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

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Effect of Ibudilast: a Novel Antiasthmatic Agent, on Airway Hypersensitivity in Bronchial Asthma Journal of Asthma, 29(4), 245-252 (1992) Effect of Ibudilast: A Novel Antiasthmatic Agent, on Airway Hypersensitivity in Bronchial 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 Medicine Toyania Medical and Pharmaceutical University 2630 Sugitani Toyama, Japan 930-01 ABSTRACT Ibudilast, a unique agent with vasodilating and anti- allergic actions, was studied in 13 asthmatics for its ef- fect on airway hypersensitivity to histamine inhalation. For personal use only. The PC20 values improved significantly from 355.6 to 620.5 &mi at 3 months and further to 731.4 pghl at 6 months following the initial treatment with ibudilast (20 mg twice daily orally). In addition, the severity of the at- tacks decreased significantly. Improvements in the PC2,, and asthmatic symptoms also were observed in the disodium c:hrornoglycate group, but these were equal to or lesser than those in the ibudilast group. No improve- ment was observed in the untreated control group. These J Asthma Downloaded from informahealthcare.com by Yeshiva University on 09/15/14 results suggest that ibudilast would be an effective agent for improving nonspecific airway hypersensitivity in asthmatics. INTRODUCTION and ibudilast have been developed in rapid succession in Japan and used for the treat- After the introduction of disodium cromo- ment of bronchial asthma. Among them, glycate (DSCG) (11, many so-called “anti- ibudilast seems to be especially unique, for allergic agents” such as tranilast (21, ketotifen vasodilating and antiallergic effects (7 3). (3), azelastine (4), amoxanox (51, repirinast (6), Therefore, this agent is used clinically for the 245 Copyright 0 1992 by Marcel Dekker, Inc. 246 Kawasaki et al. treatment of both cerebrovascular disorders advocated by the Japanese Society of Allerg- and bronchial asthma in this country. In this ology. Briefly, aerosols were generated with study, we examine what effects this unique a Devilbiss nebulizer (type 646) at an air flow agent has on airway hypersensitivity in bron- of 5 L/min. Inhalation was administered for chial asthma. 2 minutes during quiet breathing through the mouth at 5-minute intervals. First an isotonic 0.9% saline solution was inhaled, followed by MATERIALS AND METHODS increasing concentrations of histamine from 20 pg/d in twofold increments. The forced ex- Antiallergic Agents and Subjects piratory volume in one second (FEV,) was measured before the inhalation of saline and Disodium cromoglycate (DSCG) is a product after each inhalation of histamine. The test of Fujisawa Pharma Co., Ltd., Osaka, Japan, was continued until the FEV, had fallen by and is administered by inhalation therapy. 20%. The histamine PCzo was calculated by Ibudilast, 3-isobutyryl-2-isopropylpyrazold1, linear interpolation between the last two data 5-alpyridine, is a product of Kyorin Pharma points on the dose-response curve. Prior to Co., Ltd., Tokyo, Japan and administered this test, all drugs were withheld for 24 hours. orally. In order to avoid possible daily changes in Thirty patients diagnosed with bronchial response to histamine, the test was performed asthma were studied; 17 male and 13 female, between 9 A.M. and 12 A.M. 15 extrinsic and 15 intrinsic types of asthma. Their ages ranged from 18 to 58 years old Study Design (mean 36.4 years) and all were nonsmokers. When their asthmatic symptoms were well- All patients were treated initially with 0- controlled with @stimulantsand/or xanthine stimulants and/or xanthine derivatives. derivatives, they were enrolled in this study. When the asthmatic symptoms were under No patient was receiving corticosteroid or control, ibudilast (20 mg bid orally) or DSCG gold therapy. The characteristics of the pa- (20 mg qid by inhalation) was administered tients in the ibudilast, DSCG and control in addition to @-stimulantsand/or xanthines. For personal use only. groups are shown in Table 1. Patients were evaluated for airway hypersen- sitivity, clinical symptoms, the serum IgE Histamine Inhalation Test levels and peripheral eosinophil counts at 3 and 6 months following the initiation of anti- The histamine inhalation test was con- allergic agents. Severity of asthmatic symp- ducted in accordance with the method toms was evaluated in the month prior to Table 1. Patient Characteristics J Asthma Downloaded from informahealthcare.com by Yeshiva University on 09/15/14 IBUDl LAST DSCC CONTROL Number 13 7 10 Age 37.4~(f 14.4) 29.2~(f 6.8) 40.1~(f 13.2) Duration of illness 5.2~(f 2.3) 10.9y (f9.3) 5.0~(f 4.8 TY Pe extrinsic 5 5 5 intrinsic 8 2 5 Severity of disease mild 7 5 7 moderate 6 2 3 Observation period (weeks) 25.9 f 6.2 25.0 f 6.4 27.1 _+ 5.9 Maintenance medications P-Agonist 9/13 (69.2%) 6/7 (85.7%) 7/10 (70.0%) Theophyl I i ne 11/13 (84.6%) 6/7 (85.7%) 9/10 (90.0%) Ibudilast and Airway Hypersensitivity 247 each histamine inhalation. Symptoms were shown individually in Table 2. The PCz0, classified into four grades; severe, moderate, values significantly increased from 355.6 mild, and symptom free. This was in accord- pg/ml to 620.5 M/ml at 3 months and further ance with the severity and the frequency of to 731.4 pg/ml at 6 months following the in- the asthmatic attacks. “Symptom free” was itial treatment with ibudilast. Individual im- defined as having had no asthmatic attack in provement in airway hypersensitivity for 6 the one month period prior to each test. months was observed in 7 patients and ex- The effects on airway hypersensitivity were acerbation in 1 patient and no change oc- assessed by the changes in FC20. Namely, a curred in 5 out of 13 cases (Fig. 1). There was twofold increase in PC20 after treatment was no significant difference in the baseline value defined as improvement (1+), and more than for the FEVl among these points. Decrease a fourfold increase in PC20 as improvement in severity of the disease also improved (2+). On the contrary, a twofold decrease in significantly. Among the 13 cases, 4 became PC20 was defined as exacerbation (- 1). symptom free at 3 months and 8 at 6 months (Fig. 2). There was no statistical difference in Statistics the eosinophil counts and serum IgE levels (Fig. 3). Data are expressed as the mean k SD. Statistical significance was evaluated by the Wilcoxon’s test or Fisher’s exact probability Changes in Airway Hypersensitivity test, and a p c 0.05 level of significance was and Severity of Symptoms in Ibudilast-, adopted throughout the study. DSCG-Treated, and Control Groups RESULTS The improving effects of ibudilast on airway hypersensitivity and severity of symptoms Changes in Airway Hypersensitivity and were roughly compared with those of DSCG. Clinical Symptoms in Ibudilast-Treated As shown in Table 3, improvements in PCzo Bronchial Asthma Patients and clinical symptoms were also observed in For personal use only. the DSCG-treated group, but were poorer The changes in FEV1, PCza,and clinical than in the ibudilast group. No improvement symptoms in 13 ibudilast-treated patients are was observed in the control group. Table 2. Changes in FEV,, PC20, and Symptoms in lbudilast Group FEVl (Ll PC20 (aglrnll JUDGEMENT SYMPTOM J Asthma Downloaded from informahealthcare.com by Yeshiva University on 09/15/14 CASE BEFORE 3M 6M BEFORE 3M 6M 3M 6M BEFORE 3M 6M 1 1.90 2.72 1.97 144.0 1292.3 599.5 Free Free Free 2 1.75 1.17 1.20 78.1 380.3 376.0 MiId Free Free 3 1.35 1.55 1.45 24.6 103.1 221.0 Mild Mild Free 4 2.32 2.45 2.50 90.6 82.8 456.1 Mild Mild Free 5 2.05 1.70 2.32 172.2 708.1 477.0 Mild Free Free 6 1.50 1.45 2.25 68.0 152.7 156.0 Mild Mild Free 7 3.42 3.45 3.90 261.4 484.1 774.4 Mild Mild Free 8 3.55 3.47 3.90 2102.2 1092.8 3848.1 Free Free Free 9 2.15 2.45 2.42 4352.7 7071.1 4701.2 Mild Mild Mild 10 2.25 2.15 2.00 876.3 625.0 1486.5 Mild Mild Mild 11 1.80 1.77 1.72 1486.5 2769.8 1371 .O Mild Mild Mild 12 1.85 2.08 2.00 2240.8 1150.9 1 500.1 Mild Mild Mild 13 3.10 3.1 7 1.80 709.0 587.9 236.8 Moderate Mild Mild 2.23 f 0.7 2.28 f 0.8 2.26 i 0 .8 355.6 620.5 731.4 248 Kawasaki et al. 10,000- Ip<0’05 1 5,000- -h E .m 2,500- 3 Y K 1,250- 0 .-c I cE S 625- a 0 S 8 31 3- a .-C 156- E m c .-UJ 7 0- I 3 9- 2 0- I I I I I Before 3M 6M Figure 1. Changes in Pc20 of histamine in ibudilast-treated group. For personal use only. (%) ,oo UJ c s 80- a .-c J Asthma Downloaded from informahealthcare.com by Yeshiva University on 09/15/14 (II Q 60 - r 0 a 40- H moderate c C mild a symptom-free 2 a 20- n 01 Before 3M 6M Figure 2. Changes in severity of disease in 13 cases of ibudilast-treatedgroup. Ibudilast and Airway Hypersensitivity 249 ' 00' 2000 e m E 801: -h E .E 1500 v 2.
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