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Drug Invest. 7 (l): 34-40, 1994 0114-2402/941000 1-0034/$03 .5010

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Azelastine in Pollen-Induced Allergic Rhinitis A Pharmacodynamic Study of Onset of Action and Efficacy

F. Horak, S, Jager, J, Toth, U Berger and E, Nirnberger

University ENT Clinic, Vienna, Austria

Summary The manifestation of rhinitic symptoms in 9 patients with grass pollen-induced rhinitis was studied during long term allergen exposure at physiological concentrations in the 'Vienna Challenge Chamber' . Patients were pretreated with a single dose of azelastine (either 2.2mg orally or 0.28mg intranasally) or placebo. Nasal resistance was estimated by active anterior rhinomanometryevery 15 minutes. Analysis of changes in nasal airways resistance demonstrated significant protection against allergen-induced nasal obstruction (p < 0.01) for azelastine admin­istered by either route. The onset of action of treatment in relation to nasal obstruction was significantly more rapid for the nasal spray (135 minutes) than for the tablet (205 minutes) [p < 0.01) formulation. Similarly, the onset of effect derived from subjective assessment of symp­tom severity was markedly more rapid (60 minutes) after intranasal azelastine than after admin­istration of the oral form (120 minutes). Tolerability of azelastine was good, with no side effects reported with either oral or intranasal therapy.

Azelastine is a phthalazinone derivative that not only possesses potent histamine HI-receptor blocking activity (Casale 1989; Zechel et al. 1981), but also inhibits the release of several mediators involved in the pathogenesis of allergic respiratory disease (Achterrath-Tuckermann et al. 1988; Chand et al. 1985). Oral azelastine 1.1 to 2.2mg twice daily has been found to be effective in the treatment of both seasonal (Weiler et al. 1988) and perennial (Meltzer et al. 1988) allergic rhinitis, with an onset of action as early as 2 hours after dosing. Indeed, when compared with terfenadine 60mg twice daily, azelastine I.lmg twice daily for 6 weeks has been shown to be equivalent, and a dose of 2.2mg twice daily was superior in terms of both efficacy and safety (Lenhard & Gerhardt 1988).

Because allergic rhinitis is predominantly asso­ciated with nasal symptoms, it is logical to admin-

ister treatment intranasally for a rapid and localised effect. A nasal spray delivering azelastine O.14mg in aqueous solution per actuation has been devel­oped, and is currently being used in both seasonal and perennial rhinitis. The aim of the present study was to evaluate and compare the onset of effect and protective efficacy of orally administered azelast­ine, intranasal azelastine and placebo against rhi­nitis symptoms experienced during continuous exposure to physiological concentrations of inhal­ant allergens.

Methods Patients

Nine patients, 4 females and 5 males, with a mean age of 24.8 (range 21 to 31) years and with a 2-year or more history of seasonal allergic rhinitis caused by grass pollen, were studied. The diagno-

Azelastine in Pollen-Induced Rhinitis

sis of grass pollen allergy was confirmed in all cases by positive skin prick testing, nasal challenge and radioallergosorbent test (RAST) class 3 or 4 to grass pollen allergen (g3). The study was per­formed prior to the onset of the grass pollen season, when all patients were asymptomatic. Patients with perennial rhinitis, polyposis, vasomotor rhinitis or asthma were excluded from the study, as were those currently undergoing hyposensitisation. No concomitant medication other than the contracep­tive pill was allowed throughout the study period.

All patients were required to give written, in­formed consent to participate in the study. The study was approved by the Ethics Committee asso­ciated with the Medical Faculty of the University of Vienna and was carried out in accordance with the requirements of the Declaration of Helsinki.

Study Design

The study was conducted as a randomised dou­ble-blind/open crossover trial. The double­blindedness was in relation to the comparison of azelastine nasal spray and placebo nasal spray only because the topically used formulation was of pri­mary interest. The comparison between azelastine nasal spray and tablets was conducted in an open manner only. Each patient was randomly allocated to receive a single dose of one of each of the test medications within the 3 different study days, sep­arated by a washout period of 2 weeks. Nasal spray preparations were presented as pump aerosol sprays releasing 0.14ml per actuation and contain­ing either azelastine HCI 0.1 % aqueous solution (i.e. 0.14mg per spray) or placebo. The dose of azelastine was 1 spray per nostril (0.28mg total). Azelastine and placebo aerosols were visually in­distinguishable to ensure blind comparison. Azelastine tablets contained 2.2mg azelastine HCl. All medications were administered 15 minutes prior to allergen exposure.

Allergen Exposure

Natural exposure to aeroallergens is subject to extreme regional and chronological fluctuations. Experimentally, challenge tests usually consist of

35

short exposures to allergen solutions, or aerosols, in concentrations often in excess of those normally experienced. As a result, such challenges make it difficult to quantify exactly the therapeutic re­sponse to an antiallergic treatment or to calculate the onset of action of a medication under natural conditions. Ideally, patients need to be continu­ously exposed to a specific allergen over a period of several hours at concentrations mimicking nat­ural exposure. The Vienna Challenge Chamber (VCC) [Horak & Jager 1987] is a self-contained, air-conditioned system where aero allergenic con­tent is dispersed homogeneously and continuously controlled, allowing changes in the pathophysiol­ogy of the respiratory tract to be monitored during a more physiological type of exposure.

On each of the 3 investigative days all 9 patients were exposed simultaneously to continuous challenge with grass pollen (1000 pollen grains per m3 air) in the VCC for a period of 4 hours. Mea­sures of efficacy (see below) were recorded in the morning, just prior to medication, and 15 minutes after administration of medication, at which point allergen exposure was commenced. Further meas­urements were conducted every 15 minutes throughout the 4-hour exposure (i.e. for a total of 255 minutes after administration of study treat­ment). The only exception to this schedule was the measurement of nasal secretion, which was esti­mated every 30 minutes during the study period.

0.3

J 0.28

g 0.26 N

J: E 0.24 .8-

(/)

~ 0.22 a: <I 0.2

o

_Placebo .... Oral azelastine 2.2mg - -Intranasal azelastine 0.28mg

60 120 180 240 Time (minutes)

Fig. 1. Change in total airway resistance (i\Rnas) at l50Pa (Pals/ml) during long term challenge, following premedication with placebo, oral azelastine 2.2mg or intranasal azelastine O.28mg.

36

Assessment of Efficacy/Onset of Effect

Objective Measurements Nasal resistance, Rnas (cm H20/mi. sec), and

nasal flow, Fnas (mUsec) were measured by com­puterised active anterior rhinomanometry. Record­ings were obtained at several pressure differences (75, 150, 300Pa) between anterior and posterior nares. The target variable was the change from baseline in total nasal airways resistance at a pres­sure difference of 150Pa. The weight of nasal se­cretions produced over the previous 30 minutes was recorded at 9 time-points during the study period. In addition to the above, the effect of aller­gen exposure on the lower respiratory tract was monitored by recordings of peak expiratory flow rates (PEFR).

Subjective Symptom Scores At each time-point patients were asked to score

respiratory and ocular symptoms according to a 4-point scale: 0 = none; 1 = mild; 2 = moderate; 3 = severe. Symptoms scored were sneezing, rhi­norrhoea, nasal itching, nasal obstruction, itching of the eyes, lacrimation and bronchial obstruction. An overall assessment of rhinitic symptoms was also recorded by means of a 10cm visual analogue scale (VAS).

Assessment of Tolerability

Patients were interviewed regarding adverse events during each of the 3 trial sessions. Adverse events were monitored by recording all com­plaints, including intercurrent diseases and acci­dents (but excluding pre-existing conditions) oc­curring on each study day.

Statistical Analysis

A baseline correction was conducted for the tar­get variable, Rnas, at l50Pa. To obtain a far-reach­ing, unlimited measure of the total changes during pollen exposure and hence of the therapeutic effi­cacy of azelastine, the areas under the time curves (0 to 255 minutes and 180 to 255 minutes) were calculated using linear trapezoidal rules. The ear­liest point in time after commencement of the

Drug Invest. 7 (I) 1994

Table I. lime to onset of effect of treatment

Patient lime to onset of effect (min)

no. azelastine azelastine

tablets nasal spray

195 75

2 225 180

3 180 105

4 195 180

5 195 150

6 225 75

7 240 210

8 240 165

9 120 75

Mean 205 135·

SD 41 53

• p < 0.Q1 (compared with tablet formulation).

challenge period at which a 20% difference in nasal resistance occurred between the study drug and the placebo was generously considered to be the point of 'onset of effect'. This judgement was necessar­ily designed under the auspices of no available ex­isting precise definition of 'onset of effect' of an active drug.

Statistical comparison of objective data (Rnas, Fnas) was by means of crossover analysis of vari­ance and the Wilcoxon pairs test. The significance level required for rejection of the null hypothesis was ex = 0.05. Because of the small number of patients studied, statistical analyses of subjective symptoms must be considered as descriptive only. Significance levels of subjective symptoms may therefore be misleading and have not been quoted.

Results Objective Measurements

Changes in total nasal airways resistance from baseline are shown in figure 1. A statistical com­parison of baseline and final values as well as a comparison of AVCs (0 to 255 minutes and 180 to 255 minutes) show a significant difference be­tween the study drug and placebo (p < 0.01; cross­over analysis of variance, Wilcoxon test). AI-

Azelastine in Pollen-Induced Rhinitis

though the nasal spray was numerically superior to the oral formulation, no significant difference in efficacy between the 2 formulations could be identified.

Table I shows the time to onset of effect after administration of medication, which was signifi­cantly more rapid (135 minutes) for azelastine nasal spray than for azelastine tablets (205 min­utes) [p < 0.01; Wilcoxon test]. There was no mea­surable onset of effect following premedication with placebo, as the nasal resistance curve showed a continual deterioration throughout the period of allergen exposure. Results at other pressure differ­ences between anterior and posterior nasal cavities showed a similar pattern of results to that obtained for the target variable, as did recordings of nasal flow rates.

Mean weights of nasal secretions produced at 30-minute intervals during allergen exposure are recorded in table II. There was a trend towards de­creased amounts of secretion produced following premedication with both intranasal and oral azelastine, which was especially marked in the later stages of pollen exposure (195 to 255 min­utes) after drug administration. However, no sig­nificant difference between treatments could be identified at any time-point.

There were no significant mean changes in PEFRs during the study in any of the 3 treatment

37

groups. Only 1 patient consistently reported a sub­jective sensation of bronchial constriction, which occurred during all allergen exposures irrespective of pretreatment. This was confirmed by PEFR re­cordings, which showed a fall of 29%, from 580 Llmin to a minimum of 410 Llmin following pla­cebo pretreatment, a fall of 15% (620 to 530 Llmin) with azelastine nasal spray and 17% (600 to 500 Llmin) following oral azelastine.

Subjective Symptom Scores

Figure 2 shows the results of subjective symp­tom scores throughout the period of allergen expo­sure. Scores are presented as means of the sum of the totals for combined nasal and ocular symptoms. The onset of effect of azelastine with respect to symptom control appears to occur earlier than the recorded effect on nasal patency, being 60 minutes for the nasal spray and 120 minutes for the orally administered drug. Again, no 'onset of effect' could be identified following placebo. This is also true when 'sneezing' is considered as an isolated symptom, when the onset of effect is even more rapid, being 30 minutes for intranasal application and 60 minutes for azelastine tablets (fig. 3). Results of VAS scales of overall rhinitic symptoms (not illustrated) followed a pattern that was almost identical to that for the sum of scores of the indi­vidual symptoms.

Table II. Mean weight (± SEM) of nasal secretions in preceding 30 minutes

Time after drug Placebo Weight of nasal secretions (g)

administration (min) azelastine nasal spray azelastine tablets

15 0.02 ± 0.03 0 0

45 1.58 ± 0.79 1.56 ± 0.85 1.33 ± 0.85

75 1.81 ± 0.58 1.31 ±0.74 1.40 ± 0.75

105 1.32 ± 0.39 1.41 ±0.84 1.16 ± 0.53

135 1.19 ± 0.34 0.81 ± 0.49 0.95 ± 0.45

165 0.89 ± 0.29 0.69 ± 0.42 0.87 ± 0.39

195 2.04± 0.70 0.85 ± 0.56 0.67 ± 0.30

225 1.73 ± 0.62 0.42 ± 0.32 0.64 ± 0.35

255 1.43 ± 0.44 0.43 ± 0.32 0.52 ± 0.29

38

5 -Placebo .... Oral azelastine 2.2mg - -Intranasal azelastine 0.28mg

............................................................ .". ... - - - - - - ... ...... ... ' - ::."'r. •. :..~.::.:7 .. ~.~ .. ::.~.

.. ' o 60 120 180 240

Time (minutes)

Fig. 2. Subjectively experienced symptoms ofrhinitis (visual an­alogue scale) during long term challenge, following premedica­tion with placebo, oral azelastine 2.2mg or intranasal azelastine O.28mg.

Tolerability

The tolerability of azelastine was extremely good following these single doses. No adverse events were reported with either mode of adminis­tration.

Discussion

Seasonal allergic rhinitis caused by aero­allergens such as pollens and fungal spores is a difficult condition in which to research the thera­peutic efficacy of new drugs. Spontaneous varia­tions in atmospheric allergen levels, and conse­quently in the intensity of symptoms, complicate the design and interpretation of clinical trials.

In the present study the use of the VCC allowed all patients to simultaneously undergo a stand­ardised long term challenge at physiological con­centrations of allergen. Symptoms of rhinitis pro­voked during carefully controlled conditions similar to natural pollen exposure could therefore be studied. As a result, the protective effect of azelastine in comparison with placebo was clearly apparent, despite the small number of patients in­vestigated. However, the sophisticated method used allowed a considerable amount of scaled data to be obtained from each single patient and this led to statistically calculable results.

Drug Invest. 7 (1) 1994

There were no significant differences in effi­cacy between intranasally and orally administered azelastine. Both formulations inhibited the pollen­induced rise in nasal airways resistance and the expression of rhinitic symptoms .

The finding that the allergen-induced rise in to­tal nasal airways resistance could be inhibited by azelastine is of particular interest. There are con­troversial findings in other compounds (Corrado et al. 1987; Dockhom et al. 1987; Holmber et al. 1989; Kemp et al. 1985). It therefore seems un­likely that the efficacy of intranasal azelastine against nasal obstruction is a result solely of its potent HI-receptor antagonism, but may derive from additional 'antiallergic' activity.

The time to onset of effect for both the oral and intranasal formulations of azelastine differed de­pending on the variable measured. However, and not surprisingly, intranasal azelastine was always significantly more rapid in its effect. Onset of ef­fect of both formulations in relation to expression of subjectively experienced symptoms occurred well before noticeable effects on objective tests of nasal patency. The most rapid onset of effect was related to protection against pollen-induced sneez­ing attacks, occurring within 30 minutes of instil­lation of intranasal azelastine and within 60 min­utes of oral administration.

2.5

i!! 2 § E 1.5

% E ~ c <0

~ O.

- Placebo ..... Oral azelastine 2.2mg - - Intranasal azelastine 0.28mg

60 120

Time (minutes)

180 240

Fig. 3. Mean symptom scores for severity of sneezing and itching of the nose and eyes during long term challenge, following pre­medication with placebo, oral azelastine 2.2mg or intranasal azelastine O.28mg.

Azelastine in Pollen-Induced Rhinitis

Sneezing and nasal hypersecretion result from the interaction of the preformed mediator, hista­mine, which is released from mast cells on contact with allergen, with HI-receptors on sensory nerve endings (Cauna et al. 1969). This has been con­firmed by the fact that specific HI-receptor antag­onists are very effective in relieving these symp­toms (Holmber et al. 1989; Howarth & Holgate 1984). However, it is generally accepted that, in addition to histamine, other newly generated me­tabolites of arachidonic acid, such as prostaglandin D2 (PGD2) and leukotrienes C4 and D4 (LTC4 and LTD4) contribute to allergen-induced nasal block­age (Bisgaard et al. 1986; Miadonna et al. 1987; Walsh et al. 1990). This may explain the much more rapid effect of azelastine, a potent and fast acting HI-receptor antagonist (Casale 1989; Spec­tor et al. 1987), on pollen-induced sneezing com­pared with nasal obstruction.

The mechanism through which azelastine inhib­its nasal blockage is unclear. In vitro, it has been shown to inhibit the release of LTC4 and LTD4 (Achterrath-Tuckermann et al. 1988; Katayama et al. 1987) and to antagonise their effect on guinea­pig ileum (Chand et al. 1986a; Katayama et al. 1987). In vivo, orally administered azelastine has a potent and long-lasting inhibitory effect on leukotriene-mediated bronchoconstriction in guinea-pigs (Chand et al. 1986b), but the same in­hibition is not reproduced in man (Albazzaz & Patel 1988). It therefore seems unlikely that the clinical effect of azelastine on nasal obstruction is mediated via inhibition of the release or actions of leukotrienes.

In addition to arachidonic acid derivatives, potent vasoactive peptides such as bradykinin have also been shown to induce nasal blockage (Rajakulasingam et al. 1990), as has the sensory neuropeptide, substance P (Devillier et al. 1988). The obstruction caused by vasoactive peptides has been shown to be receptor specific, in common with arachidonic acid metabolites, as the bradyki­nin metabolite, [des-arg9]-bradykinin, has no ef­fect on nasal airflow, nor does the PGD2 metabolite 9(Xll~PGF2 (Rajakulasingam et al. 1990). The ef-

39

fect of the ~2-agonist, [des-arg9]-bradykinin, is in­dicative of a direct effect of kinins on the vascular ~2-receptor. Azelastine, however, does not appear to interact with ~-receptors (Casale 1989), al­though it has been shown to block the activity of bradykinin (Inoue 1983).

Middleton et al. (1989) have suggested that probable diverse pharmacological activities do not all derive from direct receptor antagonism since it is unlikely that a single molecule could act as a receptor antagonist to such a structurally diverse group of agonists, postulating instead that azelast­ine most probably acts on a post-agonist-receptor interaction event such as an interaction with calmodulin, the ubiquitous Ca++-dependent en­zyme system.

Although the mechanism of action by which azelastine affects nasal patency is yet to be ex­plained' its efficacy against pollen-induced nasal blockage in addition to symptomatic control typi­cal of other antihistaminic compounds make it potentially extremely valuable in the treatment of allergic rhinitis.

The onset of action of azelastine in controlling symptoms occurs less than 1 hour after administra­tion by either the oral or the intranasal route, offer­ing rapid relief for rhinitis sufferers. Intranasal azelastine may prove useful for patients with rhinitis only where its proven efficacy when ap­plied topically at low doses suggest it to be a useful alternative to oral therapy with no anticipated sys­temic effects.

Acknowledgements

The author gratefully acknowledges the contribution of ASTA Pharrna AG, Frankfurt-am-Main, in supporting these studies.

References

Achterrath-Tuckermann U, Simmet T, Luck W, Szelenyi I, Peskar BA. Inhibition of cysteinyl-Ieukotriene production by azelastine and its biological significance. Agents and Actions 24: 217-223, 1988

Albazzaz MK, Patel KR. Effect of azelastine on bronchoconstriction induced by histamine and leukotriene C4 in patients with extrinsic asthma. Thorax 43: 306, 1988

40

Bisgaard H, Olsson P, Bende M. Effect of leukotriene D4 on nasal mucosal blood flow, nasal airway resistance and nasal secretion in humans. Clinical Allergy 16: 289-297,1986

Casale TB. The interaction of azelastine with human lung histamine HI, beta and muscarinic receptor sites. Journal of Allergy and Clin­ical Immunology 83: 771-776,1989

Cauna N, Hinderer KH, Wentges RT. Sensory receptor organs of the human nasal respiratory mucosa. American Journal of Anatomy 124: 1323-1328, 1969

Chand N, Diamantis W, Sofia RD. Antagonism of histamine and leukotrienes by azelastine in isolated guinea pig ileum. Agents and Actions 19: 164-168, 1986a

Chand N, Nolan K, Diamantis W, Perhach Jr JL, Sofia RD. Inhibition of leukotriene (SRS-A-mediated acute lung anaphylaxis by azelastine in guinea pigs. Allergy 41: 473-478, 1986b

Chand N, Pillar J, Diamantis W, Sofia RD. Inhibition of IgE-medi­ated allergic histamine release from rat peritoneal mast cells by azelastine and selected antiallergic drugs. Agents and Actions 16: 318-322,1985

Corrado OJ, Gomez E, Baldwin DL, Clague JE, Davies RJ. The effect of nedocromil sodium on nasal provocation with allergen. Journal of Allergy and Clinical Immunology 80: 218-222, 1987

Devillier P, Dessanges JF, Rakotosihanaka F, Ghaem A, Bousley HA, et al. Nasal response to substance P and methacholine in subjects with and without allergic rhinitis. European Respiratory Journal 1: 356-361, 1988

Dockhorn FJ, Bergner A, Connell JF, Falliers CJ, Grabiec Sv, et al. Safety and efficacy ofloratadine (Sch-29851), a new non-sedating antihistamine in seasonal allergic rhinitis. Annals of Allergy 58: 407-411, 1987

Holmber K, Bake B, Blychert LO, Pipkorn U. Effects of topical HI and 2 receptor antagonists on symptoms and local vascular reac­tions induced by nasal allergen challenge. Allergy 44: 281-287, 1989

Horak F, Jager S. The Vienna Challenge Chamber - a new method of allergy exposition tests. Wiener Klinische Wochenschrift 99: 509-510, 1987

Howarth PH, Holgate ST. Comparative trial of two non-sedative HI antihistamines, terfenadine and astemizole, for hayfever. Thorax 39: 668-672, 1984

Inoue Y. Basic studies on the antiallergic drug, 4-(p-chlorobenzyl)-2-[N-methylperhydroazepinyl-( 4)]-I-(2H)-phthalazinone hydro­chloride (azelastine). Nippon Ika Daigaku Zasshi 50: 371-378, 1983

Katayama S, Tsunoda H, Sakuma Y, Kai H, Tanaka I, et al. Effect of azelastine on the release and action of leukotriene C4 and D4. In­ternational Archives of Allergy and Applied Immunology 83: 284-289, 1987

Drug Invest. 7 (1) 1994

Kemp GJP, Buckley CE, Gershwin ME, Buchman E, Cascio FL, et al. Multicentre, double-blind, placebo controlled trial of terfenad­ine in seasonal allergic rhinitis and conjunctivitis. Annals of Al­lergy 54: 502, 1985

Lenhard G, Gerhardt G. Azelastine, a new drug in the treatment of allergic rhinitis. New England and Regional Allergy Proceedings 9: 366, 1988

Meltzer EO, Storms WW, Pierson WE, Cummins LH, Orgel HA, et al. Efficacy of azelastine in perennial allergic rhinitis: clinical and rhinomanometric evaluation. Journal of Allergy and Clinical Im­munology 82: 447-455, 1988

Miadonna A, Tedeschi A, Leggiere E, Lorini M, Folio G, et al. Behaviour and clinical relevance of histamine and leukotrienes C4 and B4 in grass pollen-induced rhinitis. American Review of Re­spiratory Diseases 136: 357-362, 1987

Middleton E, Ferriola P, Drzewiecki G, Sofia RD. The effect of azelastine and some other antiasthmatic and antiallergic drugs on calmodulin and protein kinase C. Agents and Actions 28: 8-15, 1989

Rajakulasingam K, Polosa R, Holgate ST, Church MK, Howarth PH. Comparative nasal responses to bradykinin, kallidin and des-arg9

bradykinin in non-rhinitic and atopic rhinitic subjects. Clinical and Experimental Allergy 20 (Suppl. 1): 57, 1990

Spector SL, Perhach JL, Rohr AS, Rackelefsky GS, Katz RM, et al. Pharmacodynamic evaluation of azelastine in subjects with asthma. Journal of Allergy and Clinical Immunology 80: 75-80, 1987

Walsh S, Robinson C, Howarth PH. The nasal effects of prostaglan­din D2 in non-rhinitic and atopic rhinitic subjects. Abstract. Clini­cal and Experimental Allergy 20: 115, 1990

Weiler JM, Donnelly A, Campbell BH, Connell JT, Diamond L, et al. Multicentre, double-blind, multiple dose, parallel-groups effi­cacy and safety trial of azelastine, chlorpheniramine, and placebo in the treatment of spring allergic rhinitis. Journal of Allergy and Clinical Immunology 32: 801-811, 1988

Zechel HJ, Brock N, Lenke D, Achterrath-Tuckermann U. Pharma­cological and toxicological properties of azelastine, a novel anti­allergic agent. Arzneimittel-ForschunglDrug Research 31: 1184-1193,1981

Correspondence and reprints: Prof. Dr Friedrich Horak, Universitat HNO-Klinik, AKH Wien, Wahringer Giirtel 18-20, A-I090 Vienna, Austria.