Allergology International (1998) 47: 59-67
Original Article
Effect of a thromboxane A2 receptor antagonist, ramatroban (BAY u 3405), on inflammatory cells, chemical mediators and non-specific nasal hyperreactivity after allergen challenge in patients with perennial allergic rhinitis
Nobuhisa Terada, Takayuki Yamakoshi, Masaya Hasegawa, Hirokazu Tanikawa, Hiroshi Nagata, Ken-ichi Maesako and Akiyoshi Konno
Department of Otorhinolaryngology, Chiba University School of Medicine, Chiba, Japan
ABSTRACT that ramatroban decreases important pathogenic factors in allergic rhinitis, resulting in an improvement In some clinical studies performed in patients with in nasal symptoms. perennial allergic rhinitis, ramatroban, a new throm boxane A2 receptor antagonist, significantly improved Key words: eosinophil, nasal allergen challenge, nasal symptoms. As yet the mechanism of action of this nasal mucosal reactivity, perennial allergic rhinitis, drug has not been fully elucidated. In the present study ramatroban, thromboxane A2 receptor antagonist. we investigated the effects of ramatroban on changes in nasal reactivity and levels of inflammatory cells and mediators in nasal lavage fluid after allergen INTRODUCTION challenge. Ramatroban was administered orally at a daily dose of 150 mg (b.i.d.) for 4 weeks to 11 patients Recent research has indicated that various mediators may with perennial allergic rhinitis exhibiting positive participate in the pathogenesis of allergic rhinitis in addi responses to nasal allergen challenge with house dust tion to histamine, which is known to play an important mite. Analysis of variance revealed that there was a role. These include leukotrienes (LT) and other inflam significant decrease in eosinophil counts and eosino matory mediators, such as prostaglandins (PG), throm phil cationic protein levels in nasal lavage fluid when boxane A2 (TXA2) and platelet-activating factor (PAF). compared with values immediately before allergen Prostaglandin D2 (PGD2) causes swelling of the nasal challenge before and after ramatroban treatment. rnucosc.' Thromboxane A2 causes constriction of lower Histamine, tryptase and albumin levels were signifi airway smooth muscle and increases vascular perme cantly decreased in analysis of variance before and ability and airway hvperreoctivitv.?" In the nasal mucosa, after ramatroban treatment. The degree of nasal where smooth muscle is localized in blood vessels, TXA2 reactivity to histamine was also significantly decreased probably plays an important role in the aggravation of after the ramatroban treatment. These findings indicate nasal allergic symptoms by increasing vascular perme ability and airway hyperreactivity.
Ramatroban (BAY u 3405)5 is a TXA2 receptor Correspondence: Dr Nobuhisa Terada, Department of antagonist synthesized by Bayer AG (Wuppertal, Otorhinolaryngology, Chiba University School of Medicine, Germany). Ramatroban has been reported to inhibit Inohana 1-8-1, Chuo-ku, Chiba, 260 Japan. Email:
Time (min) Fig. 1 The study schedule. Nasal -15 0 10 30 60 120 allergen (house dust) challenge and III I I I nasal lavage were performed at 15 and 0 min before and then 10, 30 Nasal allergen challenge t and 60 min after allergen challenge, and nasal reactivity to histamine was Nasal lavage t t t examined at 2 h after allergen chal Nasal reactivity to histamine lenge before and after 4 weeks treat ment with ramatroban (150 mg/day) The last tablet of ramatroban was administered 2 h before nasal allergen challenge. EFFECTS OF RAMATROBAN ON NASAL CHALLENGE 67 each side. lavage fluid recovered was measured, mixed 0.5 g or more, until these symptoms were attained. The thoroughly, filtered through a nylon filter net (Nippon number of sneezes and the weight of nasal secretions Rikagaku Kikai Co., Tokyo, Japan) to remove mucin and were measured during 10 min following application of then centrifuged for 20 min at 4°C at 400 g. The each dilution. Nasal secretion was collected as follows: supernatant was stored frozen at -80°C until assayed for the secretion was wiped off with tissue paper of a known chemical mediator levels. The sediment was subjected to weight during 10 min. Then, a patient was asked to blow inflammatory cell count measurement. his or her nose with the tissue paper after 10 min and the levels of mediators in nasal lavage fluid were measured weight of the nasal secretion collected in the tissue was by a third party, blinded to the purpose and details of the measured. study (Mitsubishi Kagaku Bio-Clinical laboratories Inc., Nasal reactivities to histamine before and after Tokyo, Japan). Eosinophil cationic protein (ECP), ramatroban treatment were evaluated using the histamine, tryptase and albumin were assayed using a following three parameters: (i) the threshold histamine Pharmacia ECP radioimmunoassay (RIA) kit (Pharmacia, concentration to induce one or more sneezes and to Uppsala, Sweden), a Histamine CT EIKEN kit (Eiken produce 0.5 g or more nasal secretion; (ii) the sum of Chemical, Tokyo, Japan), a Pharmacia Tryptase RIA CT® the number of sneezes and the amount of nasal (Pharmacia) and a Superior Microalbumin kit (Japan secretion induced by 0.001-0.25% histamine solution; DPC, Tokyo, Japan), respectively. and (iii) the degree of nasal reactivity, determined as a Cell counts were performed separately by two combination of the number of sneezes and the amount scientists. Eosinophils were counted by a hemato of nasal secretion induced by 0.001-0.25% histamine cytometer after staining cells with Hinkelman's stain. dilution, using the six grades shown in Table 1. Mean values of the counts obtained by two scientists were used for data analysis. Clinical symptoms
Patients were given allergy diaries to record nasal symp Nasal reactivity to histamine toms during the study period. Scores for nasal symptoms were evaluated using Okuda's evaluation criteric," with a Physiological saline solution and 0.001, 0.01, 0.1, 0.25, four grade scale of 3+,2+, + and -, at each scheduled 0.5 and 1% concentrations of histamine hydrochloride visit. General clinical laboratory findings (hematology, were prepared. Using a micropipette, physiological biochemical profile and urinalysis) were examined before saline and the histamine solutions were infused, at a vol and after ramatroban treatment, together with results ume of 20 III each, near the anterior end of the median of investigation of subjective and objective adverse plane of the right and left inferior conchae with increasing reactions. concentrations of histamine hydrochloride. Nasal pro vocation by histamine titration was continued for all Statistical analyses patients up to 0.25% histamine. Furthermore, nasal provocation was continued in patients in whom sneezing The following analysis was made for cell counts and had not been evoked once or more and/or in whom the mediator levels by converting measured values to log amount of nasal secretion produced had not exceeded arithms, as a study of the variance of measured values
Table 1. Criteria for the degree of nasal reactivity, obtained by combining the number of sneezes and the amount of nasal secretion induced by 0.001, 0.01, 0.1 and 0.25% histamine solution ------Degree of nasal reactivity + 2+ 3+ 4+ 5+ ---- No. sneezes* 0 1-2 3-6 7-10 11-15 :::;16 Amount of nasal secretion (g)t :::;0.7 0.8-1.0 1.1-3.0 3.1-6.0 6.1-10.0 s 10.1 When the degree determined for sneezing differed from that determined for nasal secretion, the higher degree was chosen and reduced by one grade. *Sum of the number of sneezes induced by 0.001, 0.01, 0.1 and 0.25% histamine solution; tsum of the amount of nasal secretion induced by 0.001,0.01,0.1 and 0.25% histamine solution. 62 N TERADA ET AL. implied that any of them were close to log-normal gen challenge after ramatroban administration in com distribution rather than normal distribution. Changes parison with before administration (Fig. 2). after allergen challenge against values immediately before allergen challenge were determined by the Mediator levels in nasal lavage fluid Wilcoxon signed rank test before ramatroban treatment Eosinophil cationic protein and at 4 weeks after ramatroban treatment. Different logarithmic values and logarithmic change rates [In Before treatment, ECP levels in nasal lavage fluid were (value after challenge/value immediately before significantly increased at 10 (P = 0.0039), 30 challenge)] before and after ramatroban treatment were (P = 0.0313) and 60 min (P = 0.0313) after challenge. compared using an analysis of variance for repeated However, after ramatroban treatment, a significant measures (ANOYA). When significant differences were increase in ECP levels was noted only 10 min after noted, comparisons were made at every time point with challenge (P = 0.0391). the Wilcoxon signed rank test. There were significant differences noted in logarithmic The Wilcoxon signed rank test was also used for com change rates between before and after ramatroban parison of nasal mucosal reactivity and nasal symptoms treatment by ANOYA (P = 0.0118). The logarithmic between before and after ramatroban treatment. change rates tended to decrease before and after P < 0.05 was considered statistically significant. ramatroban treatment at 10 min after allergen challenge Measured values are expressed as the mean ± SEM and (P = 0.0742). Comparison by logarithm before and after cell counts and mediator levels are expressed as the administration exhibited significant differences at 10 min geometric mean (± geometric standard error). Statistical after allergen challenge (P = 0.0195; Fig. 3a). analysis was made with the statistical software package SAS (SAS Institute Inc., Cary, NC, USA).
2.5 Q) 0) RESULTS c ** ~ Changes in eosinophil counts in nasal lavage 0 2.0 ..J:: r*, fluid u ~ * Before ramatroban treatment, eosinophil counts in nasal 0 '0) 1.5 ....0 lavage fluid were 143 ± 1.55 and 116 ± 1.40 /mL 15 <, Q) min before and immediately before nasal allergen 0) c * challenge, respectively; the counts were significantly ~ 1.0 0 increased 30 and 60 min after challenge, being 189 ± ..J:: U 1.46, 536 ± 1.57 (P = 0.0039) and 803 ± 1.51 /mL .... 2 0.5 (P = 0.0039) at 10, 30 and 60 min after challenge, '0 respectively. After 4 weeks ramatroban treatment, the .s eosinophil counts in nasal lavage fluid were 236 ± 1.40 o and 204 ± 1.29 /mL 15 min before and immediately o 10 30 60 before nasal allergen challenge, respectively. After Time after challenge (min) challenge, a significant increase was noted only at 60 min after challenge, with counts of 323 ± 1.45, 234 ± 1.44 and 472 ± 1.24 /mL (P = 0.0195) at 10, 30 and Fig. 2 Effect of ramatroban on the infiltration of eosinophils 60 min after challenge, respectively. in nasal lavage fluid after nasal allergen challenge. Eosinophil Analysis of variance showed significant differences in counts were measured before (0) and after (.) 4 weeks logarithmic change rates of eosinophil cell counts ramatroban treatment. Values are the mean ± SEM of logarithmic change rate from values before challenge [In (after between before and after ramatroban treatment (P = challenge/before challenge)] in nine patients. *P < 0.05, **P 0.0382; ANOYA). Logarithmic change rates against < 0.0 1 compared with before challenge (0 min). r*--, values immediately before allergen challenge exhibited a P < 0.05 compared with corresponding values before and significant decrease (P = 0.0391) at 30 min after aller- after ramatroban treatment. EFFECTS OF RAMATROBAN ON NASAL CHALLENGE 63
(a) (b) 15 10
8 _10 ::::;- ---I 6 E E <, <, en en c c 4 -5 "l 2 ...J*
0 0 ------~ -15 0 10 30 60 -15 0 10 30 60
(c) (d)
3 150
2 _ 100 ::::;- ---I E E <, l <, en en c * :::L J 50
_._-_._~--** --~~-- 0 ---_._---_... -~ 0 -----. -15 0 10 30 60 -15 0 10 30 60 Time after challenge (mi n)
Fig. 3 Effect of ramatroban on chemical mediators in nasal lavage fluid after nasal allergen challenge. (a) Eosinophil cationic protein (b) histamine, (c) tryptase and (d) albumin were measured before (--0--) and after (--e--) 4 weeks ramatroban treatment. Values are the geometric mean ± geometric SEM in nine patients. *P < 0.05, **P < 0.01 compared with values for 0 min before challenge. } P < 0.05, ~* P < 0.01 compared with corresponding values before and after ramatroban treatment.
Histamine Tryptase
Before ramatroban treatment, histamine levels in After allergen challenge, tryptase levels in nasal lavage nasal lavage fluid were quite high, even 15 min fluid were somewhat, but not significantly, increased at all before nasal allergen challenge. Although they monitoring points both before and after ramatroban decreased immediately before challenge due to the treatment. first nasal washing performed 15 min previously, they Comparison of logarithms before and after rama were significantly increased 10 min after challenge troban treatment exhibited significant differences by (P = 0.0391; Fig. 3b). Four weeks after ramatroban ANOYA (P = 0.0003). Tryptase levels were significantly treatment, no significant increases were noted in lower after ramatroban treatment at 15 min before histamine levels at any time point after allergen challenge, immediately before challenge and 30 and 60 challenge. min after challenge (P = 0.0195, 0.0039, 0.0391 and Comparison of logarithms before and after 0.0234, respectively; Fig. 3c). ramatroban treatment exhibited significant differences by ANOYA (P = 0.0026). Histamine levels were significantly Albumin lower after ramatroban treatment at 15 min before challenge (P = 0.0273) and 10 (P = 0.0117), 30 (P = After allergen challenge, albumin levels in nasal 0.011 7) and 60 min (P = 0.0273) after challenge. lavage fluid were significantly increased (P < 0.05) at 64 N TERADA ETAL.
(a) all time points tested, both before and after rama NS troban treatment. There was a tendency towards a decrease in logarithmic 6 change rates before and after ramatroban treatment by ANOVA (P = 0.0688). The logarithmic change rates were 5 significantly lower after ramatroban treatment at 30 min (P c = 0.0391) after allergen challenge. Significant differences E 0 4 were noted in logarithms before and after ramatroban r-- <, treatment by ANOVA (P = 0.0333), particularaly at 30 min
Fig. 4 Effect of ramatroban on nasal hyperractivity to histamine. The number of sneezes (a) and the amount of nasal Clinical symptoms secretions (b) were measured for 10 min after 0.25% histamine Clinical efficacy was determined for 10 of 11 patients solution challenge before and after 4 weeks ramatroban treatment in nine patients. Values are individual values and are participating in the study, excluding one patient whose also given as the mean ± SE (j). **P < 0.01 between before nasal symptoms were evaluated as mild in the run-in and after ramatroban treatment. NS, not significant (P ~ 0.1). period. Scores for nasal obstruction were significantly EFFECTS OF RAMATROBAN ON NASAL CHALLENGE 65
decreased from (mean ± SD) 1.8 ± 0.4 points before treatment to 0.9 ± 0.6 points after the 4 week rama troban treatment (P = 0.0078). 5+
> Adverse reactions U 4+ o No subjective/objective adverse reactions or abnormal ~ changes in laboratory test results were observed. o 3+ V) o c: '0 2+ DISCUSSION (I) (I) Thromboxane A and its receptors take part in the m+ 2 (I) o pathogenesis of allergic disorders via complex mecha nisms involving other inflammatory mediators. For
example, leukotriene (LT)C 4 and LTD4 induce broncho constriction via cyclo-oxgenase products, including
o 4 TXA29 11 and platelet-activating factor (PAF)-induced airway reactivity is inhibited by OKY 046, a TXA synthe Time after treatment (weeks) 2 tase inhibitor.'? Prostaglandin (PG)D2 and PGF2a induce airway constriction by binding to TXA receptors.P'!" In Fig. 5 Changes in the degree of nasal reactivity to histamine 2 before and after 4 week ramatroban treatment in nine patients. addition, ramatroban, a TXA2 receptor antagonist, has The degree of nasal reactivity was judged on the basis of both been shown to inhibit bronchoconstriction induced by the the sum of the numbers of sneezes and the sum of the amount TXA2 analog U46619, PGD 2 and PGF2a and even that by of nasal secretions induced by 0.001, 0.01, 0.1 and 0.25% the allergens LTC 4 and LTD4 . 17 These findings indicate histamine solution using the criteria shown in Table 1. that blockade of TXA receptor function by ramatroban *P < 0.05 between before and after ramatroban treatment. 2 can reduce levels of various mediators, such as LTC 4,
LTD4, PAF and PGD 2, which cause swelling of the nasal mucosa. In fact, ramatroban has been shown to improve various pathophysiological conditions in an experimental model of allergic rhinitis" and clinical findings in patients with perennial allergic rhinitis have confirmed the efficacy of rornotrobcn.? In the present study, inflammatory mediator levels and eosinophil counts in nasal lavage fluid after allergen challenge were compared before and after treatment with ramatroban in patients with perennial allergic
rhinitis. The effect of a TXA2 receptor antagonist on nasal reactivity to histamine was also examined. As shown in the present study, 4 week ramatroban treatment significantly inhibited the increase in eosinophil counts in nasal lavage fluid 30 min after allergen challenge. It also reduced ECP levels after challenge.
However, it has not been reported whether or not TXA2 itself possesses an effect on eosinophil chemotaxis. It is unclear how ramatroban reduces allergen-induced eosinophil infiltration and ECP levels in the nasal mucosa. Its possible mechanisms of action include the following: 1. It has been observed that ramatroban inhibits the release of RANTES (regulated on activation normal T 66 N TERADA ET AL.
expressed and secreted chemokine) induced by U46619 promote airway hvperreoctivitvv' Thromboxane A2 from human blood (S Sawada, pers. comm., 1996). It is synthetase inhibitors and TXA2 receptor antagonists, known that RANTES promotes adhesion of eosinophils to including ramatroban, have been reported to suppress 21 23 vascular endothelial cells, increases the passage of bronchial hyperreactivity in asthmatics. - Chung et al. eosinophils through vascular endothelial intercellular have attributed airway hyperreactivity induced by TXA2 to spaces and also has an eosinophil chemotactic effect. 18 its promotion of acetylcholine release from nerve Inhibition of eosinophil chemotaxis to nasal mucosa terminols." observed in the present study was possibly a result of In the present study, ramatroban treatment decreased inhibition of RANTES by ramatroban. levels of the basophil cell-derived mediators histamine 2. Eosinophils are considered to undergo chemotaxis from and tryptase. Levels of histamine and tryptase in nasal microvascular vessels to the nasal mucous membrane lavage fluid were significantly lower after treatment than proper, while increased vascular permeability appears to before treatment, even before allergen challenge. Our promote eosinophil chemotaxis in the presence of findings indicate that not only allergen-induced but also eosinophil chemotactic factors. Ramatroban inhibits spontaneous secretion of these mediators was inhibited increases in vascular permeability, as confirmed in the by ramatroban treatment. Proliferation of mast cells is present study by the finding that it significantly inhibited known to be enhanced by T cell-derived cytokines, such allergen-induced increases in albumin levels in nasal as interleukin-3, -4, -9 and _10. 25,26 It has also been lavage fluid, resulting in inhibition of eosinophil infiltration. reported that ramatroban inhibits lymphocyte infiltra The degree of nasal reactivity to histamine was tion.:" The present study suggests that decreases in significantly decreased after 4 weeks ramatroban tryptase levels in nasal lavage fluid resulted from a treatment, with a tendency towards a decrease in the decrease in the numbers of activated mast cells due to a number of histamine-induced sneezes and a significant decrease in lymphocyte infiltration into inflammatory decrease in the amount of histamine-induced nasal tissue. It has been recently reported that RANTES also secretion. These findings confirmed that ramatroban causes chemotaxis of mast cells. 28 Decreases in his attenuates non-specific nasal hyperreactivity. The tamine and tryptase levels may result from decreases in mechanism responsible for the reduction in nasal numbers of mast cells due to the inhibition of production hyperreactivity includes the following possibilities: and release of RANTES, as they also result from 1. We have previously reported a good correlation decreases in eosinophil counts. between ECP levels and nasal reoctivity." Inhibition of In conclusion, ramatroban, a TXA2 receptor antagon nasal reactivity by ramatroban may result from decreased ist, attenuated non-specific nasal hyperreactivity and ECP levels, because a high correlation was found decreased eosinophil counts, ECp, histamine, tryptase between the degree of nasal reactivity and ECP levels. and albumin levels in nasal lavage fluid. Our findings
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