`
`Paper 134
`
`Topical azelastine has a 12-hour duration of action as
`assessed by histamine challenge-induced exudation of
`Q;2-macroglobulin into human nasal airways
`
`L. GREIFF, M. ANDERSSON, C. SVENSSON and C. G. A PERSSON*
`
`Departments of Otorhinolaryngology, Head and Neck Surgery and *Clinical Pharmacology, Lund University Hospital,
`Lund, Sweden
`
`Summary
`
`Background Oral anti-histamine drugs are widely used in the treatment of seasonal
`allergic rhinitis. Recently, anti-histamines have become available also for topical treatment
`Objective The present study, involving healthy subjects, examined the effect of topical
`azelastine on iuminal entry of a2-niacroglobulin and symptoms evoked by repeat histamine
`challenges during 24 h. The effect was cotnpared to a clinical dose of the oral anti-histamine
`cetirizine and to placebo treatments.
`Methods Placebo and azelastine (0.254 mg per nasal cavity) were delivered as two
`consecutive actuations per nasal cavity using a nasal spray device. Oral placebo and
`cetirizine (lOmg) were given as single doses in a placebo-controlled (double-dummy),
`double-blind, and cross-over design. Histamine-challenges were given 1 h before treatment,
`and 1, 6. 9, 12. and 24 h after each treatment. The nasal mucosal surface was lavaged after
`each challenge. The lavage-fiuid levels of a2-macroglobulin were determined to assess
`mucosal exudation of bulk plasma, and nasal symptoms were scored.
`Results Histamine (40-400 figlmL) produced dose-dependent exudation and symptoms.
`Compared between each treatment and placebo, azelastine and cetirizine reduced the 40
`and/or 400^g/mL histamine-induced mucosal exudation of plasma from l-12h after
`treatment. In addition, cetirizine reduced the 40|tg/mL bistamine-induced mucosal exuda-
`tion of plasma 24 h after treatment. Differences between the two treatments were not evident
`regarding nasal symptoms.
`Conclusion Histamine challenge-induced mucosal exudation of plasma appears to be a
`useful method for studies of the duration of action of antihistamines. We conclude that
`topical azelastine is suited for b.i.d. therapy and that neither the exudative process nor
`watery secretion may impede the efficacy or the duration of action of tbis nasal drug.
`
`Keywords: allergy, antihistamine, rhinitis
`
`Clinical and Experimental Allergy, Vol. 27, pp. 438-444. Submitted 14 May 1996; revised
`16 July 1996: accepted 22 September 1996.
`
`Introduction
`
`Antihistamines have been used in the treatment of allergic
`airwaysdiseaseformorethan40yr. Recently, antihistamines
`such as azelastine have been introduced also for topical use in
`
`Correspondence: L. Greiff. Department of Otorhinolaryngology,
`Head and Neck Surgery, Lund University Hospital. S-221 85 Lund.
`Sweden.
`
`438
`
`allergic rhinitis. The duration of the pharmacological effect
`would be a major aspect of topical antihistamines in deciding
`dose intervals for efficacy around the clock. Weiler et at. [ 1J
`have shown that a clinical dose of topical azelastine may
`reduce major symptoms of seasonal allergic rhinitis for up to
`10 or 12h during natural pollen exposure. In a study invoi-
`^'"^ patients with seasonal allergic rhinitis OUt of season.
`Thomas et al. [2] have demonstrated that topical azelastine
`reduces histamine challenge-induced sneezes for lOh after
`
`© 1997 BlackweU Science Ltd
`Exhibit 1147
`IPR2017-00807
`ARGENTUM
`
`000001
`
`
`
`Duration of action of topical azelastine
`
`439
`
`treatment, whereas the histamine challenge-induced increase
`in nasal airway resistance (as measured by posterior rhino-
`manometry) was reduced for only l - 2h after treatment. It
`appears that further information on the duration of action of
`topical azelastine is warranted, particularly concerning its
`ability to counteract different pharmacological effects of
`histamine.
`We have shown previously that repeated histamine chal-
`lenges may evoke reproducible exudative effects (luminal
`entry of bulk plasma) over several hours [3]. The exudative
`action of histamine applied on the human nasal mucosa is
`concentration-dependent in the range 40-2000 ^g/mL [4].
`Hence, repeated histamine-induced mucosa! exudation of
`plasma might be employed as a method for determination of
`the duration of action of antihistamine drugs. Furthermore,
`the plasma exudation response may be a major action of
`histamine because this effect brings a wide range of adhesive
`proteins and other biologically active peptides/proteins to the
`lamina propria, the basement membrane, the epithelium, and
`the mucosal surface of the allergic mucosa.
`In the present study, we have examined the duration of
`the pharmacological effect of topically applied azelastine on
`luminal entry of plasma induced by repeated histamine-
`challenges. In addition, we have examined treatment effects
`on histamine-induced nasal symptoms. The effects of topi-
`cally applied azelastine have been compared to the effect of
`the oraJly administered aniihistamine drug cetirizine and to
`placebo.
`
`Methods
`
`Study design
`
`The study was of a placebo-controlled (double-dummy),
`double-blind, and cross-over design. Subjects were treated
`on three occasions, i.e. with active nasal spray (azelastine)
`and placebo tablets, with placebo nasal spray and active
`tablets (cetirizine), and with placebo nasal spray and pla-
`cebo tablets. The wash-out time was 2 weeks. Placebo and
`drug treatments were given as single doses and histamine-
`challenges were given 1 h before and 1, 6, 9, 12, and 24h
`after each treatment. The nasal mucosal surface was lavaged
`after each challenge and the lavage-fluid concentrations of
`a2-macrogiobulin were determined as an index of mucosal
`exudation of plasma. Furthermore, baseline and histamine-
`induced nasal symptoms were scored after each challenge.
`
`Subjects
`
`Twelve healthy subjects, 23-28 yr of age (mean age 25 yr),
`received histamine-challenges and placebo and drug treat-
`ment. The subjects had no history of general, allergic or
`recent nasal disease, and no history of recent drug treatment.
`
`The study was approved by the local ethics conninittee, and
`informed consent was obtained.
`
`Nasal pool challenge and lavage technique
`
`A nasal pool device was used for concomitant histamine-
`challenge and lavage ofthe nasal mueosa [4]. The nasal pool
`device is a compressible plastic container equipped with a
`nasal adapter. The adapter is inserted into one ofthe nostrils
`and the container is compressed by the sitting subject
`leaning forward in a 60° flexed neck position. The nasal
`poo! fluid is then instilled in one of the nasal cavities and
`maintained in contact with a large and reproducible area of
`the mucosal surtace for a determined period of time. When
`the pressure on the device is released, the fluid returns into
`the container. In the present study the total volume of the
`nasa] pool fluid was 14 mL.
`
`Drug treatment and histamine challenges
`
`The topical placebo and azelastine (0.254 mg per nasal
`cavity) drug solutions were delivered as two consecutive
`actuations per nasal cavity using a nasal spray device
`(0.254 mg azelastine corresponds to 0.280 mg azelastine
`hydrochloride). Oral p!acebo and cetirizine (!Omg) were
`given as sing!e oral doses. Using the nasal pool device,
`isotonic saline and histamine (40 and 400/ig/mL) were
`employed as challenge and lavage solutions 1 h before,
`and 1, 6, 9, 12 and 24h after each treatment. The solutions
`were given consecutively at each time point, and each
`solution was maintained in the unilateral nasal cavity for
`10min. The lavage fluids were centrifuged (325g, 10 min,
`4°C) and samples were obtained from the supernatant and
`frozen (—20°C) to await analysis of a2-macroglobulin.
`
`Analysis of (X2-macroglobulin
`
`The lavage fluid levels of a2"niacroglobulin were measured
`using a radio immunoassay sensitive to 7.8ng/mL. Rabbit
`anti-human a2-macroglobulin (Dakopatts, Copenhagen,
`Denmark) was used as anti-serum and standard human
`serum (Behringwerke Diagnostica, Marburg, Germany) as
`standard. Human
`a2-™acroglobulin
`(Cappel-Organon
`Teknika, Turnhout, Belgium) was iodinated using the lac-
`toperoxidase method. Tracer and standard (or sample) was
`mixed with anti-serum before adding goat anti-rabbit anti-
`serum (Astra Draco, Lund, Sweden). The bound fraction
`was measured using a gamma counter (Pharmacia, Uppsala,
`Sweden). The intra- and inter-assay coefficients of variation
`are between 3.8-6.0% and 3.1-7.2%, respectively.
`
`Symptom score
`
`Nasal symptoms, i.e. sneezes, secretion and blockage, were
`
`1997 Blackwell Science Ltd, Clinical and Experimental Allergy, 27, 438-444
`
`000002
`
`
`
`440
`
`L. Greiff Qi al.
`
`I
`
`T
`
`Time (hours)
`
`T
`
`12
`
`24
`
`Fig 1. Histamine produced dose-dependent
`mucosal exudation of bulk plasma (a^-
`macro-globulin) 1 h before treatment and
`l-24h after placebo treatment. The
`response to 40/ig/mL histamine decreased
`with time (Friedman P < 0.05). The
`reduction was significant at 6 and 12 h after
`treatment compared with before treatment.
`(Comparisons between levels obtained
`betbre treatment and I -24 h after
`treatment, *P < 0.05, **P<0.01.)
`Although mean values were reduced by
`repeat histamine challenge, there was no
`significant tachyphylaxis to 400^g/mL
`histamine (Friedman P > 0.05).
`D = control saline; HI = histamine (40/tg/
`mL); E = histamine (400/xg/mL).
`
`30n
`
`25
`
`20
`
`15
`
`10
`
`5 0
`
`E
`
`ooo(
`
`0E C
`
`M
`B
`
`scored by the subjects immediately after each cballetige
`using a symptom score: No —0, mild—1, moderate = 2,
`severe = 3 symptoms.
`
`before and after placebo were 0.69, 0.86 and 0.84. The
`latter coefficients are influenced by any degree of tachy-
`phylaxis to histamine and by any effects of topical and oral
`placebo.
`
`Statistics
`
`Differences in histamitie-induced nasal symptoms and 02-
`macroglobulin levels between the placebo and the two
`antihistamine treatments were analysed by tbe Wilcoxon
`signed rank (WSR) test. Differences in nasal symptoms and
`a2-macroglobulin levels within each treatment group were
`analysed by tbe Friedman test and the WSR test. A P-value
`less than 0.05 was considered significant. Data are presented
`as mean ± SEM.
`
`Re.sults
`
`Reproducibility of control saline and histamine challenges
`
`The mean of the intra-individual coefficients of variation
`calculated on lavage fluid levels of ai-macroglobulin after
`challenges with control saline, histamine (40^g/mL) and
`histamine (400/xg/mL), respectively, on three occasions
`before treatment were 0.71, 0.61 and 0.71. The mean of
`intra-individual coefficients of variation calculated on
`lavage fluid levels of a2-macroglobulin after cballenges
`with control saline, bistamine (40|tg/mL) and bistamine
`(400^g/mL), respectively, at the six challenge series
`
`Effect of treatment on mucosal exudation within the placebo
`group
`
`Tbe response to 40/ig/mL bistamine in the placebo group
`decreased witb time (Friedman P < 0.05). The reduction
`was significant at 6 and 12 h after treatment compared with
`before treatment (WSR /* < 0.05 and 0.01. respectively)
`(Fig. 1), confirming a certain degree of tacbypbylaxis to
`histamine [5]. Because of tbis tachypbylaxis in tbe plasma
`exudation response to histamine after placebo treatment, tbe
`primary comparisons in tbe present study are performed
`between each treatment and placebo at eacb time point.
`Altbough mean values were reduced by repeat challenge,
`tbere was no statistically significant
`tachyphylaxis to
`400/i,g/mL bistamine (Friedman P > 0.05).
`
`Effect of treatment on mucosal exudation between the
`treatmetit groups
`
`There were no differences in lavage fluid levels of a2-
`macrogiobulin after control saline and histamine challenge,
`respectively, between the treatment groups and placebo
`I b before treatment. Tbe azelastine-induced reduction in
`
`1997 Blackwell Science Ltd. Clinical and Experimental Allergy, 27. 438-444
`
`000003
`
`
`
`Duration of action of topical azelastine
`
`441
`
`A. 1 hour before treatment
`
`B. 1 hour after treatment
`
`20n
`
`15-
`
`0
`
`40
`
`400
`
`Histamine
`
`(^g/mL)
`
`C. 6 hours after treatment
`
`0
`
`40
`Histamine
`
`400
`
`E. 12 hours after treatment
`
`I
`
`T1
`
`400
`
`,
`
`"^ • T
`
`1—[;:;:;;;:& M
`0
`40
`
`Histamine
`
`40n
`
`30-
`
`20-
`
`f 10-
`a
`
`10H
`
`E —
`
`
`
`8-1
`
`6-
`
`I 4H
`
`ou f
`
` 2-
`B
`
`T
`
`**
`
`4 '*
`
`I
`
`I.
`
`40
`
`400
`
`-| . . . .-^TOM
`0
`
`Histamine
`
`D. 9 hours after treatment
`
`0
`
`40
`
`400
`
`Histamine (\iglmL)
`
`F. 24 hours after treatment
`
`I 10H
`cto
`
`5-
`
`o<
`
`s
`^
`
`15n
`
`E •
`
`^ 10H
`
`25-
`
`15-
`
`10H
`
`Iu
`
`CO
`£
`
`Ia3£
`
`
`
`o
`
`I
`
`0
`
`4a
`Histamine (|ig/mL)
`
`400
`
`\991 hXackweW SdencsUd. Clinical and Experimenlal Allergy.27.
`
`000004
`
`
`
`442 L Greiff etal
`
`histamine (40/xg/mL) mueosal exudation was significant
`when compared with placebo at 1 and 9h after treatment
`(Eig. 2B and D) and the reduction in histamine (400 fig/mh)
`mucosal exudation was significant compared with placebo
`at 1, 6, 9, and 12 h after treatment (Eig 2B, C, D and E). The
`cetirizine-induced reduction in histamine (40/xg/niL) muco-
`sal exudation was significant compared with placebo at 1,6,
`9, and 24 h after treatment (Fig. 2B, C, D and E) and the
`reduction in histamine {400figlmL) mucosal exudation was
`significant compared with placebo at 1, 6, 9 and 12h after
`treatment (Fig. 2B, C, D and E).
`
`Effect of treatment on nasal symptoms between the
`treatment groups
`
`The treatment with azelastine as well as cetirizine reduced
`the histamine-induced sneezes and secretion but not block-
`age when symptoms between the treatment groups and
`placebo were compared (Table 1 A-C). There were no
`differences for either symptom between the treatment
`groups before treatment. When comparing the differences
`between azelastine and ceterizine, respectively, and pla-
`cebo, azelastine as well as cetirizine significantly reduced
`the sneezes after histamine (400/ig/mL) 1, 9 and 12 h after
`treatment (Table 1 A). Azelastine reduced the secretion after
`histamine (40/^g/mL) lh after treatment as well as after
`bistamine (400/ig/mL) 12-12h after treatment (Table IB).
`Cetirizine reduced the secretion after histamine (400/xg/
`mL) and 24 h after treatment as well as after histamine
`(40 fig/mL) 9 h after treatment.
`
`i
`
`Discussion
`
`Tbe present study, involving healthy subjects, has demon-
`strated tbat a single dose of topical azelastine significantly
`reduces nasal bistamine challenge-induced mucosal exuda-
`tion of a2-macrogiobulin for 12 h. In addition, tbis drug witb
`a similar duration of action reduced the sneezing and tbe
`secretory responses evoked by tbe histamine cballenges.
`Topical azelastine was generally comparable to oral cetirizine
`concerning effect and duration of action.
`j
`^
`In allergic rbinitis, the acute response to allergen
`cballenge is dependent on bistamine, and treatment witb
`anti-histamines bave marked anti-allergy effects in allergen
`cballenge models [6-8]. Histamine cballenge, similar to
`acute allergic airway conditions, produces several symp-
`
`toms along witb mucosal exudation of plasma. As expected
`[9], mucosai exudation of Q!2-macroglobulin, contrasting
`measurements of symptoms, was a sensitive and graded
`response suited for quantitative measurements (tbis study).
`Histamine at the lower concentration (40/ig/mL) thus pro-
`duced significant mucosal exudation of plasma in the
`absence of symptoms, and at tbe larger concentration
`(400^g/mL) it produced an approximately 20-fold inerease
`in lavage fluid levels of Q:2-macroglobulin compared to
`baseline. The mean exudative response to bistamine was
`redueed by repeated challenges (seen with botb dose levels
`but statistically significant only with the lower dose). Such a
`reduction has previously been recorded in the nose [5] and
`may relate to a tachypbylaxis that may occur with bista-
`mine-type mediators at the level of microvascular perme-
`ability regulating cells [10]. Tbe primary comparison was,
`therefore, made between eacb treatment and placebo.
`Tbe anti-exudative effect and its duration was 12 h for botb
`drugs. Cetirizine appeared at least as potent as azelastine witb
`somewhat superior inhibition at 6 and 9 h after treatment.
`Cetirizine also was tbe only drug tbat sbowed some efficacy
`after 24 h and then exclusively against tbe low concentration
`of bistamine- These data may need confirmation, particularly
`since tbey differed from tbe 12-b findings. Tbe present
`findings suggest tbat around tbe elock anti-exudative effects
`require administration twice daily of eitber topical azelastine
`or oral ceterizine.
`Tbe present observations on symptoms confirm and
`extend tbe work by Thomas et al. [2] who observed a 10-b
`duration of action of topical azelastine on histamine-induced
`sneezing. Tbomas et al. [2] ftirtber reported tbat topical
`azelastine only bad effect for 2h on bistamine cballenge-
`induced increase in nasal airway resistance. In accordance,
`tbe present study demonstrated little effects in general on
`nasal blockage: Only a non-significant tendency {P = 0.06)
`was recorded at 1 h after topical azelastine treatment. In
`addition, this study recorded a 12-h duration of effect of
`secretion by azelastine. Tbis may reflect a true pbarmacolo-
`gical inbibition althougb tbe recording of 'subjective' secre-
`tion eould bave been somewbat influenced by tbe repeated
`nasal lavage procedures.
`'
`A potentially more important aspect concerns the fact that
`azelastine bad a long duration of action despite the lavages
`since tbese eould bave removed tbe topically applied drug.
`Indeed, tbe antibistaminic efficacy of azelastine at 1 h before
`tbe first lavage had been carried out was generally not
`
`Fig 2. Effects of topical azelastine, oral ceterizine and placebo on histamine challenge-induced mucosal exudation of bulk plasma (o;2-
`macroglobulin). Treatments were given at time point zero and challenges with eontrol saline histamine (40 and 400/xg/mL) were given 1 h
`before treatment and 1-24 h after each treatment. (Comparisons between each treatment and placebo, *P<0.05. **P<0.01).
`D = azelastine; 03 — cetirizine; M = placebo.
`' •
`
`1997 Blackwell Science Ltd, Clinical and Experimental Allergy, 27, 438-444
`
`000005
`
`
`
`Duration of action of topical azelastine
`
`443
`
`Tabie 1. Effects of topical azelastine, oral eeterizine and placebo on histamine ehallenge-indueed sneezes. Histamine challenges were
`given 1 h before treatment and 1, 6, 9, 12, and 24h after each treatment. (Comparisons between eaeh treatment and placebo, */* < 0.05,
`**/'<0.01).
`
`Azelastine
`
`Cetirizine
`
`Histamine
`
`Histamine
`
`Plaeebo
`
`Histamine
`
`Time
`
`Control
`
`40 fig/mL
`
`ImL
`400 M&
`
`Control
`
`40 Mg/mL
`
`400 Mg/mL
`
`Control
`
`40 fig/mL
`
`400 Mg/mL
`
`2.17 ± 0.69
`1.42 ± 0.53
`0.33 ± 0.26
`1.67 ±0.51
`LOO ±0.39
`0.42 ± 0.26
`
`0.08 ± 0.08
`0.33 ±0.19
`0.25 ±0.25
`
`00 0
`
`0 0 000 0
`
`1.33 ±0.38
`0*
`
`0 0
`
`*
`0*
`0
`
`0.50 ± 0.29
`
`00000
`
`0 00000
`
`0.89
`
`0.36
`
`1.92 ±
`0*
`
`00
`
`*
`0*
`0.50 ±
`
`0.25 ±0.18
`
`0 0 0 0 0
`
`0 0 0 000
`
`-1
`
`1 6 9
`
`12
`24
`
`Table 2. Effects of topical azelastine, oral eeterizine and placebo on histamine challenge-induced secretion. Histamine challenges were
`given 1 h before treatment and 1, 6, 9, 12, and 24 h after each treatment. (Comparisons between each treatment and placebo, *P < 0.05,
`
`Azelastine
`
`Cetirizine
`
`Placebo
`
`.
`
`;
`
`••
`
`• ; - ' ••
`
`J.
`
`.
`
`Histamine
`
`Histamine
`
`Histamine
`
`Time
`
`Control
`
`40 Mg/mL
`
`400Mg/mL
`
`Control
`
`40 Mg/mL
`
`400 Mg/mL
`
`Control
`
`40 Mg/mL
`
`ug/tnL
`400 J
`
`0.42 ±0.19
`0.50 ±0.15
`0.42 ±0.15
`0.50 ±0.15
`0.25 ±0.13
`0.33 ±0.14
`
`1.17 ±0.24
`1.00 ±0.21
`0.83 ± 0.24
`1.08 ±0.26
`0.92 ±0.15
`1.08 ±0.23
`
`0.08 ± 0.08
`
`000
`
`.08 ± 0.08
`
`00
`
`0.58 ±0.19
`0.25 ±0.18
`0.17 ±0.11
`0*
`0.08 ± 0.08
`0.08 ± 0.08
`
`1.17 ±0.21
`0.50 ±0.19
`0.50 ±0.19
`0.25 ±0.13*
`0.50 ±0.15
`0.33 ±0.15**
`
`.17±0.11
`
`0 0
`
`0000
`
`LOO ±0.17
`0.33 ±0.14*
`0.33 ±0.19*
`0.42 ±0.15*
`0.25 ±0.13*
`0.75 ± 0.25
`
`0.42 ±0.15
`O.i7±O.ll*
`0.33 ±0.19
`0.17 ±0.11
`0.17±0.11
`0.25 ±0.13
`
`to.u
`tO.O8
`t:0.08
`tO.O8
`
`000
`
`.17:
`0.08:
`0.08:
`0.08:
`
`-1
`
`169
`
`12
`24
`
`Table 3. Effects of topical azelastine, oral ceterizine and placebo on histamine challenge-induced blockage. Histamine challenges were
`given 1 h before treatment and 1, 6, 9, 12, and 24 h after each treatment. (Comparisons between each treatment and placebo, *JP < 0.05,
`**P<O.Ol).
`
`Azelastine
`
`Cetirizine
`
`. .... ,
`
`.,,
`
`Histamine
`
`-
`
`Histamine
`
`Placebo
`
`Histamine
`
`Time
`
`Control
`
`40 Mg/mL
`
`400 Mg/mL
`
`Control
`
`40 Mg/mL
`
`400 Mg/mL
`
`Control
`
`40 Mg/mL
`
`400 Mg/mL
`
`0.17 ±0.11
`0.17±0.11
`0.25 ±0.13
`0.17±0.U
`0.08 ± 0.08
`0.08 ± 0.08
`
`1.08 ±0.19
`0.33 ± 0.22
`0.42 ±0.19
`0.42 ±0.15
`0.33 ±0.14
`0.50 ±0.15
`
`2.00 ±0.17
`0.92 ± 0.26
`1.50 ±0.23
`1.50 ±0.19
`1.25 ±0.33
`1.50 ±0.19
`
`0.11
`0.19
`0.08
`0.11
`0.13
`
`0.17 ±
`0.33 ±
`0.08 ±
`0.17 ±
`0.25 ±
`0
`
`1.17 ±0.27
`0.75 ± 0.25
`0.67 ± 0.19
`0.50 ±0.19
`LOO ±0.25
`0.17 ±0.11*
`
`2.00 ± 0.25
`1.33 ±0.31
`1.42 ±0.23
`1.42 ±0.29
`1.83 ±0.27
`0.75 ± 0.22*
`
`0.08 ± 0.08
`0.50 ±0.15
`0.25 ±0.13
`0.25 ±0.13
`0.25 ± 0.07
`0.42 ±0.19
`
`0.58 ±0.15
`0.68 ±0.19
`0.75 ± 0.25
`0.83 ± 0.30
`0.58 ±0.19
`0.92 ± 0.23
`
`1.92 ±0.19
`1.58 ± 0.29
`1.50 ±0.29
`1.58 ±0.34
`1.58 ±0.31
`1.58 ±0.34
`
`-1
`
`169
`
`12
`24
`
`1997 Blackweli Science Ltd, Clinical and Experimental Allergy, 27, 438-444
`
`000006
`
`
`
`444
`
`L. Greiff Qtal
`
`greater than that recorded at later time points. This observa-
`tion further indicates that the repeated histamine-evoked
`plasma exudation and secretory responses across the nasal
`mucosa did not impede the efficacy of the topical drug. On
`one hand il was reassuring to know that the topical anti-
`histamine drug is not washed away from mucosal sites of
`histamine actions by proteinaceous and watery lavages of
`the mucosal tissue and surface. On the other hand these data
`may underscore the importance of careful studies of any
`contribution of systemically absorbed azelastine to the nasal
`actions of this drug.
`The primary effect parameter in the present study was the
`induced plasina exudation response. Histamine may act
`directly on the endothelial cells of post-capillary venules
`to increase the macromolecuiar permeability of the sub-
`epithelial airway microcirculation (II]. Through the gaps in
`the venular wall non-sieved bulk plasma is extravasated
`along a hydrostatic pressure gradient: When this response Is
`evoked in the superficial microcirculation of the airway
`mucosa, the extravasated plasma first distributes in the
`lamina propria and then moves up between epithelial cells
`and produces paracellular pathways for its clearance into the
`airway lumen [i2|. Since the lumenal entry is a prompt
`event and a major clearance route for exuded plasma, the
`extravasation process in the airways can be well monitored
`by analysing the concentrations of plasma proteins in airway
`mucosal surface liquids. The present study confirms the
`exudative effect of histamine and demonstrates, as
`expected, marked anti-exudative effects of oral cetirizine
`and nasal azelastine. It is likely that the anti-permeability
`effects of the antihistamines in the present study reflect
`actions on H|-receptors on the permeability regulating
`endothelial cells ofthe subepithelial microcirculation [131.
`Effects on the permeability of the epithelial lining are not
`likely as the movement of bulk plasma through paraceilular
`epithelial pathways appears to be a self-sustained process
`regulated by an increased hydrostatic pressure created by
`the exudate itself [12].
`We conclude that topical azelastine and systemical cetir-
`izine reduce histamine-induced mucosal exudation of
`plasma and symptoms in human nasal airways. The duration
`of the pharmacological effects of azelastine support a b.i.d.
`dose regimen of this antihistamine. We suggest that hista-
`mine-induced mucosal exudation of bulk plasma is a useful
`clinical experimental model to determine the duration ofthe
`pharmacological effect of anti-histamines.
`
`Acknowledgements
`
`The present study is supported by the Swedish Medical
`
`Research Council (project 8308), the Medical Faculty of
`Lund University, and the Swedish Association against
`Asthma and Allergy. We thank Ms Berit Holmskov and
`Ms Christel Larsson for expert laboratory and bioanalytical
`assistance.
`
`References
`
`1 Weiler JM, Mellzer EO, Benson PM et al, A dose-ranging
`study ofthe efficacy and safety of azelastine nasal spray in the
`treatment of seasonal allergic rhinitis wilh an acute model, j
`Allergy Clin [mmunol 1994; 94:972-80.
`2 Thomas KE, Oilier S. Ferguson H, Davies RJ. The effect of
`intranasal azelastine. Rhinolast*, on nasal airways obstruction
`and sneezing following provocation testing with histamine and
`allergen. Clin Exp Allergy 1992; 22:642-7.
`3 Svensson C. Baumgarten CR, Pipkom U, Alkner U, Persson
`CGA. Reversibility and reproducibility of histamine induced
`plasma leakage in nasal airways. Thorax 1989: 44: 13-18.
`4 Greiff L, Pipkom U. Alkner U, Persson CGA. The "nasal pool-
`device' applies controlled concentrations of solutes on human
`nasal airway mucosa and samples its surface exudations/
`secretions. Clin Exp Allergy 1990; 20:253-9.
`5 Greiff L. Andersson M. Svensson C. Alkner U, Persson CGA.
`Glucocortieoids may not inhibit plasma exudation by direct
`vascular affects in human airways.Enr Resp J 1994; 7:1120-4.
`6 Bousquet J. Lebel B. Chanal I, Morel A. Michel EB. Anti-
`allergic activity of H]-reccptor antagonists assessed by nasal
`challenge. J Allergy Clin Immunol 1988; 82:881-7.
`7 Naclerio RM, Kagey-Sobotka A. Liehtenstein LM, Eiredhoff L,
`F*roud D. Terfenadine, an H| antihistamine. inhibits histamine
`release in vivo in the human. Am Rev Respir Dis 1990;
`142:167-71.
`8 Greiff L, Persson CGA, Svensson C, Enander 1, Andersson M.
`Loratadine reduces allergen-indueed mucosal output of 02-
`macroglobulin and tryptase in allergic rhinitis. J Allergy Clin
`Immunol 1995; 96:97-103.
`9 Svensson C, Andersson M, Greiff L, Alkner U, Persson CGA.
`Exudative hyperresponsiveness of the airway microcirculation
`in seasonal allergic rhinitis. Clin Exp Allergy 1995; 25:942-50.
`10 Svensjo E. Joyner WL. The effects of intermittent and con-
`tinuous stimulation of microvessels in Ihe cheek pouch of
`hamsters with histamine and hradykinin on the development
`of leaky sites. Microvasc Endothel Lymph 1984: 1:381-96.
`11 Majno G, Palade GE, Schoefl GI. Studies on inflammation II.
`The site of action of histamine and serotonin along the vascular
`tree: a topographic study. J Biophys Biochem Cytol 1961;
`11:607-26.
`12 Persson CGA, Andersson M, Greiff L et al. Airway perme-
`ability. Clin Exp Allergy 1995; 23:807-14.
`13 Grega GJ, Persson CGA. Svensjo E. Endothelial cell reactions
`to inflammatory mediators assessed by fluid and solute flux
`analysis. In: Ryan US, ed. Endothelial eells. Boea Raton; CRC
`Press, 1988:103-19.
`
`1997 Blackwell Stiente Ltd. Clinical and Experitnental Allergy, 27, 438-444
`
`000007
`
`
`
`This document is a scanned copyof a printed document. No warranty is given about
`the accuracy of the copy. Users should refer to the original published version of the
`material.
`
`000008
`
`000008
`
`