How to Use Anti-Allergy Drugs

ⅥBronchial Asthma

JMAJ 45(9): 375–380, 2002

Ken OHTA

Professor, Department of Medicine, Teikyo University School of Medicine

Abstract:Currently, anti-allergy drugs are classiﬁed, on the basis of their action

mechanism, into 5 types including mediator-release inhibitors, histamine H1

antagonists, thromboxane A2 inhibitors, leukotriene antagonists, and Th2 cytokine inhibitors. The asthma treatment guideline released in Japan stipulates treatment with one of these types of anti-allergy drugs, regardless of the severity of disease. There are no deﬁnite grounds for the choice of anti-allergy drugs. When the patient has complications involving other allergic diseases, the physician chooses, in order

of preference, histamine H1 antagonists, mediator-release inhibitors, and Th2 cytokine inhibitors, depending on the indications with the concomitant allergic

disease. When symptoms are severe, leukotriene antagonists and thromboxane A2 inhibitors are chosen. The physician may also consider increased doses of steroid inhalants and sustained release theophylline. At present, the use of two or more anti-allergy drugs together is not acknowledged, but this will be the subject of research in the future, because anti-allergy drugs with different mechanisms of action used at the same time will theoretically increase their effects.

Key words:Mediator-release inhibitors; Histamine H1 antagonists;

Thromboxane A2 inhibitors; Leukotriene antagonists; Th2 cytokine inhibitors

Introduction and its major component, the house dust mite (dermatophagoides). About 70% of these Bronchial asthma is an obstructive respira- patients had diseases involving atopic con- tory disease characterized by reversible occlu- ditions. The test results revealed that allergic sion, hypersensitivity, and chronic inﬂamma- reactions can be considered an important tar- tion of the airway. Allergic reactions play an get of asthma treatment. important role as a factor in inducing airway inﬂammation. When asthma patients are tested What Are Anti-allergy Drugs? for allergies, using a skin reaction test, about 70% exhibit the presence of IgE antibodies “Anti-allergy drug” is the general term for by showing positive reactions to house dust drugs that regulate the release and action of

This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 125, No. 10, 2001, pages 1559–1563). The Japanese text is a transcript of a lecture originally aired on February 14, 2001, by the Nihon Shortwave Broadcasting Co., Ltd., in its regular program “Special Course in Medicine”.

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Table 1 Biological Activity of Inﬂammatory Mediators Considered to Be Involved in Asthma1)

Action Histamine PGD2 PGF2␣ TXA2 LTB 4 LTC 4, D4, E4 PAF

¤¤ מ¤¤¤ ם Bronchial smooth muscle contraction ?¤ ם ? ם םםמ Airway hyperresponsiveness ¤¤ ? מ מםם Capillary permeation enhancement ם ¤ מ ? םםם Airway mucus secretion enhancement ¤ ? ¤?? םם Leukocyte migration activity .and “?” in the table refer to “action”, “strong action”, “no action” and “unknown or not deﬁnite,” respectively ”מ“ ,”¤“ ,”ם“

Table 2 Types and Names of Drugs for Long Term Asthma Control2)

1. Steroids 2) Histamine H1 antagonists 1) Steroid inhalants i) Ketotifen fumarate i) Beclometasone propionate ii ) Azelastin hydrochloride ii ) Fluticasone propionate iii) Oxatomide* 2) Oral steroids iv ) Mequitazine 2. Sustained release theophylline v) Terfenadine

3. Long-acting ␤2 stimulants vi) Epinastine hydrochloride 4. Anti-allergy drugs vii) Astemizole

1) Mediator-release inhibitors 3) Thromboxane A2 inhibitors

i) Sodium cromoglicate (1) Thromboxane A2 synthetase inhibitors ii ) Tranilast i) Ozagrel hydrochloride

iii) Amlexanox (2) Thromboxane A2 antagonists iv ) Repirinast i) Seratrodast v) Ibudilast 4) Leukotriene antagonists vi) Tazanolast i) Pranlukast hydrate vii) Pemirolast potassium 5) Th2 cytokine inhibitors i) Suplatast tosilate * Contraindicated in pediatric asthma, not adult asthma.

chemical mediators involved in allergic reac- allergy drug developed. These drugs are ex- tion, mediated by IgE (immediate or type I pected to be effective in 30 to 40% of mild to allergic reaction), or inflammatory mediators moderate cases with atopic asthma, but it takes (Table 1).1) The many anti-allergy drugs cur- them 4 to 6 weeks to manifest any effect. As rently on the market are classified, on the basis these drugs do not have anti-histamin action, of their action mechanism, into 5 types includ- they do not induce drowsiness in patients. ing mediator-release inhibitors, histamine H1 antagonists, thromboxane A2 inhibitors, leuko- 2. Histamine H1 antagonists triene antagonists, and Th2 cytokine inhibitors. Histamine H1 antagonists more or less induce drowsiness, which generally remits or disap- pears within several days after the start of treat- Types of Anti-allergy Drugs (Table 2)2) ment. Histamine H1 antagonists also inhibit 1. Mediator-release inhibitors mediator release and are effective in 20 to 30% Mediator-release inhibitors include DSCG of mild to moderate cases with atopic asthma, (sodium cromoglicate), which was the first anti- but it takes them 4 to 6 weeks to manifest

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any effect. Table 3 Cytokines Produced by Th1 and Th2 Cells

Cytokines Th1 cells Th2 cells 3. Thromboxane A2 inhibitors and antagonists מם IL-2 Thromboxane A2 inhibitors consist of 2 types

מם ␥-of agents, i.e., thromboxane A2 synthetase inhibi- IFN מם ␤-tors and thromboxane A2 antagonists (receptor TNF antagonists). םם These drugs are effective in 40% of mild to GM-CSF םם ␣-moderate atopic and mixed-type asthma. Since TNF םם their effects can be observed in only 2 to 4 IL-3 weeks of treatment, it is possible to assess םמ IL-4 results at an earlier stage than with mediator- םמ IL-5 release inhibitors and histamine H1 antago- םמ nists, which must be administered for 4 to 6 IL-6 3,4) םמ *weeks before any effect can be observed. IL-10 These drugs are also reported to be effective םמ against infectious asthma. However, due to a IL-13 case of severe hepatic disorder reported after * IL-10 is produced by both Th1 and Th2 cells in humans. marketing, physicians are recommended to administer the thromboxane A2 antagonist, seratrodast, and conduct monthly hepatic func- tion tests. inhalation and an exercise-induced asthma tests. Zaﬁrlucast and Montelukast, developed in 4. Leukotriene antagonists the West, have recently been put on the market

LTC 4, D4 and E4 receptor antagonists are in Japan. available for use as leukotriene antagonists. Much attention has been focused on these 5. Th2 cytokine inhibitors drugs in Europe and the U.S., where two drugs Th2 cytokine inhibitors inhibit the produc- were developed, but Japan took the lead and tion of excessive production of Th2 cytokines developed pranlukast hydrate, which has been that induce the IgE antibodies and allergic valuated highly since it went on the market. inflammation. Among Th2 cytokines (Table 3), These drugs are effective in 50 to 60% of IL-4, which is involved in the production of the mild to moderate atopic and mixed-type IgE antibody, and IL-5, which is involved in the asthma. Since the effects of the drug appear in activation of eosinophil, have been attracting only several days to 1 week, or 2 to 4 weeks particular attention. Reports have also found at the latest, results can be assessed much that IL-5 production is enhanced in asthma sooner than with mediator-release inhibitors patients, regardless of any allergic conditions, and histamine H1 antagonists, which must be suggesting that Th2 cells are generally pre- administered for 4 to 6 weeks before any dominant in asthma. effects can be observed.5) Another report6) Currently, the only drug available in this cat- found that these drugs not only inhibited air- egory is suplatast tosilate, which was developed way inflammation but also inhibited airway in Japan. This drug inhibits the production of hypersensitivity in asthma patients. Moreover, IL-4 and IL-5 and is reported to inhibit both aspirin- and exercise-induced asthma is expected eosinophil infiltration in the airway mucosa to be inhibited with these drugs since they and airway hypersensitivity.7) However, the showed inhibitory effects in both a sulpyrine drug has to be administered for 6 to 8 weeks

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before any effect can be observed, and its effects above symptoms two or more times a week. are manifested slowly. In view of the pathology At this step, the guidelines recommend the of asthma, more attention should be paid to the continuous use of any of the anti-allergy drugs, development of Th2 cytokine inhibitors. in addition to the continuous use of low-dose inhalant steroids (beclomethasone dipropio- ␮ Positioning Anti-allergy Drugs in nate; BDP 200–400 g/day, ﬂuticasone pro- ␮ Asthma Treatment Guidelines pionate; FP 100–200 g/day) and sustained- release theophylline. This section describes how the above- mentioned anti-allergy drugs are positioned in 3. Step 3 asthma treatment guidelines, according to the Step 3 severity consists of the presence of “Asthma Prevention and Control Guidelines” chronic symptoms. At this step, the guidelines (prepared in 1998 by the Immunity & Allergy recommend the continuous use of leukotriene

Research Group of Ministry of Health & Wel- antagonists/thromboxane A2 inhibitors in ad- fare in Japan; revised in 2000).2) Anti-asthma dition to the continuous use of middle-dose drugs are classiﬁed into those that act against inhalant steroids (BDP 400–800␮g/day, FP asthma attacks, or relievers which remove 200–400␮g/day), sustained-release theophyl-

asthma symptoms, and those for long-term line, and patch/oral/inhalant ␤2 stimulants. control, or controllers which alleviate inflammation and stabilize the patient’s condition. 4. Step 4 Obviously, anti-allergy drugs are classified as Step 4 severity consists of not only very the controllers (Table 2). severe and persistent but also aggravated According to the guidelines, asthma is classi- symptoms. At this step, the guidelines suggest fied into 4 steps of severity, i.e., mild intermit- the intermittent use of oral steroids and the tent, mild persistent, moderate persistent, and continuous use of leukotriene antagonists/

severe persistent. The guidelines recommend thromboxane A2 inhibitors in addition to the the continuous or persistent use of anti-allergy continuous use of high dose inhalant steroids drugs in treating each of these steps (refer to (BDP 800–1,600␮g/day, FP 400–800␮g/day), appendix, page 368). sustained-release theophylline, and patch/

oral/inhalant ␤2 stimulants. 1. Step 1 The continuous use of anti-allergy drugs is Step 1 severity consists of the onset of asth- suggested rather than recommended in Step 1 matic symptoms such as cough and respiratory and Step 4 because their usefulness has not yet difﬁculty once or twice a week. At this stage, been fully proven. However, it has already physicians may consider using any of the been reported that these drugs could reduce anti-allergy drugs, excluding DSCG (sodium the use of high-dose inhalant steroids.8) cromoglicate), and the positioning of anti- allergy drugs is similar to that of low-dose Personal Views on the Administration ␤ inhalant steroids. Use of 2 stimulants and of Anti-allergy Drugs theophylline for controlling the symptoms as well as DSCG inhalation before exercise and As described above, anti-allergy drugs are exposure to allergens is recommended at this positioned for long-term control of asthma and step. are selected according to the severity of the patient’s condition. This leads to various ques- 2. Step 2 tions about the administration methods of Step 2 severity consists of the onset of the these drugs.

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The usefulness of anti-allergy drugs at Step 1 and sustained release theophylline. has yet to be established. In other words, the When the condition of a patient corresponds guidelines will recommend aggressive treat- to Step 3 or 4, I administer a leukotriene antag- ments with these drugs if they are proven to onist first. If ineffective, I will administer be effective as a part of an early intervention thromboxane A2 inhibitors. What is especially against asthma. At this moment the author gen- important in the treatment of patients at Steps erally starts administering anti-allergy drugs to 3 and 4 is adding a concomitant drug while pre- patients at Step 2 or higher. scribing each drug at a satisfactory dose, within I will prescribe anti-allergy drugs with anti- the safe range. This is expected to enhance the histamin action if the patient has complications actions of leukotriene antagonists and throm- involving other allergic diseases such as allergic boxane A2 inhibitors. rhinitis and atopic dermatitis, even if the Though leukotriene antagonists and throm- asthma itself is mild. Since leukotriene antago- boxane A2 inhibitors are similarly classified as nists have recently been demonstrated to be anti-allergy drugs, mechanisms of their action effective on nasal occlusion attributable to are distinct. Concomitant administration of allergic rhinitis, treatment with this type of these drugs is not allowed at present, but drug should be taken into consideration, concomitant use of anti-allergy drugs with depending on the patient’s symptoms. Based different mechanisms of action is theoretically on their pharmacological action and thera- expected to increase their effectiveness. In this peutic effects, it is all together conceivable that regard, we should investigate if the concomi- we will include leukotriene antagonists among tant administration of these drugs is beneficial. the first drugs of choice used at Step 1. For the treatment of the patient at Step 2 Future Prospects for Anti-allergy I start with a low-dose inhalant steroid and Drugs sustained-release theophylline.9) Additional anti-allergy drugs will be administered if the Due to their slow action and rather low patient’s symptoms are not controlled with efficacy rate, the development of anti-allergy satisfaction. There are no definite criteria for drugs was criticized at the initial stage. Thanks selection. When the patient has additional to earnest support and efforts, researchers in allergic diseases, drugs are chosen according Japan were able to develop the first leukotriene to the presence or absence of contraindica- antagonist and the first thromboxane A2 inhibi- tions against that disease. In such cases, physi- tor and antagonist. I strongly hope that a highly cians may choose from mediator-release inhibi- specific anti-allergy drug will be developed tors, histamine H1 antagonists or Th2 cytokine to improve asthma treatment in the future. inhibitors. When it becomes possible to predict the effi- Caution must be exercised and it is not cacy of a drug at the genetic level,10) it will always possible to administer histamine H1 become possible to perform so-called “tailor- antagonists, as they may induce drowsiness made medicine.” in some patients. Since the efficacy rate of mediator-release inhibitors is rather low, treatment with Th2 cytokine inhibitors should be REFERENCES attempted if no effect is observed in 4 to 6 1) Ohta, K.: 2. Inflammatory mediators. J Jpn Soc weeks with mediator-release inhibitors. If both Intern Med 1996; 85: 178–183. (in Japanese) types of drugs are ineffective, I will consider 2) Immunity & Allergy Study Group, Ministry of administration of leukotriene antagonists as Health & Welfare: Guideline for Prevention well as increase of doses of inhalant steroids and Control of Asthma, Revised in 1998.

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