- Email: [email protected]
Improved Case of Bronchial Asthma by Re-administration of Pranlukast from Montelukast: Evaluation of Eosinophilic Inflammation in the Peripheral Airway
Allergology International. 2005;54:633-637
CASE REPORT
Improved Case of Bronchial Asthma by Re-administration of Pranlukast from Montelukast: Evaluation of Eosinophilic Inflammation in the Peripheral Airway Hiroyuki Ohbayashi1 ABSTRACT Background: Pranlukast and Montelukast are Cysteinyl leukotriene receptor antagonists with almost the same pharmacological activity. However, I will describe a case in which these drugs showed different therapeutic effects on clinical symptoms during the daytime and eosinophilic inflammation in the peripheral airway. Methods: A 70-year-old male patient with non-atopic bronchial asthma who was treated with 400 μg!day of Budesonide TurbuhalerⓇ (BUD-TH) changed from Pranlukast (225 mg, twice daily) to Montelukast (10 mg, one tablet before sleeping), resulting in worsening clinical symptoms consisting of sputum and cough in the daytime, mainly at lunch time. Due to the fact that the symptoms did not improve sufficiently, instead of increasing the dose of BUD-TH, we investigated the clinical symptoms and pulmonary functions as well as measured the mean eosinophil count, eosinophil cationic protein (ECP) and eotaxin in the hypertonic saline-induced sputum prior to administration of Pranlukast, and 4 and 8 weeks after the re-administration of Pranlukast from Montelukast. Results: Following the re-administration of Pranlukast, the clinical symptoms disappeared within a few days and pulmonary function improved within 4 weeks. Eosinophils in the induced sputum almost completely disappeared for 4 weeks. The sputum ECP and eotaxin before and 4 weeks after the re-administration of Pranlukast changed from 700 μg!l to 192 μg!l, and 69.9 pg!ml to 30.6 pg!ml, respectively. After 8 weeks, no sputum induction was found. Conclusions: The clinical difference between these two similar antagonists may be caused by the time difference relating to when and how often each drug is administered, suggesting the existence of the lunchtime dip.
KEY WORDS asthma, eosinophil cationic protein (ECP), eotaxin, induced sputum, Pranlukast
INTRODUCTION Cysteinyl leukotriene ( CysLT) receptor antagonists are defined as drugs for the long-term control of asthma in the Guide for Asthma Management and Prevention published by the Global Institute for Asthma (GINA) 1 and in the Asthma Prevention and Management Guidelines 2003 (JGL).2 At present, the CysLT1 receptor antagonists used in Japan are Pran1Department of Internal Medicine, Tohno Kosei Hospital, JA Gifu Kosei Organization, Gifu, Japan. Correspondence: Hiroyuki Ohbayashi, Department of Internal Medicine, Tohno Kosei Hospital, JA Gifu Kosei Organization, 76−1 Toki-cho, Mizunami City, Gifu 509−6101, Japan.
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lukast , Montelukast and Zafirlukast . These three drugs show almost the same levels of CysLT1 receptor antagonism. 3 Although no significant differences in clinical effects were found in a comparative study of Pranlukast and Montelukast, 4 both drugs differ in the type of the drug form; a capsule or a small tablet, and the daily administrative time ; when and how often each drug is taken . In daily use , the recommended daily dose of Pranlukast for adults is 4 capEmail: [email protected] Received 24 December 2004. Accepted for publication 13 May 2005. !2005 Japanese Society of Allergology
633
Ohbayashi H
2002.4
2002.11 2003.4 2003.10 2004.4 2004.6
2004.9
2004.10 2004.11
sputum and cough Asthma exacerbation 600 µg/day
400 µg/day
BUD-TH Theophylline
100 mg/day
Tulobuterol hydrochloride tape
2 mg/day
Pranlukast
450 mg/day
Montelukast
450 mg/day 10 mg/day
Fi g.1 Cl i ni calcour se
sules (450 mg! day), taken twice daily (after breakfast and dinner), while the recommended daily dose of Montelukast is 10 mg! day taken once prior to sleeping. Drug compliance is highly dependent on the drug form and the administration time , especially in elderly asthmatic patients. The author has often encountered patients who found it difficult to take capsules or wished to decrease the number of capsules they were required to take, often resulting in an administrative change from Pranlukast to Montelukast. However, I have also experienced not a few patients who then requested re-administration of Pranlukast, due to aggravated subjective symptoms which developed after the change of drugs. The case report given below involves one such patient. In this case report , in addition to evaluating the changes in clinical symptoms and pulmonary functions, I also investigated the eosinophil count, eosinophil cationic protein (ECP) and eotaxin in the hypertonic saline-induced sputum before and after the readministration of Pranlukast from Montelukast.
CLINICAL SUMMARY The patient was a 70-year-old male with non-atopic bronchial asthma who visited our department in February 2001 and was given Beclomethasone dipropionate (BDP), a steroid inhalant, at a dose of 800 μg! day, based on Step 3 of the“ Severity Criteria for Bronchial Asthma”developed by the Japanese Society of Allergy.2 In May 2002, his asthma was under effective control using 400 μg !day of Budesonide Turbuday of halerⓇ (BUD-TH), a steroid inhaler, 100 mg! theophylline, 2 mg!day of a Tulobuterol patch, and 450mg !day of Pranlukast . In November 2002, because of his good stable asthmatic condition, the patient requested a decrease in the number of oral drug capsules. Therefore , 4 capsules of Pranlukast were
634
changed into one tablet of Montelukast at bedtime . For several weeks after the change , his asthmatic condition showed no remarkable change , and then the amount of sputum and cough gradually increased in the daytime , in particular at lunchtime . In June 2004, he had a moderate asthma attack and was admitted to our hospital. After admission, BUD-TH was increased to 600 μg! day and wheezing and breathing difficulty quickly improved , but the sputum associated with cough persisted during the daytime. Again based on the patient’s request, Montelukast was replaced with Pranlukast in September 2004. A few days afterwards, the sputum associated with cough at daytime disappeared spontaneously and completely . According to his daily asthma diary and a detailed interview with his family, his drug compliance was confirmed as almost 100% over this course. His clinical course for the two months is shown in Figure 1.
PATHOLOGICAL FINDINGS In order to investigate the relationship between the changes of his asthmatic condition and eosinophilic inflammation in his peripheral airway , the induced sputum tests were performed before and after the change from Montelukast to Pranlukast. Prior to performing the each test , the purpose , methods and risks of the test were explained to the patient in detail each time, in accordance with the code of ethics at our hospital which is based on the Declaration of Helsinki of 1995 (as revised in Edinburgh 2000). After informed consent was obtained , the test was conducted. The patient inhaled a 10% salt solution for 15 minutes using an ultrasonic nebulizer , and the induced sputum was collected by a deep cough after gargling. The saliva component was removed from the collected sputum, and a smear preparation of the viscous sputum component was made. This was then stained with Wright-Giemsa stain. The mean number
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Improved Asthma by Re-treatment of Pranlukast Tabl e 1 Resul t sofhyper t oni csal i nei nducedsput um t es t s Ti mePoi nt
Eo
Bef or er eadmi ni st r at i onofPr anl ukast 4weeksl at er 8weeksl at er
ECP( μg/ l )
( ＋) ( −)
Eot ax i n( pg/ ml )
700 192 nos put um i nduc t i on
69. 9 30. 6
Abbr ev i at i ons :Eo=eos i nophi l ,ECP=eos i nophi lc at i oni cpr ot ei n
Cr i t er i af orEosi nophi l s Meancount sofeosi nophi l si n5HPF( X)
J udgment
X＜ 1
( −) ( ＋) ( 2＋) ( 3＋)
1＜ or＝ X＜ 10 10＜ or＝ X＜ 20 20＜ or＝ X
Tabl e 2 Changesi npul monar yf unct i ont estdat awi t ht i me %VC( %) 2002. 4
・
・
・
%FVC( %) %FEV1. 0( %) V50( L/ s ec ) V25( L/ s ec ) V25/ H( L/ sec/ m)
70. 6
55. 1
72. 9
1. 11
0. 68
0. 46
2002. 11changef r om Pr anl ukastt oMont el ukast 2003. 4
72. 4
57. 8
68. 4
1. 02
0. 39
0. 27
2003. 10
62. 7
58. 3
64. 0
0. 83
0. 54
0. 36
2004. 4
61. 7
53. 5
69. 6
0. 57
0. 66
0. 44
2004. 6doseofBUDTHi ncr easedf r om 400μg/ dayt o600μg/ day 2004. 9( bef or echangeofdr ugs ）
46. 6
42. 8
61. 3
0. 88
0. 64
0. 44
2004. 9changebackt oPr anl ukastf r om Mont el ukast 4weeksl at er
49. 1
49. 1
65. 4
0. 86
0. 74
0. 50
8weeksl at er
51. 2
50. 1
71. 4
1. 06
0. 73
0. 50
Abbr ev i at i ons :VC＝ v i t alc apac i t y ,FVC＝ f or c edv i t alc apac i t y ,FEV1. 0＝ f or c edex pi r at or yv ol umedur i ng1s ec ond
of eosinophils per 5 microscopic views (×400) was obtained, based on the following criteria: per 5 views, one or less eosinophil, (−); one to less than 10, (+); 10 to less than 20, (2+); 20 or more, (3+). The sputum ECP and eotaxin levels were determined according to the method of Motojima et al.. 5 Induced sputum was kept at 4℃ from the time of collection to sample preparation; samples were always prepared within 6 hours. The sputum ECP and eotaxin levels were determined using an ECP FEIA kit (Pharmacia & Upjohn Diagnostics AS, Uppsala, Sweden) and an eotaxin ELISA kit (R&D Systems, MN, USA), respectively. The mean eosinophil count and the ECP and eotaxin levels in induced sputum immediately before, and 4 and 8 weeks after re-administration of Pranlukast are shown in Table 1. Pulmonary function data from April 2002, i.e., before the initial change from Pranlukast to Montelukast , to November 2004 are shown in Table 2. All pulmonary function data were measured between 11 a.m. and noon. Four weeks after the change from Montelukast to Pranlukast, the
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eosinophil count in induced sputum was negative , and sputum ECP and eotaxin were markedly decreased. Furthermore, 8 weeks after this change, no sputum could be induced . The pulmonary function values were aggravated after the change from Pranlukast to Montelukast and then improved after readministration of Pranlukast (Table 2).
DISCUSSION Pranlukast and Montelukast are CysLT1 receptor antagonists with almost the same pharmacological antiLT activity , although their administered doses and drug forms are different. 3,4 In the present case, the patient experienced subjective asthma symptoms after switching from Pranlukast to Montelukast which then improved after a change back to Pranlukast . This was objectively proved based on the results from the pulmonary function data. Collectively, the objective and subjective results suggest that Pranlukast and Montelukast had a different clinical effect in this patient.
635
Ohbayashi H
Pranlukast Blood concentration
Montelukast
MEL
12:00
4:00 19:00 ―20:00 23:00
8:00
Administration of Pranlukast Morning dip
4:00
12:00
19:00 ―20:00 23:00 Administration of Montelukast
Lunchtime dip MEL: Minimum effective level
Fi g.2 Ti mecour sechangeofbl oodc onc ent r at i on( out l i ne)
In addition to exerting strong LT receptor antagonism, CysLT1 receptor antagonists suppress eosinophil activation, leading to reduction of serum ECP, 6,7 and inhibit cellar infiltration of inflammatory cells in bronchial mucosa, 8 as well as eosinophilic migration through suppression of eotaxin, an eosinophilic migration factor . 9 However , a direct comparison of eosinophil suppression has not been performed for Montelukast and Pranlukast. We therefore found the different suppression effects of Montelukast and Pranlukast in the present case to be of particular interest, and we examined the eosinophilic conditions of the peripheral airway before and after the change of drugs , using the induced-sputum method described above . It is generally accepted that hypertonic saline-induced sputum in this study can be used to determine the main conditions of the peripheral airway,10,11 and this method has recently received attention due to its clinical applicability; it is easily performed for outpatients and shows good reproducibility. 12,13 In the present case, markedly reduced levels of eosinophils, ECP and eotaxin were found in the induced sputum after re-administration of Pranlukast, compared to the levels during treatment with Montelukast, suggesting that Pranlukast is able to reduce peripheral airway eosinophilic inflammation and implying that there may be a clinical difference between Pranlukast and Montelukast in this respect. In trials in normal volunteers in Japan, the time to reach the peak Pranlukast concentration in blood was 5.2 ± 1.1 hr and the half-life (t1!2) was 1.15 ± 0.13 hr, suggesting that Pranlukast administration twice a day is necessary to maintain an effective blood concentration of 30 ng!ml. 14 On the contrary, the peak blood Montelukast concentration was reached in 3.9 ± 1.5 hr and the t1 !2 was 4.57 ± 0.39 hr, suggesting that
636
Montelukast repeat administration at bedtime allows a sufficient blood concentration to be maintained until noon the next day. 15 However, pharmacokinetics can differ on an individual basis, and in the present case the patient showed asthma symptoms before noon , suggesting that the blood concentration of Montelukast may have already decreased below an effective concentration before noon. As shown in Figure 2, in Pranlukast-treated patients the drug concentration in the blood remained almost at its peak concentration around noon. Hence, there may be significant differences in the blood concentrations of Pranlukast and Montelukast at this time of day. Aggravated asthma symptoms that occur early in the morning are considered to be caused by a morning“dip”, and Montelukast is administered at bedtime to suppress such symptoms . However , at the 2004 American College of Chest Physician (ACCP ) Annual Congress, Medarov gave a very interesting presentation, 16 in which it was reported that the pulmonary function data of 4800 asthma patients showed a lunch-time dip around noon, i.e., the lowest pulmonary function occurred at this time, as well as a morning dip. In the present case, the patient also showed aggravated symptoms with low pulmonary function before noon during treatment with Montelukast, consistent with data from Medarov. Re-administration of Pranlukast twice a day improved the symptoms of the patient, and therefore I concluded that a difference in blood concentration between Pranlukast and Montelukast may be one of the reasons for the clinical difference between the two drugs in the patient.
REFERENCES 1. National Institutes of Health , National Heart Lung and Blood Institute. Global Initiative for asthma. Global strat-
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Improved Asthma by Re-treatment of Pranlukast
egy for asthma management and prevention. Bethesda:National Institute of Health, 2004. 2. The Immunology and Allergy Research Study Project, the Ministry of Health and Welfare. In: Makino S, Furusho K, Miyamoto A, Nishima M ( eds ) . Asthma Prevention and Management Guidelines 2003 ( JGL 1998 revised version 2). 2003;71-91(in Japanese). 3. Nakawaga N, Fujita M, Yonetomi Y, Tanaka M, Obata T, Kawano S. CysLT 1 antagonism of Pranlukast , Montelukast and Zafirlukast with serum albumin. Jap . J . Pharmaco. Therapeut. 2002;30:191-195. 4. Miyamoto A, Makino S, Kitamura S et al. Study of efficacy of cysteinyl leukotriene receptor antagonist, MK-476 on adult bronchial asthma ― Pranlukast hydrate-controlled double blind comparative study. J. Cli. Therapeut. Med. 2001;17:519-558. 5. Motojima S, Tateishi K, Kushima A, Ohashi Y, Fukuda K, Makino S. Measurement of Eosinophil Cationic Protein Concentration in Sputum of Bronchial Asthma Patients. Allergy 1991;40:100-107. 6. Yoshida S, Ishizaki Y, Shoji T et al. Effect of pranlukast on bronchial inflammation in patients with asthma. Clin. Exp. Allergy 2000;30:1008-1014. 7. Stelmach I, Jerzynska J, Kuna P. A randomized , doubleblind trial of the effect of treatment with montelukast on bronchial hyperresponsiveness and serum eosinophilic cationic protein(ECP), soluble interleukin 2 receptor(sIL2R), IL-4, and soluble intercellular adhesion molecule 1 (sICAM-1)in children with asthma. J. Allergy Clin. Immunol. 2002;109:257-263. 8. Nakamura Y, Hoshino M, Sim JJ, Ishii K, Hosaka K, Sakamoto T. Effect of the leukotriene receptor antagonist
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pranlukast on cellular infiltration in the bronchial mucosa of patients with asthma. Thorax 1998;53:835-841. 9. Chibana K, Ishii Y, Asakura T, Fukuda T. Up-regulation of cysteinyl leukotriene 1 receptor by IL-13 enables human lung fibroblasts to respond to leukotriene C4 and produce eotaxin. J. Immunol. 2003;170:4290-4295. 10. Gershman NH, Liu H, Wong HH, Liu JT, Fahy JV. Fractional analysis of sequential induced sputum samples during sputum induction: evidence that different lung compartments are sampled at different time points. J. Allergy Clin. Immunol. 1999;104:322-328. 11. Fahy JV, Wong H, Liu J, Boushey HA. Comparison of samples collected by sputum induction and bronchoscopy from asthmatic and healthy subjects. Am. J. Respir. Crit. Care Med. 1995;152:53-58. 12. Obayashi H. Evaluation of peripheral airway inflammation and efficacy of HFA-BDP inhaler(QVARTM)using induced sputum in asthma patients treated with dry-powder steroid inhaler for middle to long periods. Allergy 2005;54:2435. 13. Tsuji F, Higashida A. Induced Sputum and ECP. J . Jap . Society Int. Med. 2004;93:2116-2121. 14. Nakashima M, Kanemaru M, Uematsu T, Tsubokura S. [A phase I clinical study of a leukotriene C4, D4 and E4 receptor antagonist; ONO-1078 in healthy volunteers.] Rinsyoiyaku 1993;9(Suppl 1):3-29(in Japanese). 15. Ohnishi A, Ito M, Toyoki T et al. [A phase I clinical study of MK-476(Montelukast Sodium)a new cysteinyl leukotriene receptor antagonist.] Rinsyoiyaku 2001;17:443-470 (in Japanese). 16. Medarov BI. Hour-to-hour variation of FEV 1 !FVC. CHEST 2004;126:744S.
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CASE REPORT
Improved Case of Bronchial Asthma by Re-administration of Pranlukast from Montelukast: Evaluation of Eosinophilic Inflammation in the Peripheral Airway Hiroyuki Ohbayashi1 ABSTRACT Background: Pranlukast and Montelukast are Cysteinyl leukotriene receptor antagonists with almost the same pharmacological activity. However, I will describe a case in which these drugs showed different therapeutic effects on clinical symptoms during the daytime and eosinophilic inflammation in the peripheral airway. Methods: A 70-year-old male patient with non-atopic bronchial asthma who was treated with 400 μg!day of Budesonide TurbuhalerⓇ (BUD-TH) changed from Pranlukast (225 mg, twice daily) to Montelukast (10 mg, one tablet before sleeping), resulting in worsening clinical symptoms consisting of sputum and cough in the daytime, mainly at lunch time. Due to the fact that the symptoms did not improve sufficiently, instead of increasing the dose of BUD-TH, we investigated the clinical symptoms and pulmonary functions as well as measured the mean eosinophil count, eosinophil cationic protein (ECP) and eotaxin in the hypertonic saline-induced sputum prior to administration of Pranlukast, and 4 and 8 weeks after the re-administration of Pranlukast from Montelukast. Results: Following the re-administration of Pranlukast, the clinical symptoms disappeared within a few days and pulmonary function improved within 4 weeks. Eosinophils in the induced sputum almost completely disappeared for 4 weeks. The sputum ECP and eotaxin before and 4 weeks after the re-administration of Pranlukast changed from 700 μg!l to 192 μg!l, and 69.9 pg!ml to 30.6 pg!ml, respectively. After 8 weeks, no sputum induction was found. Conclusions: The clinical difference between these two similar antagonists may be caused by the time difference relating to when and how often each drug is administered, suggesting the existence of the lunchtime dip.
KEY WORDS asthma, eosinophil cationic protein (ECP), eotaxin, induced sputum, Pranlukast
INTRODUCTION Cysteinyl leukotriene ( CysLT) receptor antagonists are defined as drugs for the long-term control of asthma in the Guide for Asthma Management and Prevention published by the Global Institute for Asthma (GINA) 1 and in the Asthma Prevention and Management Guidelines 2003 (JGL).2 At present, the CysLT1 receptor antagonists used in Japan are Pran1Department of Internal Medicine, Tohno Kosei Hospital, JA Gifu Kosei Organization, Gifu, Japan. Correspondence: Hiroyuki Ohbayashi, Department of Internal Medicine, Tohno Kosei Hospital, JA Gifu Kosei Organization, 76−1 Toki-cho, Mizunami City, Gifu 509−6101, Japan.
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lukast , Montelukast and Zafirlukast . These three drugs show almost the same levels of CysLT1 receptor antagonism. 3 Although no significant differences in clinical effects were found in a comparative study of Pranlukast and Montelukast, 4 both drugs differ in the type of the drug form; a capsule or a small tablet, and the daily administrative time ; when and how often each drug is taken . In daily use , the recommended daily dose of Pranlukast for adults is 4 capEmail: [email protected] Received 24 December 2004. Accepted for publication 13 May 2005. !2005 Japanese Society of Allergology
633
Ohbayashi H
2002.4
2002.11 2003.4 2003.10 2004.4 2004.6
2004.9
2004.10 2004.11
sputum and cough Asthma exacerbation 600 µg/day
400 µg/day
BUD-TH Theophylline
100 mg/day
Tulobuterol hydrochloride tape
2 mg/day
Pranlukast
450 mg/day
Montelukast
450 mg/day 10 mg/day
Fi g.1 Cl i ni calcour se
sules (450 mg! day), taken twice daily (after breakfast and dinner), while the recommended daily dose of Montelukast is 10 mg! day taken once prior to sleeping. Drug compliance is highly dependent on the drug form and the administration time , especially in elderly asthmatic patients. The author has often encountered patients who found it difficult to take capsules or wished to decrease the number of capsules they were required to take, often resulting in an administrative change from Pranlukast to Montelukast. However, I have also experienced not a few patients who then requested re-administration of Pranlukast, due to aggravated subjective symptoms which developed after the change of drugs. The case report given below involves one such patient. In this case report , in addition to evaluating the changes in clinical symptoms and pulmonary functions, I also investigated the eosinophil count, eosinophil cationic protein (ECP) and eotaxin in the hypertonic saline-induced sputum before and after the readministration of Pranlukast from Montelukast.
CLINICAL SUMMARY The patient was a 70-year-old male with non-atopic bronchial asthma who visited our department in February 2001 and was given Beclomethasone dipropionate (BDP), a steroid inhalant, at a dose of 800 μg! day, based on Step 3 of the“ Severity Criteria for Bronchial Asthma”developed by the Japanese Society of Allergy.2 In May 2002, his asthma was under effective control using 400 μg !day of Budesonide Turbuday of halerⓇ (BUD-TH), a steroid inhaler, 100 mg! theophylline, 2 mg!day of a Tulobuterol patch, and 450mg !day of Pranlukast . In November 2002, because of his good stable asthmatic condition, the patient requested a decrease in the number of oral drug capsules. Therefore , 4 capsules of Pranlukast were
634
changed into one tablet of Montelukast at bedtime . For several weeks after the change , his asthmatic condition showed no remarkable change , and then the amount of sputum and cough gradually increased in the daytime , in particular at lunchtime . In June 2004, he had a moderate asthma attack and was admitted to our hospital. After admission, BUD-TH was increased to 600 μg! day and wheezing and breathing difficulty quickly improved , but the sputum associated with cough persisted during the daytime. Again based on the patient’s request, Montelukast was replaced with Pranlukast in September 2004. A few days afterwards, the sputum associated with cough at daytime disappeared spontaneously and completely . According to his daily asthma diary and a detailed interview with his family, his drug compliance was confirmed as almost 100% over this course. His clinical course for the two months is shown in Figure 1.
PATHOLOGICAL FINDINGS In order to investigate the relationship between the changes of his asthmatic condition and eosinophilic inflammation in his peripheral airway , the induced sputum tests were performed before and after the change from Montelukast to Pranlukast. Prior to performing the each test , the purpose , methods and risks of the test were explained to the patient in detail each time, in accordance with the code of ethics at our hospital which is based on the Declaration of Helsinki of 1995 (as revised in Edinburgh 2000). After informed consent was obtained , the test was conducted. The patient inhaled a 10% salt solution for 15 minutes using an ultrasonic nebulizer , and the induced sputum was collected by a deep cough after gargling. The saliva component was removed from the collected sputum, and a smear preparation of the viscous sputum component was made. This was then stained with Wright-Giemsa stain. The mean number
Allergology International Vol 54, No4, 2005 www.jsaweb.jp!
Improved Asthma by Re-treatment of Pranlukast Tabl e 1 Resul t sofhyper t oni csal i nei nducedsput um t es t s Ti mePoi nt
Eo
Bef or er eadmi ni st r at i onofPr anl ukast 4weeksl at er 8weeksl at er
ECP( μg/ l )
( ＋) ( −)
Eot ax i n( pg/ ml )
700 192 nos put um i nduc t i on
69. 9 30. 6
Abbr ev i at i ons :Eo=eos i nophi l ,ECP=eos i nophi lc at i oni cpr ot ei n
Cr i t er i af orEosi nophi l s Meancount sofeosi nophi l si n5HPF( X)
J udgment
X＜ 1
( −) ( ＋) ( 2＋) ( 3＋)
1＜ or＝ X＜ 10 10＜ or＝ X＜ 20 20＜ or＝ X
Tabl e 2 Changesi npul monar yf unct i ont estdat awi t ht i me %VC( %) 2002. 4
・
・
・
%FVC( %) %FEV1. 0( %) V50( L/ s ec ) V25( L/ s ec ) V25/ H( L/ sec/ m)
70. 6
55. 1
72. 9
1. 11
0. 68
0. 46
2002. 11changef r om Pr anl ukastt oMont el ukast 2003. 4
72. 4
57. 8
68. 4
1. 02
0. 39
0. 27
2003. 10
62. 7
58. 3
64. 0
0. 83
0. 54
0. 36
2004. 4
61. 7
53. 5
69. 6
0. 57
0. 66
0. 44
2004. 6doseofBUDTHi ncr easedf r om 400μg/ dayt o600μg/ day 2004. 9( bef or echangeofdr ugs ）
46. 6
42. 8
61. 3
0. 88
0. 64
0. 44
2004. 9changebackt oPr anl ukastf r om Mont el ukast 4weeksl at er
49. 1
49. 1
65. 4
0. 86
0. 74
0. 50
8weeksl at er
51. 2
50. 1
71. 4
1. 06
0. 73
0. 50
Abbr ev i at i ons :VC＝ v i t alc apac i t y ,FVC＝ f or c edv i t alc apac i t y ,FEV1. 0＝ f or c edex pi r at or yv ol umedur i ng1s ec ond
of eosinophils per 5 microscopic views (×400) was obtained, based on the following criteria: per 5 views, one or less eosinophil, (−); one to less than 10, (+); 10 to less than 20, (2+); 20 or more, (3+). The sputum ECP and eotaxin levels were determined according to the method of Motojima et al.. 5 Induced sputum was kept at 4℃ from the time of collection to sample preparation; samples were always prepared within 6 hours. The sputum ECP and eotaxin levels were determined using an ECP FEIA kit (Pharmacia & Upjohn Diagnostics AS, Uppsala, Sweden) and an eotaxin ELISA kit (R&D Systems, MN, USA), respectively. The mean eosinophil count and the ECP and eotaxin levels in induced sputum immediately before, and 4 and 8 weeks after re-administration of Pranlukast are shown in Table 1. Pulmonary function data from April 2002, i.e., before the initial change from Pranlukast to Montelukast , to November 2004 are shown in Table 2. All pulmonary function data were measured between 11 a.m. and noon. Four weeks after the change from Montelukast to Pranlukast, the
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eosinophil count in induced sputum was negative , and sputum ECP and eotaxin were markedly decreased. Furthermore, 8 weeks after this change, no sputum could be induced . The pulmonary function values were aggravated after the change from Pranlukast to Montelukast and then improved after readministration of Pranlukast (Table 2).
DISCUSSION Pranlukast and Montelukast are CysLT1 receptor antagonists with almost the same pharmacological antiLT activity , although their administered doses and drug forms are different. 3,4 In the present case, the patient experienced subjective asthma symptoms after switching from Pranlukast to Montelukast which then improved after a change back to Pranlukast . This was objectively proved based on the results from the pulmonary function data. Collectively, the objective and subjective results suggest that Pranlukast and Montelukast had a different clinical effect in this patient.
635
Ohbayashi H
Pranlukast Blood concentration
Montelukast
MEL
12:00
4:00 19:00 ―20:00 23:00
8:00
Administration of Pranlukast Morning dip
4:00
12:00
19:00 ―20:00 23:00 Administration of Montelukast
Lunchtime dip MEL: Minimum effective level
Fi g.2 Ti mecour sechangeofbl oodc onc ent r at i on( out l i ne)
In addition to exerting strong LT receptor antagonism, CysLT1 receptor antagonists suppress eosinophil activation, leading to reduction of serum ECP, 6,7 and inhibit cellar infiltration of inflammatory cells in bronchial mucosa, 8 as well as eosinophilic migration through suppression of eotaxin, an eosinophilic migration factor . 9 However , a direct comparison of eosinophil suppression has not been performed for Montelukast and Pranlukast. We therefore found the different suppression effects of Montelukast and Pranlukast in the present case to be of particular interest, and we examined the eosinophilic conditions of the peripheral airway before and after the change of drugs , using the induced-sputum method described above . It is generally accepted that hypertonic saline-induced sputum in this study can be used to determine the main conditions of the peripheral airway,10,11 and this method has recently received attention due to its clinical applicability; it is easily performed for outpatients and shows good reproducibility. 12,13 In the present case, markedly reduced levels of eosinophils, ECP and eotaxin were found in the induced sputum after re-administration of Pranlukast, compared to the levels during treatment with Montelukast, suggesting that Pranlukast is able to reduce peripheral airway eosinophilic inflammation and implying that there may be a clinical difference between Pranlukast and Montelukast in this respect. In trials in normal volunteers in Japan, the time to reach the peak Pranlukast concentration in blood was 5.2 ± 1.1 hr and the half-life (t1!2) was 1.15 ± 0.13 hr, suggesting that Pranlukast administration twice a day is necessary to maintain an effective blood concentration of 30 ng!ml. 14 On the contrary, the peak blood Montelukast concentration was reached in 3.9 ± 1.5 hr and the t1 !2 was 4.57 ± 0.39 hr, suggesting that
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Montelukast repeat administration at bedtime allows a sufficient blood concentration to be maintained until noon the next day. 15 However, pharmacokinetics can differ on an individual basis, and in the present case the patient showed asthma symptoms before noon , suggesting that the blood concentration of Montelukast may have already decreased below an effective concentration before noon. As shown in Figure 2, in Pranlukast-treated patients the drug concentration in the blood remained almost at its peak concentration around noon. Hence, there may be significant differences in the blood concentrations of Pranlukast and Montelukast at this time of day. Aggravated asthma symptoms that occur early in the morning are considered to be caused by a morning“dip”, and Montelukast is administered at bedtime to suppress such symptoms . However , at the 2004 American College of Chest Physician (ACCP ) Annual Congress, Medarov gave a very interesting presentation, 16 in which it was reported that the pulmonary function data of 4800 asthma patients showed a lunch-time dip around noon, i.e., the lowest pulmonary function occurred at this time, as well as a morning dip. In the present case, the patient also showed aggravated symptoms with low pulmonary function before noon during treatment with Montelukast, consistent with data from Medarov. Re-administration of Pranlukast twice a day improved the symptoms of the patient, and therefore I concluded that a difference in blood concentration between Pranlukast and Montelukast may be one of the reasons for the clinical difference between the two drugs in the patient.
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Improved Asthma by Re-treatment of Pranlukast
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pranlukast on cellular infiltration in the bronchial mucosa of patients with asthma. Thorax 1998;53:835-841. 9. Chibana K, Ishii Y, Asakura T, Fukuda T. Up-regulation of cysteinyl leukotriene 1 receptor by IL-13 enables human lung fibroblasts to respond to leukotriene C4 and produce eotaxin. J. Immunol. 2003;170:4290-4295. 10. Gershman NH, Liu H, Wong HH, Liu JT, Fahy JV. Fractional analysis of sequential induced sputum samples during sputum induction: evidence that different lung compartments are sampled at different time points. J. Allergy Clin. Immunol. 1999;104:322-328. 11. Fahy JV, Wong H, Liu J, Boushey HA. Comparison of samples collected by sputum induction and bronchoscopy from asthmatic and healthy subjects. Am. J. Respir. Crit. Care Med. 1995;152:53-58. 12. Obayashi H. Evaluation of peripheral airway inflammation and efficacy of HFA-BDP inhaler(QVARTM)using induced sputum in asthma patients treated with dry-powder steroid inhaler for middle to long periods. Allergy 2005;54:2435. 13. Tsuji F, Higashida A. Induced Sputum and ECP. J . Jap . Society Int. Med. 2004;93:2116-2121. 14. Nakashima M, Kanemaru M, Uematsu T, Tsubokura S. [A phase I clinical study of a leukotriene C4, D4 and E4 receptor antagonist; ONO-1078 in healthy volunteers.] Rinsyoiyaku 1993;9(Suppl 1):3-29(in Japanese). 15. Ohnishi A, Ito M, Toyoki T et al. [A phase I clinical study of MK-476(Montelukast Sodium)a new cysteinyl leukotriene receptor antagonist.] Rinsyoiyaku 2001;17:443-470 (in Japanese). 16. Medarov BI. Hour-to-hour variation of FEV 1 !FVC. CHEST 2004;126:744S.
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