Effect of Ibudilast: A Novel Antiasthmatic Agent, on Airway Hypersensitivity in Bronchial Asthma

Transcription

1 Journal of Asthma, 29(4), (1992) Effet of Ibudilast: A Novel Antiasthmati Agent, on Airway Hypersensitivity in Bronhial Asthma Akira Kawasaki, M.D., Kiyoshi Hoshino, M.D., Rokuo Osaki, M.D., Yutaka Mizushima, M.D., and Saburo Yano, M.D. First Department of Internal Mediine Toyania Medial and Pharmaeutial University 263 Sugitani Toyama, Japan 93-1 ABSTRACT Ibudilast, a unique agent with vasodilating and antiallergi ations, was studied in 13 asthmatis for its effet on airway hypersensitivity to histamine inhalation. The PC2 values improved signifiantly from to 62.5 &mi at 3 months and further to pghl at 6 months following the initial treatment with ibudilast (2 mg twie daily orally). In addition, the severity of the attaks dereased signifiantly. Improvements in the PC2,, and asthmati symptoms also were observed in the disodium :hrornoglyate group, but these were equal to or lesser than those in the ibudilast group. No improvement was observed in the untreated ontrol group. These results suggest that ibudilast would be an effetive agent for improving nonspeifi airway hypersensitivity in asthmatis. INTRODUCTION After the introdution of disodium romoglyate (DSCG) (11, many so-alled antiallergi agents suh as tranilast (21, ketotifen (3), azelastine (4), amoxanox (51, repirinast (6), and ibudilast have been developed in rapid suession in Japan and used for the treatment of bronhial asthma. Among them, ibudilast seems to be espeially unique, for vasodilating and antiallergi effets (7 3). Therefore, this agent is used linially for the Copyright 1992 by Marel Dekker, In. 245

2 246 Kawasaki et al. treatment of both erebrovasular disorders and bronhial asthma in this ountry. In this study, we examine what effets this unique agent has on airway hypersensitivity in bronhial asthma. MATERIALS AND METHODS Antiallergi Agents and Subjets Disodium romoglyate (DSCG) is a produt of Fujisawa Pharma Co., Ltd., Osaka, Japan, and is administered by inhalation therapy. Ibudilast, 3-isobutyryl-2-isopropylpyrazold1, 5-alpyridine, is a produt of Kyorin Pharma Co., Ltd., Tokyo, Japan and administered orally. Thirty patients diagnosed with bronhial asthma were studied; 17 male and 13 female, 15 extrinsi and 15 intrinsi types of asthma. Their ages ranged from 18 to 58 years old (mean 36.4 years) and all were nonsmokers. When their asthmati symptoms were wellontrolled and/or xanthine derivatives, they were enrolled in this study. No patient was reeiving ortiosteroid or gold therapy. The harateristis of the patients in the ibudilast, DSCG and ontrol groups are shown in Table 1. Histamine Inhalation Test The histamine inhalation test was onduted in aordane with the method advoated by the Japanese Soiety of Allergology. Briefly, aerosols were generated with a Devilbiss nebulizer (type 646) at an air flow of 5 L/min. Inhalation was administered for 2 minutes during quiet breathing through the mouth at 5-minute intervals. First an isotoni.9% saline solution was inhaled, followed by inreasing onentrations of histamine from 2 pg/d in twofold inrements. The fored expiratory volume in one seond (FEV,) was measured before the inhalation of saline and after eah inhalation of histamine. The test was ontinued until the FEV, had fallen by 2%. The histamine PCzo was alulated by linear interpolation between the last two data points on the dose-response urve. Prior to this test, all drugs were withheld for 24 hours. In order to avoid possible daily hanges in response to histamine, the test was performed between 9 A.M. and 12 A.M. Study Design Table 1. Patient Charateristis All patients were treated initially with - stimulants and/or xanthine derivatives. When the asthmati symptoms were under ontrol, ibudilast (2 mg bid orally) or DSCG (2 mg qid by inhalation) was administered in addition and/or xanthines. Patients were evaluated for airway hypersensitivity, linial symptoms, the serum IgE levels and peripheral eosinophil ounts at 3 and 6 months following the initiation of antiallergi agents. Severity of asthmati symptoms was evaluated in the month prior to IBU Dl LAST DSCC CONTROL Number Age 37.4~ (f 14.4) 29.2~ (f 6.8) 4.1~ (f 13.2) Duration of illness 5.2~ (f 2.3) 1.9y (f9.3) 5.~ (f 4.8 TY Pe extrinsi intrinsi Severity of disease mild moderate Observation period (weeks) 25.9 f f _+ 5.9 Maintenane mediations P-Agonist 9/13 (69.2%) 6/7 (85.7%) 7/1 (7.%) Theophyl I i ne 11/13 (84.6%) 6/7 (85.7%) 9/1 (9.%)

3 Ibudilast and Airway Hypersensitivity 247 eah histamine inhalation. Symptoms were lassified into four grades; severe, moderate, mild, and symptom free. This was in aordane with the severity and the frequeny of the asthmati attaks. Symptom free was defined as having had no asthmati attak in the one month period prior to eah test. The effets on airway hypersensitivity were assessed by the hanges in FC2. Namely, a twofold inrease in PC2 after treatment was defined as improvement (1 +), and more than a fourfold inrease in PC2 as improvement (2+). On the ontrary, a twofold derease in PC2 was defined as exaerbation (- 1). Statistis Data are expressed as the mean k SD. Statistial signifiane was evaluated by the Wiloxon s test or Fisher s exat probability test, and a p.5 level of signifiane was adopted throughout the study. RESULTS Changes in Airway Hypersensitivity and Clinial Symptoms in Ibudilast-Treated Bronhial Asthma Patients The hanges in FEV1, PCza, and linial symptoms in 13 ibudilast-treated patients are Table 2. shown individually in Table 2. The PCz, values signifiantly inreased from pg/ml to 62.5 M/ml at 3 months and further to pg/ml at 6 months following the initial treatment with ibudilast. Individual improvement in airway hypersensitivity for 6 months was observed in 7 patients and exaerbation in 1 patient and no hange ourred in 5 out of 13 ases (Fig. 1). There was no signifiant differene in the baseline value for the FEVl among these points. Derease in severity of the disease also improved signifiantly. Among the 13 ases, 4 beame symptom free at 3 months and 8 at 6 months (Fig. 2). There was no statistial differene in the eosinophil ounts and serum IgE levels (Fig. 3). Changes in Airway Hypersensitivity and Severity of Symptoms in Ibudilast-, DSCG-Treated, and Control Groups The improving effets of ibudilast on airway hypersensitivity and severity of symptoms were roughly ompared with those of DSCG. As shown in Table 3, improvements in PCzo and linial symptoms were also observed in the DSCG-treated group, but were poorer than in the ibudilast group. No improvement was observed in the ontrol group. Changes in FEV,, PC2, and Symptoms in lbudilast Group FEVl (Ll PC2 (aglrnll JUDGEMENT SYMPTOM CASE BEFORE 3M 6M BEFORE 3M 6M 3M 6M BEFORE 3M 6M f f i O Mi Id Moderate

4 248 Kawasaki et al. 1,- I p< 5 1 h -. E m 3 Y 5,- 2,5- (%),oo UJ s 8-.- a (II Q r a C a 2 n.- E K S a S 8 a.- C E m.- UJ I 6-4- a 2-1, I I I I I Before 3M 6 M Figure 1. Changes in P2 of histamine in ibudilast-treated group. I H moderate mild symptom-free 1 Before 3 M 6M Figure 2. Changes in severity of disease in 13 ases of ibudilast-treated group.

5 Ibudilast and Airway Hypersensitivity 249 ' ' 2 e m E 81: E v u) 4- K u) 4 2 v- Before 3 M 1.- 5,- 2,5-1, M -. h E a > - a W - a E 1 3 L $ 5 P Before 3'M 6'M Figure 3. Changes in eosinophil ounts (a) and serum IgE levels (b) in ibudilast-treated group. lbudilast rp < O o 5 i 7- DSCG Control r - NS1 I NS Before 6 M Before 6M I Before 6M Figure 4. Changes in PC2 of histamine in the three groups. -: improved ases; -: unimproved ases.

6 25 Kawasaki et al. Table 3. Changes in Airway Hypersensitivity and Severity of Symptoms in the Three Groups p2 Wml) SYMPTOM-FREE CASE (%) BEFORE 6M IMPROVED CASE (%) BEFORE 6M lbudilast (n = 13) , /13 (53.8'/)~ 2/13 (15.4%) + 8/13 (61.5'/)~ DSCC (n = 7) , (28.6%) 17 (%) (57.1%) Control (n = 1) , /1 (%) 1/1 (1.%) + /1 (%) ap <.5 ompared with the ontrol group by Fisher's exat probability test. Comparison of Fators Between Airway Hypersensitivity-Improved and Unimproved Cases The fators whih would affet the effet of antiallergi agents on airway hypersensitivity are analyzed in Table 4. A signifiant differene was observed only in the pc2 values between the two groups. The value of PCz was signifiantly lower in the improved ases (9.7 vs. 96. pg/ml). The PCzo improved signifiantly from 9.7 to 389. pg/ml(96.3 to in ibudilast only) in the improved group, and from 96. to 825. pg/ml(l632.6 to in ibudilast only) in the unimproved group. Table 4. DI SCU SSI N Antiallergi agents generally are lassified into two groups (9); the basi type whih has an antihistamine ativity, and the aidi type whih has no antihistamine ativity. Ibudilast has no antihistamine ativity, but does not belong to either of these two groups. The effets of ibudilast on airway hypersensitivity have not yet been demonstrated learly. This preliminary study indiates that ibudilast has the ability to derease airway hypersensitivity in response to histamine inhalation for patients with bronhial asthma. The PC2 values improved signifiantly from to pg/ml with Comparison of Fators Between Airway Hypersensitivity Improved and Unimproved Cases IMPROVED CASES UNIMPROVED CASES Number 9 ma 11 (6) Gender (male:female) 4:5 (4:3) 9:2 (3:3) Age 33.9 (36.) 35.1 (39.) Duration of illness (year) 7.2 f 7.9 (5.2) 7. f 6. (4.9) Type of asthma extrinsi 4 (3) 5 (2) intrinsi 5(4) 6 (4) Severity of disease moderate 4 (3) 4 (3) mild 5 (4) 7 (3) PC2 (glml) 9.7b (96.3)b 96. (1632.6) Eosinophil Vmm3) f 185. (282.4) 38.4 f (363.6) IgE (U/ml) 28.6 f (216.7) f 598. (159.8) FEV1. (L) 2.6 f.6 (2.4) 2.73 f.7 (2.45) adata in parentheses inlude only ibudilast-treated ases. bp <.5 as ompared with unimproved ases by Wiloxon's test.

7 Ibudilast and Airway Hypersensitivity month oral administration of this agent. Improvement of symptoms was also observed in parallel with airway hypersensitivity. The improving effet of this agent appeared to be equal to or greater than that of DSCG. Our result was supported by Umedas observation (Fujita-Gakuen Health University, Japan), in whih improvement of airway hypersensitivity to methaholine inhalation was observed in 4 of 6 asthmatis after 4 weeks oral administration of ibudilast (personal ommuniation). Ibudilast is now used linially in Japan for the treatment of allergi diseases suh as bronhial asthma and for erebrovasular disorders. No serious adverse effet has been reported; nausea, abdominal disomfort, et. at less than 1%. Conerning the vasodilating effet, Ohashi et al. (1) reported in anine basilar artery system that this was via the augmentation of PG12 ation by ibudilast. Antithromboti ation was also noted. Conerning the antiallergi effet, Nishino et al. (8) and Nagai et al. (11) stated that this agent demonstrated a fairly seletive antagonisti ation against slow-reating substane of anaphylaxis (SRS-A) in guinea-pig experimental asthma. Ohashi et al. (12) stated that ibudilast was a seletive antagonist of LTD4 in isolated guinea-pig smooth musle. They also reported that the mode of ibudilast ation was different from that of FPL55712, a well known SRS-A antagonist (13). In addition to an antiallergi ativity, a diret bronhodilating effet was also demonstrated by Mue et al. (14). They reported that ibudilast was more potent than aminophylline for its inhibitory ativity on methaholine- and histamine-indued bronhoonstrition in monkeys. We onluded that the observed improvement of airway hypersensitivity in the asthmatis was due to the pharmaologial ation of this agent. However, the preise mehanism for its effet still remains to be solved. We speulate that the antagonisti effet against leukotrienes may play an important role in improving airway hypersensitivity. The relationship between leukotrienes and airway hypersensitivity should be studied further. We studied the fators whih might be responsible for the enhaning effet of antiallergi agents on airway hypersensitivity (Table 4). The signifiant improvement in airway hypersensitivity by antiallergi agents was observed in the lower PC2 group. Namely, higher airway-sensitive patients responded more effetively to antiallergi agents than moderately sensitive ones. Either type of asthma or severity of disease was not losely assoiated with the effetiveness of the agents. It may be true that a small improvement in statistial differene an be obtained more easily in a severely disturbed group than in a moderately disturbed one. But we annot say whether or not this is the ase. At the present time, we have no lear explanations why the moderately sensitive patients showed no improvement with antiallergi agents. In our previous study (151, we showed that antiallergi agents were very effetive for improving airway hypersensitivity in asthmatis with short-term disease duration, but not in ases with long-term disease duration. The present study onsidered only longterm ases. We don t know the reason, but antiallergi agents seems to be less effetive in long-term rather than short-term bronhial asthma and in moderately sensitive ases rather than severely sensitive ones. For treatment of unaffeted ases, a new strategy must be evolved. In order to larify our observations, further studies with more patients will be required. This preliminary study suggests that the effet of ibudilast in apsule form on airway hypersensitivity is equal to or greater than that of DSCG by inhalation for asthmatis. This new antiasthmati agent will be useful in ombination with other agents for the treatment of bronhial asthma. REFERENCES 1. Cox JSG. Disalium romoglyate (FPL 67) ( Intal ): a speifi inhibitor of reagini antibody-antigen mehanisms. Nature 216: , Koda A, Nagai H, Watanabe S, Yanagihara Y, Sakamoto K: Inhibition of hypersensitivity reations

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