Systemic Procaterol (Meptin) as a CONTROLLER for Asthma PART 2 Good day to you doctor. Last time, I was discussing with you the role of Systemic Procaterol (Meptin) as a controller, in treating your patients with asthma. I would like to continue today on the features of Meptin that effectively targets your patient’s symptoms.

Treatment Modality for Asthma Steroids Anti-inflammatory drugs Oral/Long acting bronchodilators Anti-inflammatory effects Reduce airway hyperreactivity Sustained bronchodilation Inflammation Airway Hyperreactivity Controller Bronchoconstriction Asthmatic attack Reliever First let me review with you the treatment modality for Asthma again. Knowing that the underlying conditions of asthma are inflammation and airway hyperresponsiveness, I hope you will agree with us that bronchodilators having the following features are more recommended as an additional controller to steroids or anti-inflammatory drugs; 1. Anti-inflammatory effect, 2. Reduces airway hyperresponsiveness, and 3. Sustained bronchodilating action. Inhaled Bronchodilators Rapid onset of action Potent bronchodilation

Features of Meptin Syrup & Tablets as A Controller Long Duration of Bronchodilating Action Anti-inflammatory Effect We have tackled last time the Long Duration of Bronchodilating action of Meptin, which showed it longer in action versus other b2-stimulants. Today let me focus on the 2nd feature: Meptin as a Controller has anti-inflammatory Effect. Reduces Airway Hyperreactivity

Mechanism of Action of Meptin Anti-inflammatory Effect Bronchodilating Action b2 receptor Bronchial Smooth Muscle b2 receptor Mast Cell Muscarinic receptor . Ach . Dilation A`clase PDE histamine receptor . . Ca ATP cAMP 5`AMP Constriction Ca Ca Degranulation histamine leukotriene receptor All beta 2 agonists may have an anti-allergic effect theoretically based on the mode of action as shown in this slide. When adrenergic receptors on the cell membrane of the mast cells are stimulated by beta 2 agonists, an enzyme, adenylate cyclase is activated to convert ATP to cyclic AMP, which facilitates free calcium ions going back to its storage granules in the mast cells, leading to less availability of free calcium ions within the mast cells. As you know well, doctors, free calcium ions are needed for the mast cells to release chemical mediators such as histamine and luekotriens, since degranulation of the storage granules containing the chemical mediators is calcium ion dependent. Also, free calcium ions are needed for production of inflammatory substances such as luekotrienes, thromboxane, and prostaglandins in the arachidonic acid metabolism pathway, since an enzyme, phospholipase A2, which is involved in the first step in the pathway, is calcium ion dependent as well. Phospholipids PAF PLA2 LTC4 LTA4 LTD4 . Arachidonic Acid LTE4 TXA2 LTB4 . PGD2 . . . . . . Activation of Inflammatory Cells Inflammation Bronchoconstriction

Inhibitory Effect of Various Anti-Asthmatic Drugs on Leukotriene Release (%) *** ** : p < 0.01 : p < 0.05 : p < 0.001 * In vitro study using human lung fragment 110 100 Procaterol (　　 　 5 min　 15 hours) Isoproterenol (　　　　 5 min　　　 15 hours) Salbutamol (　　　　 5 min　　　 15 hours) Tranilast (　　　　 5 min) Azelastin (　　　　 5 min) ★ ★ ★ % to Control * * 50 * * * However, doctors, what is important here is whether such anti-inflammatory effect can be seen at its clinical dose or not. As you can see in this slide, our product, Procaterol inhibited release of luekotrienes from human lung fragments at its concentration of 10 negative 8 Mol., which is equivalent to the blood concentration of Procaterol when administered to human subjects at its clinical dose of 50 mcg in a single dose. ** * ** ** ** *** * 10 -10 10 -9 10 -8 10 -7 10 -6 10 -5 10 -4 Drug Concentration (M) Watanabe, S. et. al.: Arzneim. - Forsch., 40 (I), 6, 669-674 (1990)

Inhibitory Effect of Various Anti-Asthmatic Drugs on Histamine Release (%) ** : p < 0.01 : p < 0.05 * In vitro study using human lung fragment 110 100 Procaterol (　　 　 5 min　 　　　15 hours) Isoproterenol (　　　　 5 min　　　　 15 hours) Salbutamol (　　　　 5 min　　　　 15 hours) Tranilast (　　　　　　5 min) Azelastin (　　　　　　5 min) ★ ★ ★ % to Control ** ** 50 * The same results were seen with the inhibitory release of histamine from the human lung fragments at the drug concentration of 10 negative 8 Mol. From these data, our product, Procaterol, Meptin can exhibit its anti-inflammatory effect at its clinical dose. ** * ** ** ** * ** ** ** ** 10 -10 10 -9 10 -8 10 -7 10 -6 10 -5 10 -4 Drug Concentration (M) Watanabe, S. et. al.: Arzneim. - Forsch., 40 (I), 6, 669-674 (1990)

Anti-inflammatory Effects of Meptin Subjects : Seven Bronchial Asthmatic Children of ages 8-15 （M:4，F:3） Method : PAF was given 0.025 ml intradermally. After 15 min. the wheal area was marked then was covered with a tape. Meptin tablet 50mcg was administered 2 hrs. before the same procedure was done. (㎝ ) 2 PAF Related Cutaneous Reaction 2.0 * wheal area 1.0 This anti-inflammatory effect of our product, Procaterol, Meptin was also confirmed in a clinical use, as shown in this slide. In skin test using platelet aggregating factors forming skin wheal as inflammatory reactions, the size of skin wheal was significantly reduced by the administration of Meptin 50 mcg tablets, proving its anti-inflammatory effect at its clinical dose in human subjects. : p < 0.05 * Meptin Tablet (50μg) Control Group Tokuyama, K.: Kokyu, 12 (5), 645 (1993)

Inhibitory Effects of Meptin on IAR and LAR Subjects: 12 bronchial asthmatic patients of ages 15-26 (M:8，F:4) Method: Meptin tablet 50mcg or Meptin Air was administered 1 hr. and 15 min., respectively, before the allergen challenge. *** + (n = %) (n = %) 10 Meptin tab 50μｇ Control -5 Meptin Air 20μｇ -10 -10 ** PFR Change Rate (IAR) PFR Change Rate (LAR) ** Meptin Tablets 50μｇ -20 Meptin Air 20μｇ * -15 Another possible evidence proving our product, Procaterol, Meptin has anti-inflammatory effect is the data shown in this slide. In this study, late asthmatic response was inhibited by Meptin tablets as well as Meptin Air. As you know well, doctors, the late asthmatic response with an allergen exposure normally develop 12 to 20 hours after the exposure to allergens because it takes a longer time, involving inflammatory process. In spite of the fact that Meptin Air has a duration of bronchodilating action of only 6 to 8 hours, the late asthmatic response was also inhibited by Meptin Air in this study, suggesting that possible reason of this inhibition is not due to its bronchodilating action, but its anti-inflammatory effect. From these data shown to you, I hope it is now clear to you that our product, Procaterol, Meptin has anti-inflammatory effect at its clinical dose. -30 -20 -40 -25 mean±S.E. ** : p < 0.05 mean±S.E. * : p < 0.05 ** : p < 0.001 -50 -30 Control + : p < 0.05 (vs Meptin tab 50μg) Kokubu, et. al.: Kokyu, 10 (6), 686 (1991)

Dosage and Administration: Meptin® Syrup The usual adult dosage is 10 ml of Meptin® Syrup (50 µg of procaterol hydrochloride) once before bed or twice (in the morning and before bed) a day by oral route. The dosage in children 6 years of age or older is 5 ml of Meptin® Syrup (25 µg of procaterol hydrochloride) once before bed or twice (in the morning and before bed) a day by the oral route. The dosage in children less than 6 years of age is 0.25 ml of Meptin® Syrup (1.25 µg of procaterol hydrochloride) per Kg body weight once before bed or twice (in the morning and before bed) a day by the oral route. The dosage may be adjusted according to the patient’s age and severity of symptoms. Meptin® Syrup The usual adult dosage is 10 ml of Meptin® Syrup (50 µg of procaterol hydrochloride) once before bed or twice (in the morning and before bed) a day by oral route. The dosage in children 6 years of age or older is 5 ml of Meptin® Syrup (25 µg of procaterol hydrochloride) once before bed or twice (in the morning and before bed) a day by the oral route. The dosage in children less than 6 years of age is 0.25 ml of Meptin® Syrup (1.25 µg of procaterol hydrochloride) per Kg body weight once before bed or twice (in the morning and before bed) a day by the oral route. The dosage may be adjusted according to the patient’s age and severity of symptoms.

Dosage and Administration: Meptin® Tablet 50 µg The usual adult dosage of Meptin® Tablet is one tablet (50 µg), orally once before bed or twice (in the morning and before bed) per day. The dosage should be adjusted according to the patient’s age and severity of symptoms. Meptin® Tablet 25 µg The usual dose of Meptin® 25 µg tablet is two tablets (50 µg) once before bed or twice (in the morning and before bed) per day by the oral route. The dosage in children 6 years of age or older is one tablet (25 µg), once before bed or twice (in the morning and before bed) per day by the oral route. The dosage should be adjusted according to the patient’s age and severity of symptoms. Let me just remind you once again on the recommended dosage and administration of Meptin Tablets: Meptin® Tablet 50 µg The usual adult dosage of Meptin® Tablet is one tablet (50 µg), orally once before bed or twice (in the morning and before bed) per day. The dosage should be adjusted according to the patient’s age and severity of symptoms. Meptin® Tablet 25 µg The usual dose of Meptin® 25 µg tablet is two tablets (50 µg) once before bed or twice (in the morning and before bed) per day by the oral route. The dosage in children 6 years of age or older is one tablet (25 µg), once before bed or twice (in the morning and before bed) per day by the oral route. The dosage should be adjusted according to the patient’s age and severity of symptoms.

MEPTIN: ORAL & INHALED DURATION OF ACTION ORAL: 10 to 12 hours ONSET OF ACTION ORAL: 30 to 60 minutes INHALED: 3 to 5 minutes This slide details to you doctor that Meptin is available in both oral and inhaled form. The difference is in the duration and onset of action for your patients.

WHAT MATTERS FOR YOUR PATIENT? Beneficial for Nocturnal and Exercise-induced Asthma Convenient dosaging Taste is preferred by children and adults Inhaled: 8 to 10 hrs Oral: 10-12hrs Once a Day or Twice a Day only Syrup Form is in Orange Flavor Cost-Effective Available in Tablet, Syrup, and Inhaler Device Let me just show you this slide as well, to detail how Procaterol gives many benefits for your patient. As for Onset and duration of action: Meptin Inhaled acts as rapid as 3 to 5 minutes, and lasts 8 to 10 hours. Meptin Oral acts from 30 to 60mins and lasts 10 up to 12 hours. For dosaging, it is only needed to be taken once or twice daily. For taste, Meptin Syrup is preferred by children because of its palatable orange flavour. For Cost, it is priced at par than other bronchodilators. For Form, it is available in Tablet, Syrup, and also inhaler devices, together with Obucort Swinghaler. All these contribute to making Meptin an ideal choice for patients in treating asthma symptoms. Affordable for acute or chronic treatment Effective and safe delivery

Thank you for your time in listening to my presentation, doctor. As you can see, here is the line up of our respiratory products. Meptin Syrup, Tablets, and Swinghaler, together with Budesonide Obucort, are all approved for the relief of asthma symptoms. Meptin has been, and ever will be the reliable choice through the years for Asthma management and control.