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 antiallergic actions, was studied in 13 asthmatics for its effect 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 attacks 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 improvement 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 hypersensitivity, 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

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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

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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

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e m E 801: -h E .E 1500 v 2. u) 4- - K 600 a 3 > 0 -a 0 1000 W -.- -a 400 0 E .-c 3 u) L P 0 $ 500 200

c v- 0 Before 3 M 6 M Before 3'M 6'M

Figure 3. Changes in eosinophil counts (a) and serum IgE levels (b) in ibudilast-treated group.

lbudilast DSCG

For personal use only. Control

10.000- rp

5,000- 7- - 2,500-

1,250-

625- J Asthma Downloaded from informahealthcare.com by Yeshiva University on 09/15/14 313-

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I --Before 6M Before 6M Before 6M

Figure 4. Changes in PC20 of histamine in the three groups. -: improved cases; -: unimproved cases. 250 Kawasaki et al.

Table 3. Changes in Airway Hypersensitivity and Severity of Symptoms in the Three Groups

pc20 Wml) SYMPTOM-FREE CASE (%) BEFORE 6M IMPROVED CASE (%) BEFORE 6M lbudilast

(n = 13) 355.6 -, 731.4 7/13 (53.8'/0)~ 2/13 (15.4%) + 8/13 (61.5'/0)~ DSCC

(n = 7) 292.2 -, 392.5 217 (28.6%) 017 (0%) + 417 (57.1%) Control

(n = 10) 380.7 -, 348.6 0/10 (0%) 1/10 (10.0%) + 0/10 (0%) ap < 0.05 compared with the control group by Fisher's exact probability test.

Comparison of Factors Between DI SCU SSI0 N Airway Hypersensitivity-Improved and Unimproved Cases Antiallergic agents generally are classified into two groups (9); the basic type which has The factors which would affect the effect of an antihistamine activity, and the acidic type antiallergic agents on airway hypersensitivi- which has no antihistamine activity. Ibudi- ty are analyzed in Table 4. A significant dif- last has no antihistamine activity, but does ference was observed only in the pC20values not belong to either of these two groups. The between the two groups. The value of PCz0 effects of ibudilast on airway hypersensitivi- was significantly lower in the improved cases ty have not yet been demonstrated clearly. (90.7 vs. 960.0 pg/ml). The PCzo improved This preliminary study indicates that significantly from 90.7 to 389.0 pg/ml(96.3 to ibudilast has the ability to decrease airway 387.4 in ibudilast only) in the improved hypersensitivity in response to histamine group, and from 960.0 to 825.0 pg/ml(l632.6 inhalation for patients with bronchial to 1535.3 in ibudilast only) in the unimproved asthma. The PC20 values improved For personal use only. group. significantly from 355.6 to 731.4 pg/ml with

Table 4. Comparison of Factors Between Airway Hypersensitivity Im- proved and Unimproved Cases IMPROVED CASES UNIMPROVED CASES Number 9 11 (6)

J Asthma Downloaded from informahealthcare.com by Yeshiva University on 09/15/14 ma Gender (male:female) 4:5 (4:3) 9:2 (3:3) Age 33.9 (36.0) 35.1 (39.0) Duration of illness (year) 7.2 f 7.9 (5.2) 7.0 f 6.0 (4.9) Type of asthma extrinsic 4 (3) 5 (2) intrinsic 5(4) 6 (4) Severity of disease moderate 4 (3) 4 (3) mild 5 (4) 7 (3) PC20 (cglml) 90.7b (96.3)b 960.0 (1632.6) Eosinophil Vmm3) 273.9 f 185.0 (282.4) 380.4 f 286.1 (363.6) IgE (U/ml) 208.6 f 196.5 (216.7) 471.8 f 598.0 (159.8) FEV1.0 (L) 2.06 f 0.6 (2.04) 2.73 f 0.7 (2.45) aData in parentheses include only ibudilast-treated cases. bp < 0.05 as compared with unimproved cases by Wilcoxon's test. Ibudilast and Airway Hypersensitivity 25 1

6-month oral administration of this agent. Im- We studied the factors which might be provement of symptoms was also observed in responsible for the enhancing effect of anti- parallel with airway hypersensitivity. The allergic agents on airway hypersensitivity improving effect of this agent appeared to be (Table 4). The significant improvement in air- equal to or greater than that of DSCG. Our way hypersensitivity by antiallergic agents result was supported by Umedas’ observation was observed in the lower PC20 group. (Fujita-Gakuen Health University, Japan), in Namely, higher airway-sensitive patients which improvement of airway hypersensi- responded more effectively to antiallergic tivity to methacholine inhalation was ob- agents than moderately sensitive ones. Either served in 4 of 6 asthmatics after 4 weeks oral type of asthma or severity of disease was not administration of ibudilast (personal com- closely associated with the effectiveness of the munication). agents. It may be true that a small improve- Ibudilast is now used clinically in Japan for ment in statistical difference can be obtained the treatment of allergic diseases such as more easily in a severely disturbed group bronchial asthma and for cerebrovascular than in a moderately disturbed one. But we disorders. No serious adverse effect has been cannot say whether or not this is the case. At reported; nausea, abdominal discomfort, etc. the present time, we have no clear explana- at less than 10%. Concerning the vasodilating tions why the moderately sensitive patients effect, Ohashi et al. (10) reported in canine showed no improvement with antiallergic basilar artery system that this was via the agents. In our previous study (151,we showed augmentation of PG12 action by ibudilast. that antiallergic agents were very effective Antithrombotic action was also noted. Con- for improving airway hypersensitivity in cerning the antiallergic effect, Nishino et al. asthmatics with short-term disease duration, (8)and Nagai et al. (11)stated that this agent but not in cases with long-term disease dura- demonstrated a fairly selective antagonistic tion. The present study considered only long- action against slow-reacting substance of term cases. We don’t know the reason, but anaphylaxis (SRS-A) in guinea-pig experi- antiallergic agents seems to be less effective mental asthma. Ohashi et al. (12) stated that in long-term rather than short-term bronchial ibudilast was a selective antagonist of LTD4 asthma and in moderately sensitive cases For personal use only. in isolated guinea-pig smooth muscle. They rather than severely sensitive ones. For treat- also reported that the mode of ibudilast ac- ment of unaffected cases, a new strategy must tion was different from that of FPL55712, a be evolved. In order to clarify our observa- well known SRS-A antagonist (13). In addi- tions, further studies with more patients will tion to an antiallergic activity, a direct bron- be required. chodilating effect was also demonstrated by This preliminary study suggests that the ef- Mue et al. (14).They reported that ibudilast fect of ibudilast in capsule form on airway was more potent than aminophylline for its hypersensitivity is equal to or greater than inhibitory activity on methacholine- and that of DSCG by inhalation for asthmatics. J Asthma Downloaded from informahealthcare.com by Yeshiva University on 09/15/14 histamine-induced bronchoconstriction in This new antiasthmatic agent will be useful monkeys. We concluded that the observed im- in combination with other agents for the provement of airway hypersensitivity in the treatment of bronchial asthma. asthmatics was due to the pharmacological action of this agent. However, the precise mechanism for its effect still remains to be REFERENCES solved. We speculate that the antagonistic effect against leukotrienes may play an impor- tant role in improving airway hypersensi- 1. Cox JSG. Disalium cromoglycate (FPL 670) (‘Intal’): a specific inhibitor of reaginic antibody-antigen tivity. The relationship between leukotrienes mechanisms. Nature 216:1328-1329, 1967. and airway hypersensitivity should be 2. Koda A, Nagai H, Watanabe S, Yanagihara Y, studied further. Sakamoto K: Inhibition of hypersensitivity reactions 252 Kawasaki et al.

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