obtained during the study. The Independent Clinical Trial Safety Monitoring Committee, at its last meeting in January 2013, recommended that the TIOSPIR trial continue as per protocol without any changes [39]. All of the above makes it unlikely that there is a relationship between the use of Spiriva Respimat and deaths. In this regard, we can recall the INSPIRE study [40], in which therapy with Spiriva HandiHaler was compared with therapy with salmeterol/fluticasone. The compared groups of patients in this study did not differ in either the number of exacerbations of COPD or spirometry. In addition, in the salmeterol/fluticasone group, cases of pneumonia were observed 2 times more often than in the Spiriva group. But at the same time, the number of deaths was higher in Spiriva’s group. This result was completely unexpected, because The significantly larger and longer UPLIFT trial demonstrated the ability of tiotropium to reduce mortality in patients with COPD [4], while reliable data on the reduction in mortality with salmeterol/fluticasone (aerosol) therapy were not obtained [41]. An analysis of the study methodology conducted by the leading specialist in the field of respiratory research, Samy Suissa [42], convincingly showed that the differences in mortality were due to methodological errors in the INSPIRE study (lack of complete information on patients who dropped out of the study, despite the fact that the study was not completed according to the protocol for more than 1/3 of patients). Respimat: technical device In the inhaler, the active substance is placed in a metal cartridge designed for 60 doses. The drug in the cartridge is reliably protected from environmental influences. Before the first use, the cartridge is inserted into the inhaler, then to prepare for use, you need to activate the inhaler idle 3 times in a row after the appearance of an aerosol cloud. Respimat does not contain propellants, i.e. liquid substances, the active evaporation of which creates pressure in the MDI, pushing the aerosol out. The absence of a propellant in Respimat allows us to avoid a situation in which the propellant, entering the respiratory tract along with the drug, quickly evaporates on the bronchial mucosa, creating a cooling effect, which can provoke bronchospasm in sensitive patients [43]. The aerosol supply in Respimat is carried out mechanically. By turning the transparent sleeve until it clicks, the patient compresses the spring, and when the inhaler is activated, the spring pushes the next dose of the drug through the so-called uni-block, in which an aerosol is created. The main part of the inhaler, the uni-block, consists of 2 functional parts: a filter and a nozzle with 2 holes. Having passed through the filter, the drug solution leaves the uni-block through 2 holes with a diameter of 8 microns, the pressure and collision of 2 liquid flows at a certain angle forms an aerosol consisting of 55% particles of optimal (from 1 to 5 microns) diameter. Conclusions Respimat has a number of features that distinguish this device from other inhalers. In particular, low speed and prolonged aerosol release create optimal conditions for drug delivery to the respiratory tract, and 55% of the dose is represented by particles of optimal size. The inhaler provides a minimal degree of deposition in the oropharynx and contains a smaller amount of the drug compared to Spiriva HandiHaler. These properties should make tiotropium therapy even safer. Respimat is distinguished by a simple inhalation technique. As a result, patients from the first days confidently treat the inhaler. The positive properties of responds make it possible to optimize therapy with thiotropy and, ultimately, improve the quality of medical care for patients with COPD.

References 1. Disse B et al. Life Sci 1993, 52: 537-44. 2. Gross NJ, Co E, Skorodin MS. Chest. 1989 Nov;96(5):984-7. 3. Buels KS, Fryer AD. Handb Exp Pharmacol. 2012;(208):317-41. 4. Tashkin DP et al. UPLIFT Study Investigators. N Engl J Med 2008;359:1543-54 5. Celli B, ZuWallack R, Wang S, Kesten S. Chest. 2003 Nov;124(5):1743-8. 6. O'Donnell DE et al. Eur Respir J. 2004 Jun;23(6):832-40. 7. Yoshimura K et al. Int J Chron Obstruct Pulmon Dis. 2012;7:109-17 8. Casaburi R et al. Eur Respir J 2002; 19:217-224 9. Vincken W et al. Eur Respir J 2002; 19:209-216 10. Celli B et al. CHEST 2010; 137(1): 20-30 11. Donohue JF et al. Chest. 2002 Jul;122(1):47-55 12. Vasudevan NT et al. Cell Cycle. 2011 Nov 1;10(21):3684-91 13. Vogelmeier C et al. N Engl J Med 2011;364:1093-103 14. Chong J, Karner C, Poole P. Cochrane Database Syst Rev. 2012 Sep 12;9:CD009157. 15. Van Noord JA, et al. Eur Respir J. 2005;26:214-222 16. Johnson M. Proc Am Thorac Soc. 2005;2(4):320-5 17. Fabbri LM et al. Lancet. 2009;374(9691):695-703 18. Aaron CD et al. Ann Intern Med. 2007;146:545-555. 19. Hochrainer D, Hölz H, Kreher C, et al. J Aerosol Med 2005; 18; 273–82. 20. Newman SP et al. Thorax 1991;46;712-716 21. Melani AS et al. Respir Med 2011; 105:930-938. 22. Laube BL et al. Eur Respir J 2011; 37: 1308-1331 23. Malmberg LP et al. Intern J of COPD 2010:5 257–26 24. De Backer W et al. J Aerosol Med and Pulmonary Drug Delivery 2010; Vol. 23 #3: 137–148 25. Rosenborg J et al. Eur Respir J 1999; 14:62s. 26. Criée CP et al. J Aerosol Med. 2006 Winter;19(4):466-72. 27. Ziegler, J., Wachtel H. (2001), Drug delivery to the Lungs XII, 54-57 28. van Noord et al. Respir Med 2009; 103: 22-29 29. Barczok M et al. Presented at VIII Deutsches Aerosol Therapie Seminar, Marburg, Germany. November 2003. 30. Brand P et al. International Journal of COPD 2008:3(4) 763–770 31. Rodrigo GJ et al. Pulmonary Pharmacology & Therapeutics 2012;25:40-47 32. Miyazaki et al. Pulmonary Pharmacology & Therapeutics 2008; 21: 879–883 33. van Noord J et al. Respir Med 2009;103:22–9. 34. Ichinose M et al. Respir Med 2010;104:228–36. 35. Tiotropium Respimat Pharmacokinetic Study in COPD https://www.clinicaltrials.gov/ct2/show/NCT01222533? 36. Bateman E, et al. Respir Med 2010; 104: 1460-72 37. Bateman E et al. Int J Chron Obstruct Pulmon Dis. 2010 Aug 9;5:197-208. 38. Singh S et al. BMJ. 2011 Jun 14;342:d3215 39. Metzdorf N. Thorax Online First, published on February 12, 2013 as 10.1136/thoraxjnl-2013-203228 40. Wedzicha JA et al. Am J Respir Crit Care Med Vol 177. pp 19–26, 2008 41. Calverley PM et al. N Engl J Med 2007;356:775–789. 42. Suissa S. Am J Respir Crit Care Med. 2008 Nov 15;178(10):1090-1 43. Berger W. Curr Drug Deliv. 2009 Jan;6(1):38-49

Description of the drug SPIRIVA® RESPIMAT® (SPIRIVA RESPIMAT)

Tiotropium bromide is a quaternary ammonium compound, sparingly soluble in water.

Tiotropium bromide has linear pharmacokinetics within therapeutic limits after intravenous administration and dry powder inhalation.

When administered by inhalation, the absolute bioavailability of tiotropium bromide is 19.5%, which indicates the high bioavailability of the drug fraction reaching the lungs. Cmax in blood plasma is achieved 5 minutes after inhalation. Tiotropium bromide is poorly absorbed from the gastrointestinal tract. For the same reason, food intake does not affect the absorption of tiotropium. When taking tiotropium bromide orally in solution form, the absolute bioavailability was 2-3%.

Plasma protein binding - 72%. Vd - 32 l/kg. At steady state, Cmax in blood plasma in patients with COPD is 17-19 pg/ml 5 minutes after inhalation of powder at a dose of 18 mcg and decreases rapidly. Css in blood plasma was 3-4 pg/ml.

Does not penetrate the BBB.

The degree of biotransformation is insignificant. Tiotropium bromide is broken down nonenzymatically to alcohol N-methylscopine and dithienylglycolic acid, which do not bind to muscarinic receptors.

Metabolic disturbances are possible when using inhibitors of CYP2D6 and 3A4 isoenzymes (quinidine, ketoconazole, gestodene). Thus, the isoenzymes CYP2D6 and 3A4 are included in the metabolism of the drug. Tiotropium bromide, even at supratherapeutic concentrations, does not inhibit cytochrome P450 isoenzymes 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A4 in human liver microsomes.

After inhalation administration, terminal T1/2 is 5-6 days. The total clearance when administered intravenously to healthy young volunteers is 880 ml/min, with an individual variability of 22%. Tiotropium bromide after intravenous administration is excreted mainly in the urine unchanged - 74%. After inhalation of the powder, renal excretion is 14%, the rest, not absorbed in the intestine, is excreted in the feces. The renal clearance of tiotropium bromide exceeds the CC, indicating tubular secretion of the drug. After long-term administration of the drug once a day in patients with COPD, the equilibrium state of pharmacokinetic parameters is achieved after 2-3 weeks, with no further cumulation observed.

In elderly patients, there is a decrease in the renal clearance of tiotropium bromide (326 ml/min in patients with COPD under 58 years of age, up to 163 ml/min in patients with COPD over 70 years of age), which is apparently due to a decrease in renal function with age. After inhalation, urinary excretion of tiotropium bromide is reduced from 14% (young healthy volunteers) to 7% (patients with COPD), but in elderly patients with COPD there was no significant change in plasma concentrations when inter- and intra-individual variability was taken into account (after inhalation of powder increases AUC0-4 by 43%).

If renal function is impaired after inhalation and intravenous administration, the concentration of the drug in the blood plasma increases and renal clearance decreases. With mild renal impairment (creatinine clearance 50-80 ml/min), often observed in elderly patients, the increase in the concentration of tiotropium bromide in the blood plasma is insignificant (after intravenous administration, an increase in AUC0-4 by 39%). In patients with COPD with moderate or severe decrease in renal function (creatinine clearance <50 ml/min), after intravenous administration of ipratropium bromide, a double increase in its plasma concentration was observed (82% increase in AUC0-4), compared with plasma concentrations blood, determined after inhalation administration of dry powder.