(Chin J New Drugs Clin Rem 2006 oct; 25 (10): 730-33 Seratrodast in treatment of 107 patients with asthma LI Xin, ZHAO Jian-ping, LOU Ya-fang, CHEN Hui, ZHU Dan, TU Jun-wei (Department of Respiratory Medicine, Jinhua Municipal Central Hospital, Jinhua ZHENANG 321000, China). ABSTRACT Aim: To evaluate the efficacy and safety of domestic seratrodast granules in the treatment of asthma, Methods: A total of 213 patients with asthma were randomly divided into two groups: seratrodast group (group A) and montelukast group (group B). One hundred and seven ratients in group A were treated with seratrodast 80 mg, po, qd for 8 wk, and 106 patients in group B were treated with montelukast 10 mg, po, {qd for 8 wk. The outcoming effects of clinical efficacy, lung function efficacy, and adverse reactions were ‘compared between the two groups. Results: The clinical efficacy rates and lung function efficacy rates were 73.8 % (79/107) v8 75.5 % (80/106) and 55.1 % (59/107) vs $5.7 % (59/106) in group A and group B, respectively. The clinical and Tung function improvements showed much better in mild and moderate asthma patients than those with severe patients (P<0.05). The incidences of adverse reaction occurrence were 5.6 % (6/107) and 4.7 % (5/106) in group A and B, respectively, without serious cases in both groups and also no statistically significant difference between them (P>0.05).. Conelusio eratrodast is a new, safe, and effective drug in treating patients with asthma and possesses reliable efficacy and less adverse reaction similar to montelukast. Key words: asthma; respiratory f unction tests; randomized controlled trials; seratrodast; montelukastINTRODUCTION It is well known that, variety of inflemmatory cells and inflammatory mediators involved in the pathogenesis of asthma. Thromboxane A; (TXA:) which promotes clotting, was reported to be an important mediator. inthe airway hhyperresponsiveness and allergic inflammation. ‘Therefore, TXA: inhibitors have been implicated in the treatment of bronchial asthma ‘7! Seratrodast, a TXA; receptor antagonist, in previous studies showed a good clinica: efficacy and safety in the treatment of bronchial wheezing 4) Ip order to evaluate the efficacy and safety of domestic seratrodast granules in the treatment of mild asthma during March 2005 - September 2005, we randomized, and compared the effect of seratrodast with montelukast in 213 asthmatic patients, M. IALS AND METHODS Inclusion and Exclusion criteria Study included 213 male and female (1) patients ‘with age 18 or more; (2) patients comply with the diagnostic criteria of Guidelines for the prevention and treatment of bronchial asthma "; (3) patients with good compliance for correctly fill out & daily record card and recording, peak expiratory flow correctly. Exclusion eriteria were (1) patients with upper or lower respiratory tract, emphysema, ‘bronchiectasis; (2) patients with heart, liver, renal infections, chronic bronchitis, diseases or severe blood diseases; (3) lactating women or pregnant women; or who do not meet the criteria according to clinician. Grouping Grouping method was based on bronchial asthma prevention and treatment guidelines “', patients were divided into three groups: group 1 (mild persistent), group 2 (moderate persistent) and Group 3 (severe persistent), Patients from group 1, 2, 3 were further randomly divided in to six subgroups as 1A, 1B, 2A, 2B, and 3, 3B using a random number table. In. seratrodast treatment group (A, 2A and 3A group, a total of 107 cases) patients were given seratrodast granules cr Pharmaceutical Co., Ltd; Approval number Zhunzi 120040315) equivalent t0 80 mg of seratrodast, po, qd, for 8 weeks, daily after (brand name: Changnuo, by dinner. ‘Treatments In Montelukast group (IB, 2B and 3B group, & total of 106 cases): patients were given with montelukast (Brand name: Singulair, Merck Division of Merck Sharp & Dohme (UK); production Hangzhou MSD Pharmaceutical Co., approval number: Zhunzi 120030002] of 10 mg, po, qd, treatment 8 wk daily after dinner. During the investigation, Salbutamol inhalation (Brand name: Ventolin; production Glaxo Wellcome, each suction 100 yg; New Drug Approval Number: Yaozhun X No. 142) was used as on required basis. In 3A the 3B groups, patients were continuously on inhaled budesonide (Brand name: Pulmicort Turbuhaler, AstraZeneca, each suction 200 jg, imported drug registration No: 120030583) 400 yg, bid. During study period, patients were not allowed to use other anti-asthmatic agents, oral or intravenous corticosteroids or any anti-allergic drug, Efficacy Evaluation Patients were observed for (1) Readings of ‘moming and night peak expiratory flow (PEF) taken daily on peak flow meter (American Health ‘Scan products) before appliance of inhalation, clinical symptoms, and PEF veriation rate (%) = (highest PEF of the day - lowest PEF of the day) / (Mean PEF of the same day) * 10096; evaluated at week 4 and at end of the study (week 8). (2) Determination of the forced expiratory volume in | -second (FEVI) and PEF at baseline (day 0) and fon moming of follow-up visit, 4 h before using inhalation of Salbutamol (Japan CHEST33 spirometer). (3) Daily requirement of number of Salbutamol inhalation puffs; (4) Adverse events reported during study period; (5) Number of patients suffered from acute asthma attacks, and use a variety of other asthma drugs or corticosteroids in order to control asthma adverse reactions. symptoms or serious Treatments were stopped when abnormal fluctuations or worsening of allergic reactions symptoms noted, Grading symptoms (1) Cough: a cough; + mild criteria of clinical signs and intermittent cough (does not affect the work and sleep); ++ range between mild and severe; ++ day and night cough or severe cough, (affect the life and sleep). (2) Wheezing: a wheezing; + mild occasional wheezing (does not affect sleep and activity); +++ range between mild and severe wheezing; +++ sever wheezing, cannot be supine, and (affect sleep and activity). (3) Whooping ‘woo sound: slightly: beep; + mild whooping with pain, deep fast breathing; ++ moderate symptoms (descending bird sound); +++ lungs with full of ‘whooping woo sound. Clinical efficacy criteria ‘The clinical efficacy criteria created according to the guiding principles of "clinical studies of new drugs (Western Medicine) developed by the Pharmaceutical Council of the Ministry of the People's Republic of China which was based on clinical, antitussive the antiasthmatie drug research guidelines, the above signs and symptoms, each " +" scored 1 point. The improvement rate (%) = total score after a treatment - before treatment / Pre-treatment total score * 100%, Clinical efficacy criteria: (1) clinically controlled - overall improvement rate of > 80%; (2) markedly improved - overall improvement rate of 60% to 80%; (3) improved - overall improvement rate of 30% to <60%; (4) no efficacy - the overall improvement rate < 30%, Pulmonary ventilation function efficacy criteria PEF or FEVI improvement rate (%) = (PEF or FEVI after treatment - PEF or FEV1 before {reatment)/pretreatment PEF or FEV x 100%. (1) Clinically controlled: improvement rate of PEF or FEV1 after teatment > 33%; (2) markedly improved: rate of improvement in PEF or FEV after treatment 25% 10 35%; (3). improved: improvement rate in PEF or FEVI after treatment 15% to 25% (4) no efficacy: Rate of improvement after treatment PEF or FEV1 <15%.Statistical Analysis Stat jcal analysis was done using SPSS 11.0 statistical software; categorical data was analyzed with the 72 test, tHest was used to compare the continuous date between the 2 groups, single- factor analysis of variance was used to compare the significant difference between the groups followed by LSD multiple comparison test. ‘Table 1: Comparative demographic data of patients allocated i RESULTS. ‘There was no significant difference observed in the demographic data of the patients enrolled in 2 treatment groups (P> 0.05), as shown in Table 1. ‘The present study conducted according to the protocol and clinical tral conditions, and patient between allocations the two groups were comparable. both the groups a No. of patients 36 ae 48 23 258 Sex (@) : 7 . Male a 84 26 2 9 WV Femal . 7 . emia fr 12 2 23 4 14 | Age (a) 4izis 40213" 42415 44x17" 4811 46 212" Hight (em) 1621116349" 15813 157SIS* 15813 160811" Duration of the disease jo3295 111492 119295118206" 136275 142282* {amomths) ‘Allergic rhinitis @) No 1S 13° 22 2m 9 1 Yes ai 18° 26 23 4 13¢ “Atopic dermatitis (n) No 31 28° 3 a“ 15, 9" Yes 3 Fa 5 o 8 o Family history of asthma (x) 24 22% 25 24* u 10* _ 12 2B 26* 12 | ‘Smoking history (n) No u 28 a3 ae 16 20° Yes 2 x 5 rt 7 st ey 6407 34209 52409 S311" T4211 73412 EVI, percent of the . : . [Epecedsinegay 833143 6529s a6 PEF variation rate (%) 2423-520" 342323 32M 36322135 Group A: Seratrodast group (asthma IA-mild, 2A-moderate, 3A-severe); Group A: Montelukast group (asthma 1B-mild, 2B-moderate, 3B-severe); FEV1: Forced expiratory volume in 1 second; PEF: Peak expiratory flow rate; The comparative analysis on 72 test or test between LA group and IB, 2A and 2B 'A and 3B groups: *P>0.0S‘We compared the clinical efficacy of both the ‘treatments atthe end of week 8, The average asthma symptom scores for the patients in group A.and group B were improved significantly (P <0.01) as compared to baseline (before treatment), where the clinical efficiency of group 1A and 2A was significantly higher than the ‘group 3A (P<0.01), whereas efficiency in 1B icantly higher than the group 3B (P <0.05). Ridit analysis showed that, there was no significant difference observed and 2B group was si ‘between group A and group B for clinical efficacy rate (P> 0.05), See Table 2. We also observed a gradual improvement in the pulmonary function test (PEF, PEF variability ‘and FEV1) from baseline atthe end ofthe study period, the differences observed were statistically significant (P <0.01), where {improvement was more significant in group LA, 2A than group 3A (P <0.05 and P <0.01, respectively), whereas 1B, 2B group showed a higher improvement as compared to group 3B (P <0.05 and p <0.01, respectively), as shown in Table 3. ‘Table 2: Comparison of clinical effieacy rates at the end of 8 week treatment eed 31 (73.8) 0.5* B 10629 53) 04912 1A 36 13, (83) 0.2843" | 2A 48 1S (81) 0.2932" 3A zB 3 @_ 0 1B ar 10 02857 2B 50 17 (86) 02715* 3B 25 2 (44) 0.5* Rid analysts (8) of group A and group B, compared TA Group with Group 2A and 3A group, and compared 1B group with 2B and 3B groups: *P>0.05, °P <0.01 Effect on pulmonary ventilation function After the end of 8 week treatment, group A and ‘group B showed no significant difference in the improvement rates of pulmonary ventilation function on Ridit analysis (P> 0.05). However, the improvement observed in group 1A and group 2A, for pulmonary ventilation function, was significantly higher than group 3A (P <0.01), whereas group 1B and 2B showed superior lung, ventilation as compared to 3B group (P <0.01, Table 4).‘Table 3: Comparison of changes observed in Forced expiratory volume in 1 (FEV1) and peak expiratory flow (PEF) rates before and after treatment (Mean + SD) Before Groups Parameters (0-36) FEV1, percent ofthe expected value (%) Morning PEF (Lis) Night PEF (Lis) PEF variability (%) 24 FEVI(L) (0-48) FEVI, percent of the ‘expected value (%) Morning PEF (Lis) Night PEF (Lis) PEF variability (%6) 3A FEVI@) (=23) _ FEVI, percent ofthe ‘expected value (%) Morning PEF (Lis) ‘Night PEF (Lis) PEF variability (%) 1B FEVI@) FEVI, percent ofthe OSD expected valve (4) Morning PEF (Lis) Night PEF (Lis) PEF variability (%) 2B FEVI(L) FEVI, percent of the (=50) expected value (%) treatment (Baseline) iA_‘FEVI() 24204 383) 3.2204 4.1140,22 2483 1. 8340.22 6583, 3.2340.21 45803 34.132.2 1334021 4835 2.248012 3.234021 36.3221, 2380.5 8143, 3.1404 4.0203 2544 1,940.3, 6443 After wk 4 treatment 2805 084 3.6403 4314023 1884 2.134022 75 3.7240.23, 4.8203 2743 1.424022 $347 2.414022 3,3340.24 3383 2.7404 8043 3.6204 4.43£0.24 1985 2.114023 Tas Difference 0424011" wae 0.43 40.23" 0.2140.12" 63" 0.33 20.24" 843 0.54 20,23" 0.3320,22 - Tas 0.1340.11° 4.242.3¢ 0.22 9.13" 0.1240.11° 3.082," 0.420.220 yaa 0.530,3" 0.4240.22 5.282.2 0.230.248 aaa After wk 8 treatment “31203 9543 4.1203 4.634023, 1384 2.3203 7936 4.0203 5.0803 2244 11524021 5847 2.628022, 3.524021 2,920.3 9625 3,903 45203 484 2.4303 7935 Difference o7ae024 12a3 0.9103" 0510.3" “113 0.510.220" lass 0.8140.22 0.5240.23 “last 0.2240:13" ae 0,3340.13° 03340.11 633° 0,6330,23¢ i4ss o.ss0.4"" 0.50.3" “104 0.503" Issa‘Morning PEF (L/s) Night PEF (Lis) 4.6403 PEF variebility (%6) 3244 3B FEVI() 1.2803 FEVI, percent of the 4646 (0-25) - expected value (%) Moming PEF (is) 2.1403 Night PEF (Lis) 3.003 PEF variability (%6) 3584 ITS 4.8140.22 244 1.334021 S148 2340.3 3.2403, 324 33280.21 TENE 4003 0.7803 0330.14" 643" 0.1240.12° sas 0..2340.11" 0. 2240.14" -3.242.4° 4.9204 2083 1.5804 s7a7 2.5240.22 3, 3140.22 274 0.420.234 1284 0.2340.11" has 0.4330.14" 0.3440.12" 7.28.28 Difference in values before and after treatinent, analyzed by Fest, "P< 0.05, "P < 0.01, Analysis of variance by LSD method pair wise comparisons of group 1A, 2A and 3A, and group 1B, 2B aad 3B group: ‘P< 0.05, <0.01 ‘Table 4: Comparative efficacy in improvement of pulmonary ventilation function (%) before and after the treatment ee a a) Co eee a ea ee A 107, 20 39, 23 25 (85.1) 0.5* B 106 22 37 23 4 (55.7) 0.4585, 7 36 9 14 7 6 (4) 0.36498 283 48 9 20 10 9 (60) 0.3836 = 23 2 5 6 10 30) 0.5% a 31 9 ul 6 5 65) 0.3387 2B 50 nt 19 12 8 (60) 0.3758* a 25 2 7 5 n 36) 0.s* Ridit analysis (8) of group A and group B, compared Group TA with Group 2A and 3A, and compared 1B group with 2groupB and 3B: *P>0.05, §P <0.01Cont mots Patients ron Cee re ait (Bassline) vee) neal ‘able 5: Changes in the daily intake of number of Salbutamol inhalation puffs Deane ae) nea 1A 36 2413 O8=16 16413" 05212 -19#13" 2A ® 37219 1927 18ai3s* 13210 24214" 3A B 62212 47216 -15#L8 4115 21217 1B 31 22316 09814-13817" 05412-17215" 2B 50 40221 21217 -19415" 17214 23218" 3B 25 GlaL7 «45420 -1.6e13 43219-18820" | and group 1B 2B and 3B group: “P > 0.05 ‘Changes in the daily intake of number of Salbutamol inhalation pufis before and after treatment, analyzed by test, *P < 0.01. Analysis of variance by LSD method pair wise comparisons of group 1A , 2A and 3A, Changes in the daily intake of number of Salbutamol inhalation puts There was a gradual decrease noted in the daily requirement of number of Salbutamol inhalation puffs parallel to the treatment duration Difference in the daily requirement of number of Salbutemol inhalation puffs before and after treatment was very significant (P <0.01). No significant difference observed between the Group 1A, 2A and Group 3A, whereas 1B, 2B and 3B were required similar intake of Salbutamol inhalation (P> 0.05). See Table 5. Adverse events In the present study, 5.6% (6/107) cases from group A reported the adverse reactions, including nausea, dizziness, loss of appetite, but the symptoms were mild and tolerable, and did not affect the treatment schedule. In Group B, fi cases of adverse reactions are manifested as mild ss. The adverse reaction rate was 4.7% (5/106). The difference in the incidence of adverse reactions between two groups Was not significant (P> 0.05), DISCUSSION In this study, seratrodast was found to be as safe and effective as well known leukotriene receptor antagonist, montelukast in the treatment of acute ‘exacerbation of bronchial asthma drug. Therefore it can be used clinically in the treatment of asthma, ‘The results showed that, both the drug treatments improved asthma clinical symptoms and ‘pulmonary function significantly, moreover daily intake of inhalation was observed to be significantly reduced, Both the agents showed 00d efficacy in the mild and moderate asthma than in severe asthmatic patients, no serious adverse reactions were noted. ‘There was no significant difference observed between the two drug treatments in the clinical efficiency, and improvement in the lung function parameters. In addition, similar incidence of adverse reactions was noted, as reported in the previous research by YIN Kai-Sheng etal (2004). In short, TXA; receptor antagonist seratrodast ‘and leukotriene receptor antagonist montelukasthave similar clinical efficacy and safety. ‘Therefore novel agent, seratrodast, has better clinical value in the treatment for bronchial REFERENCES 1, Tamaoki J, Kondo M, Nakata J, Nagano Y, Isono K, Nagai A. Effect of a thromboxane AQ) antagonist on sputum production and its physicochemical properties in patients with mild to moderate asthma, Chest. 2000 Juls118(1):73-9. 2. Baba K, Sakakibara A, Yagi T, Niwa S, Wakayama -H, Takagi -K.Long-term observations of the clinical course after step down of corticosteroid inhalation therapy in adult chronic asthmatics: correlation with serum levels of eosinophil cationic protein. Respirology. 2002 Sep;7(3):255-66 3. Terao S, Shiraishi M, Matsumoto T, Ashida Y. ‘Thromboxane A2 antagonist-discovery of seratrodast. Yakugaku Zasshi, 1999 May; 119(5):377-90. 4. YIN Kai-sheng et at. 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