PREFACE 'He lives most life whoever breathes most air'

(Elizabeth Barrett Browning)

Research over the past decade has provided information concerning the onset and treatment of allergic diseases, including bronchial asthma, allergic rhinitis and atopic dermatitis. Recent studies also indicated that allergic inflammation is the basic pathophysiology of allergic diseases and is closely associated with their progression and exacerbation. Our understanding of the mechanism of allergic inflammation with regard to therapeutic agents has improved as a result of immunological and molecular biological studies. Bronchial asthma is a common disease affecting almost 300 million people in the world, and the prevalence of the disease is steadily increasing. It is characterized by reversible airway obstruction, airway inflammation and airway hyperresponsiveness. Various kinds of mediators released from inflammatory cells and resident cells in the airway have been shown to play essential roles in the pathogenesis of bronchial asthma. Among these mediators, Thromboxane A2 (TXA2) has attracted attention as an important mediator in the pathophysiology of asthma because of its potent bronchoconstrictive activity. Thromboxane A2 is believed to be involved not only in late asthmatic responses but also in bronchial hyperresponsiveness, a typical feature of asthma. Lung tissues produce a large amount of Thromboxane A2. In addition to platelet aggregation and artery smooth muscle contraction, TXA2 strongly induces airway smooth muscle contraction and bronchial hyperresponsiveness. Not only TXA2, but many arachidonate cyclooxygenase metabolites such as PGD2, PGF2 alpha, PGH2, and others stimulate TP (PGH2/TXA2) receptor and can take a pathophysiological role for bronchial asthma. Strategies for inhibition of TXA2 effects include antagonism of the TXA2 receptor (TP receptor) and inhibition of thromboxane synthase. TP receptor antagonists could block the effects of all the bronchoconstrictor prostanoids because TXA2 as well as the bronchoconstrictor PGs (PGD2 and PGF2a) act through activation of lung TP receptor. Results of double-blind, placebo-controlled clinical trials have proven the efficacy of the thromboxane receptor antagonist Seratrodast in the treatment of patients with asthma. This monograph, dedicated to Seratrodast, presents an up to date compilation of the various characteristic features that make it a safe and efficacious drug, supporting its use as an important controller medication in preventing and treating asthma.

TABLE OF CONTENTS
1 INTRODUCTION 1 Chronic Respiratory Diseases 3 CURRENT THERAPEUTIC MANAGEMENT OF ASTHMA 5 THERAPEUTIC GAP IN TREATMENT 7 PROSTANOIDS AND THEIR INVOLVEMENT IN THE PATHOPHYSIOLOGY OF ASTHMA 8 THROMBOXANE A2 (TXA2) AND ASTHMA: A NEW CONCEPT 8 Background 9 TXA2 an important mediator in asthma 10 Airway smooth muscle contraction : Bronchoconstriction 11 Airway Hyperresponsiveness: A Key Feature Of Asthma 12 Plasma extravasation : Microvascular Leakage 12 Mucous Secretion 12 Smooth muscle proliferation 12 Neuromodulatory effects 12 Impairment of Mucociliary Clearance 14 SERATRODAST: A POTENT LONG ACTING THROMBOXANE A2 ANTAGONIST 14 Chemical name 14 Molecular formula 14 Molecular weight 14 Pharmacokinetics 15 Mechanism of action TXA2 receptors Antagonism VS Thromboxane synthase inhibition 16 16 Redirection Hypothesis Pharmacodynamics 17 17 Decreases EAR & LAR 18 Relieves Airway Hyperresponsiveness: A key element in pathophysiology of Asthma 18 Decrease in Airway Inflammation 19 Decreases Sputum Production and Changes Physicochemical properties of Sputum 20 Increases Cough Threshold in Chronic Bronchitis patients 21 INDICATIONS 21 OTHER USES 21 DOSAGE AND ADMINISTRATION 21 ADVERSE REACTIONS 22 CONTRAINDICATIONS 22 PRECAUTIONS 22 OVERDOSAGE SERATRODAST: CLASSIFIED AS CONTROLLER MEDICATION IN GINA AND JAPANESE 23 GUIDELINES 23 GINA GUIDELINES 24 Japanese guidelines for adult asthma Controllers (Agents for long-term management) 28 INDIAN EXPERIENCE WITH SERATRODAST 28 Bioequivalence Study 29 Clinical Trial 34 Preclinical Study 35 CLINICAL REFERENCES 40 SALIENT FEATURES 41 REFERENCES 42 PRESCRIBING INFORMATION

INTRODUCTION INTRODUCTION
Chronic Respiratory Diseases
Chronic respiratory diseases are a group of chronic diseases affecting the airways and the other structures of the lungs. Common chronic respiratory diseases, as they appear in the International Classification of Diseases are asthma, bronchiectasis, and chronic obstructive lung disease including chronic obstructive pulmonary disease, bronchitis & emphysema.
[1]

Hundreds of millions of people around the world suffer from preventable chronic respiratory diseases. Table 1: Estimates of the global prevalence of preventable chronic respiratory diseases. Chronic Respiratory Disease Asthma Chronic Obstructive Pulmonary Disease Allergic Rhinitis Other Respiratory Diseases Year of Estimation 2004 2000 1996 - 2006 2006
[1]

Global Prevalence 300 million 210 million 400 million > 50 million

Asthma is defined by the Global Initiative for Asthma (GINA) as: A chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. For many patients, Controller medications must be taken daily to prevent symptoms, improve lung function and prevent attacks.[2]

An estimated 300 million people are affected by asthma worldwide and the burden is likely to rise substantially in the next few decades. Prevalence of asthma in India is about 2.5-5%

The prevalence of asthma has increased following changes to a modern, urban lifestyle. Globally, 2,50,000 people die of asthma every year. Asthma deaths are related to lack of proper treatment.
[1]

Various chemical mediators and cytokines are involved in the onset and development of the pathogenesis of asthma. Among these mediators, leukotriene D4 and Thromboxane A2 are potential targets of antiasthmatic drugs. They are thought to play important roles in airway smoothmuscle contraction, development of mucosal oedema and airway Hyperresponsiveness, increase in mucosal secretions and leads to narrowing of the airways.
[3]

Immune Response
Th 0 Cell (Th2)
Cylokine (IL-4,5,13 etc) Antigen Presenting Cell
Adoptive Immune Response Innate Immune Response

Inflammatory Response
Antigen Chemical Mediators

Tissue Reaction

Mast cell

B Cell

Eosinophil

Antigen

Antibody lgE

Histamine, Leukotrienes, Prostaglandins, Cytokines, Chemokines

Air Flow limitation, Bronchoconstriction, Hyper Secretion, Edema, Airway Wall Remodeling

Allergic Reaction

Innate Immune Response Adoptive Immune Response Th2 polarized Immune Response

Inflammation Caused by Pro-inflammatory Mediators released from Mast Cells

Bronchial Asthma

Figure 1: The Process of Allergic Asthma (Adapted from : Nagai H. Recent research and developmental strategy of anti-asthma drugs. Pharmacol Ther. 2012 Jan;133(1):70-8. Epub 2011 Sep 6.)

CURRENT THERAPEUTIC MANAGEMENT OF ASTHMA

In most countries, guidelines for asthma therapy have now been introduced and these form the framework of modern management, with a stepwise escalation in therapy. Asthma therapies are now classified as relievers that provide rapid relief of symptoms (short-acting 2-agonists, anticholinergics) that are used as needed and controllers which provide long-term control of symptoms that are used as a regular treatment (corticosteroids, theophylline, long-acting inhaled 2-agonists, cromones, antileukotrienes and immunomodulators).[4] Table 2: Therapeutic Classification of anti asthma drugs[47]
CLASSIFICATION CONTROLLERS MEDICATION 1. Taken daily on a long-term basis 2. Prophylactic & preventive medication DRUGS 1. Inhaled corticosteroids 2. Anti-allergic agents
[Anti-histamine, Leukotriene inhibitor, Thromboxane A2 inhibitor, Th2 cytokine inhibitor, Mast cell stabilizer, etc]

RELIEVERS

1. Taken on demand 2. Quick relief for the severe symptoms

1. Rapid-acting inhaled 2-agonists 2. Systemic glucocorticoids 3. Anti-cholinergics 4. Methylxanthines

As per GINA Guidelines, controller therapy achieves good clinical control and reduces the risk of asthma exacerbation.

Reduce

Level of control
Controlled Partly controlled Uncontrolled Exacerbation

Treatment Action
Maintain & find lowest controlling step Consider stepping up to gain control Step up until controlled Treat as exacerbation

Increase

Reduce
Step 1 Step 2

Treatment Steps

Increase
Step 4 Step 5

Step 3

Asthma education - Environmental control

As needed rapidacting 2-agonist As needed rapid-acting 2-agonist

Select one
Low dose ICS* Leukotriene modifier**

To step 3 treatment, select one or more Medium or High dose Low dose ICS plus ICS plus long-acting long-acting 2-agonist 2-agonist Select one
Medium or High dose ICS Low dose ICS plus Leukotriene modifier Low dose ICS plus sustained release theophylline Leukotriene modifier** Sustained release theophylline

To step 4 treatment, and either

Oral glucocorticosteroid (Lowest dose) Anti IgE Treatment

Controller options**

* ICS= Inhaled glucocorticosteroid ** Receptor antagonist or synthesis inhibitors ** Preferred controller options in shaded box Alternative reliever treatments include inhaled anticholinergics, short-acting oral b2-agonists, some long acting b2-agonists, and short acting theophylline. Regular dosing with short and long acting b2-agonists is not advised unless accompanied by regular use of an inhaled glucocorticosteroid.

Figure 2: Asthma management approach based on control. (GINA GUIDELINES 2011)[2]

THERAPEUTIC GAP IN TREATMENT

Cyclo-oxygenase metabolites of arachidonic acid are also implicated in the inflammatory cascade of asthma. These metabolites include thromboxane A2 (TXA2), prostaglandin F2a (PGF2a) and prostaglandin D2 (PGD2) which are capable of producing potent bronchoconstriction, airway microvascular leakage, and bronchial hyperresponsiveness through the activation of thromboxane A2 receptors (TP receptors). TXA2 may participate in the thickening and the remodeling of the airway wall which may contribute to the airway hyperresponsiveness, a typical feature of asthma. Prostaglandin E2 and prostacyclin (PGI2) are bronchoprotective.[5] PGE2 and PGI2 relax human bronchi via the activation of an EP type receptor, probably EP2.[6]

Arachidonic Acid

Cyclooxygenase

PG-G2

Prostacyclin Synthase PGE2 Isomeras

PGH2

PGD2 Isomeras

PGI2

Thromboxane Synthase

PGF2 Reductase

PGD2

PGE2

9a, 11b-PGF2

TXA2

PGF2a

BRONCHODILATION & AIRWAY PROTECTION

BRONCHOCONSTRICTION & AIRWAY HYPERRESPONSIVENESS

Figure 3: Prostanoid synthesis pathway.[6]

Airway inflammation and airway hyperresponsiveness are recognized as the characteristic features of bronchial asthma, and airway hyperresponsiveness is closely associated with inflammation in patients with asthma. Based on this concept, inhaled corticosteroids have become key drugs for the treatment of bronchial asthma, because of the powerful anti-inflammatory activity of these agents. However, long term treatment with corticosteroids, even when inhaled, may cause adverse effects such as osteoporosis in premenopausal women and suppression of HPA axis.
[7] [50]

Anti-TXA2 agents have beneficial effects on asthmatic response and airway hyperresponsiveness, and also allow reduction of concomitant corticosteroid use. Therefore, we believe that it may be appropriate to use anti-TXA2 agents in combination with other anti asthmatic agents for the control of bronchial asthma.[7] The existing therapy for asthma in India does not have modulators (Synthase inhibitor or receptor antagonist) for TXA2, a potent constrictor of airway smooth muscle. So, it will be prudent to have controller medications which can decrease or block the actions of TXA2. This gap in therapy can be filled by having a Thromboxane modulator. A large number of thromboxane synthase inhibitors and thromboxane receptor antagonists have been developed by the pharmaceutical industry. Among them are the thromboxane synthase inhibitor ozagrel and the thromboxane A2 receptor antagonist, Seratrodast, both of which are available as anti-asthmatic agents in Japan.[5]

HPA axis suppression Dose related systemic absorption of inhaled corticosteroids rarely can cause suppression of the hypothalamicpituitary-adrenal (HPA) axis

Cyclo-oxygenase metabolites of arachidonic acid like thromboxane A2 (TXA2) and prostaglandin D2 (PGD2) have now been recognized as important mediators in the pathophysiology of asthma. Drugs targeting TXA2 (Receptor antagonists) will fill the necessary gap in the therapy of asthma in India.

PROSTANOIDS & THEIR INVOLVEMENT IN THE PATHOPHYSIOLOGY OF ASTHMA

It is well accepted that prostanoids and isoprostanes (arachidonic acid metabolites) play a key role in the pathophysiology of diseases associated with inflammation process, platelet aggregation and vasoconstriction/relaxation. Consequently, the inhibition of their production and/or the blockade of their respective receptors have largely contributed to the comprehension of their mode of action, of their implication in the pathology and have still demonstrated the clinical efficacy in amongst other bronchial asthma.[8]
Membrane Phospholipids

P-450 Epoxygenase Pathway Arachidonic Acid

Lipoxygenase Pathway

COX-1
PGG2 PGH2
Thromboxane Synthase

COX-2

Prostaglandin Synthase

TXA2

PGI2

PGE2

PGD2

PGF2

Pulmonary Diseases Figure 4: Generation of prostaglandins and thromboxane A2 by enzymatic pathway and generation of isoprostanes by nonenzymatic pathway from arachidonic acid.[9]

Table 3: Effects of Prostanoids Implicated in the Pathophysiology Of The Respiratory Tract (Asthma)[8]
Mediator PGD2 PGF2 PGE2 TXA2 8-iso-PGF2 Receptors DP FP EP TP TP* Bronchoconstriction ++ ++ ++ + Airway Secretion + + + ? ? Chemotaxis ? ? + ? AHRa + + + +

aAHR, airway hyperresponsiveness; -, no effect; , possible effect; +, small effect; ++, moderate effect; ?, uncertain or undetermined effect; *, unknown specific receptor (modified from Barnes et al., 1998).

THROMBOXANE A2 (TXA2) AND ASTHMA: A NEW CONCEPT

Background Thromboxane A2 (TXA2) is a biologically potent arachidonic acid metabolite derived from the cyclo-oxygenase pathway.[10] It is formed by the action of thromboxane synthase on prostaglandin endoperoxide H2 present mainly in activated platelets and macrophages.[11,12] Thromboxane A2 is a potent bronchial smooth muscle spasmogen in vitro, and it has been implicated in airway inflammation and in the genesis of bronchial hyperresponsiveness in asthma.[13]

The lung tissues are capable of forming large amounts of TXA2 from lung monocytes, mast cells, alveolar macrophages, neutrophils and platelets.

Table 4: Synthesis and release of TXA2[6.8]

Cells producing TXA2 Locations of Receptors Effects Produced Strategy for Inhibition

Platelets, Monocytes, Localized to both Airway obstruction Thromboxane Alveolar macrophages, plasma membrane & Bronchial synthase Inhibitors neutrophils & cytosolic compartments hyperresponsiveness Thromboxane lung parenchyma are mainly distributed Microvascular receptor antagonists in tissues rich in leakage vasculature such as lung, heart & kidney

Phosphatidylcholine Phospholipase A2 Arachidonic Acid Cyclo-oxygenase Lipooxygenase

Asthma Various Agents g Inducin ergens, ll (Like A noids, rosta P etc.) rienes Leukot timulation S Act via Receptor A2 of TX

TXA2 Receptor Possessing cells

Figure 5: Thromboxane A2 production and receptor blockage by TXA2 Antagonists.[7]

The lung tissues are capable of forming large amounts of TXA2. A significant increase in thromboxane B2, a metabolite of TXA2, has been observed in the bronchoalveolar lavage fluid from patients with bronchial asthma compared with that from healthy individuals.[13,14] TXA2 an important mediator in asthma: TXA2, a potent bronchoconstrictor, causes increase in plasma extravasation, airway hyper-responsiveness, mucous secretion, smooth muscle proliferation & other neuromodulatory effects by acting on TP receptors. TXA2, an arachidonate derivative, has multiple activities, such as releasing acetylcholine continuously from nerve ending, contracting smooth muscle and increasing vascular permeability.[15]

TXA2, a potent bronchoconstrictor, causes increase in plasma extravasation, airway hyper-responsiveness, mucous secretion, smooth muscle proliferation & other neuromodulatory effects by acting on TP receptors.

Airway smooth muscle contraction: Bronchoconstriction TXA2 is considered to be an important mediator in the pathophysiology of asthma for several reasons. TXA2 (and prostaglandin D2) induces potent contraction of the airway smooth muscles through its action on the TP receptors. TXA2 plays a crucial role in the pathogenesis of bronchial asthma since it is a potent constrictor of bronchial smooth muscles and a stimulator of airway smooth muscle cells proliferation. It was shown that TXA2 is increased in the airways of patients suffering from asthma after allergen challenge.
[8] [5]

Figure 6: Proinflammatory actions of TXA2. Solid red receptors indicate pathways that enhance airway inflammation TXA2 activates leukocytes and increases airway obstruction by inducing airway smooth muscle contraction and goblet cell mucus secretion.[46]

Intracellular mechanism Activation of prostanoid TP receptors present in bronchial smooth muscle cells by TXA2 leads to intracellular calcium mobilization leading to: Bronchoconstriction Bronchial smooth muscle hyperplasia and Airway remodeling which occur in response to chronic airway inflammation of asthma.[8] Airway Hyperresponsiveness: A Key Feature of Asthma TXA2 has also been implicated in airway hyperresponsiveness. TXA2 induces airway hyperresponsiveness by stimulating vagal sensory endings and by activating the [45) reflex pathway. There is increasing evidence that thromboxane modulators attenuate the increased bronchoconstrictor responses to methacholine and acetylcholine in patients with asthma. This confirms an involvement of TXA2 and/or prostaglandin D2 in the pathogenesis of bronchial hyperresponsiveness in humans.
[5]

THROMBOXANE A2 Role in Asthma

Potent Bronchoconstriction

Induction of Airway Hyperresponsiveness

Impairment of Mucociliary Clearance

Increased Microvascular Leakage

Figure 7: Pharmacological actions of TXA2 in Asthma.[16]

Plasma extravasation : Microvascular Leakage Plasma exudation induced by inhaled PAF or by leukotriene D4 (LTD4) instilled via the airway route is partly inhibited by a TX synthase inhibitor and TP receptor antagonists, suggesting that endogenously released TXA2 may cause airway microvascular leakage in responses to these mediators.[6] Mucous Secretion Pretreatment with a TP receptor antagonist attenuated the mucous gel layer response to U -46619 (TXA2 mimetic) as well as to leukotrienes. These findings support the role of TXA2 in pulmonary diseases, such as asthma, which are associated with bronchorrhea. In human airway tissue explants, PGF2a and PGD2 significantly increased mucous glycoprotein release.[6] Smooth muscle proliferation TXA2 elicits the proliferation of human airway smooth muscle cells as well as vascular smooth muscle cells. It may therefore participate in the airway wall remodeling in [6] asthma that includes airway smooth muscle hypertrophy and hyperplasia. Neuromodulatory effects TXA2 has been shown to potentiate cholinergic neurotransmission, indicating that [6] TXA2 may be involved in the facilitation of the effect of acetylcholine on the airways. Impairment of Mucociliary Clearance TXA2 also leads to impairment of mucociliary clearance. In a study involving 19 asthmatic patients the nasal clearance time had improved after a thromboxane synthase inhibitor was given indicating that thromboxane A2 plays an important role in [16,17] mucociliary transport in patients with asthma.

Airway hyperresponsiveness directly correlates with the clinical severity of asthma and interventions that reduce airway hyperresponsiveness will be useful in improving

Mast Cell

Alveolar Macrophages

Eosinophils

Platelets

PAF LTC4, D4 & B4 Bradykinin Endothelin Endotoxin Ozone

TXA2 Producing Cells

PGD2

TXA2

PGF2a TXA2

Induces release of Ach (Neuromodulatory effect)

TP Receptor

Enhances airway smooth muscle proliferation

Induces airway smooth muscle contraction

Increases viscoelasticity of sputum

Induces bronchial smooth muscle vasoconstriction

Increases tracheal mucous secretion

Regulates eosinophil degranulation

Increases airway microvascular leakage

Figure 8: Synthesis and release of TXA2 and other bronchoconstrictor prostanoids by activated lung resident cells or inflammatory infiltrating cells result in TP receptor stimulation and its effects.[6]

Cysteinyl leukotrienes induce the release of TXA2 by acting on TXA2 producing cells

SERATRODAST: A POTENT LONG ACTING THROMBOXANE A2 ANTAGONIST Chemical Name: (+)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid

Figure 9: Structure of Seratrodast

Molecular formula: C22H26O4 Molecular weight: 354.4 Pharmacokinetics Following single and repeated oral administration, Seratrodast is rapidly and dosedependently absorbed. Food does not significantly affect the bioavailability of Seratrodast; however, the time required to reach peak serum levels may be slightly increased. The peak plasma concentrations of Seratrodast increase proportionally with dose reaching steady-state within 7 days of administration. Following once daily doses of 80mg for 15 days in patients with mild to moderate asthma, the peak plasma concentration of Seratrodast is 8.80 mcg/mL with an average Tmax of 2.4 hours. The area under the plasma concentration time curve (AUC) for Seratrodast is 22.96 mcg x hr/mL, the average apparent volume of distribution is 33 L and it has high protein binding capacity (more than 99%). The AUC and T1/2 were 1.5-2 times higher and the Tmax, tended to be prolonged in elderly subjects as compared with healthy young volunteers.[18,19,20]

Seratrodast is a long acting TP receptor antagonist, reaching steady state plasma concentration within 7 days and is given orally once daily.

Time (h) Figure 10: Mean plasma concentrations of Seratrodast following single doses of 20, 40, 80 or 120 mg.[20]

Seratrodast is metabolized to 5-methylhydroxySeratrodast and 4-hydroxySeratrodast by cytochrome P450 (CYP) isoenzymes. It is also partially (35%) glucuronidated in plasma and may be subject to enterohepatic recycling.[21] Following oral administration of 40 to 120 mg/day in healthy subjects, renal clearance ranged from 5.10 to 8.94 mL/hr (average 7.0 mL/hr) after a single dose and at steady-state. The percentage of the dose excreted as unchanged drug in the urine ranged from 0.42% to 1.37% (average 0.83%) after a single dose and at steady-state. The plasma concentrations decline biexponentially with an average half-life of 20 and 36 hours after single and multiple [18,19,20] administrations, respectively. Mechanism of action: Seratrodast, a quinone derivative is a novel, potent, orally active and long acting TXA2/PGH2 receptor antagonist. In addition, Seratrodast has PGF2, PGD2 and 9, 11-PGF2 antagonistic effects. The results of the studies indicate that Seratrodast is potent agent that inhibits allergic asthma induced by many of the chemical mediators which are involved in human bronchial asthma.[20]

TXA2 Receptors Antagonism VS Thromboxane Synthase Inhibition

Redirection Hypothesis:
Thromboxane synthase inhibitors effectively suppress TXA2 synthesis; however, inhibition of thromboxane (TX) synthase results in an increased availability of the precursor PGH2 with the possibility of prostanoid synthesis redirection from TXA2 to other prostaglandins according to the enzyme equipment of the cells.

Figure 11: Redirection Hypothesis[6]

Therefore, accumulated PGH2 or increased synthesis of prostaglandins, such as PGF2a and PGD2, may substitute for TXA2 in causing TP receptor stimulation or may increase the stimulation of other prostanoid receptors with a resulting reduction in the potential effects of TX synthase inhibition.[6] A possible adverse effect of anti-TXA2 agents is a tendency to bleeding due to suppression of platelet aggregation. This effect is more pronounced for TXA2 synthase inhibitors than for TXA2 receptor antagonists because PGI2 production, which has anti-platelet aggregation activity is enhanced by blocking the pathway [7] from PGH2 to TXA2.
TXA2 synthase inhibitors are less effective than receptor antagonist as there is increased production of other bronchoconstrictor mediators (PGD2, PGF2a), which stimulates TP receptors.

Pharmacodynamics
Decreases EAR & LAR Allergen provocation of atopic asthmatic subjects induces an immediate airway response (IAR) which is followed by a late airway response (LAR) in 60% of the patients. LAR is associated with contraction of airway smooth muscle and an influx of inflammatory cells into the airway, edema in bronchial mucosa, and accumulation of mucus in the lumen of the airway. Seratrodast, administered orally before antigen challenge inhibited both IAR and LAR in a dose-dependent manner and Seratrodast [22,23] administered orally after the IAR inhibited LAR.
Antigen IgE Antibody Mast cell Basophil

Mediators for Bronchospasm Histamine LTC4, D4 PAF PGD2

TxA2
Neutrophil

PAF LTB4 HETEs ECF-A NCF-A

Mediators for Chemotaxis of inflammatory Cells

CD4+T cell

Eosinophil

IL-3 IL-5 GM-CSF MBP ECP EPO+H2O2+Hallde PAF(?)

TxA2
LTC4, D4 PAF (?) Injury of airway epithelium

Seratrodast
Irritant receptor exposure Contraction Inflammation of airway epithelial cell (Contraction, edema) Non-specific stimuli Neural mediator

Immediate phase airway response (IAR)

Late phase airway response (LAR)

Airway hyperresponsiveness

Figure 12: Anti asthmatic actions of Seratrodast in experimental Allergic asthma.[24]

Relieves Airway Hyperresponsiveness: A key element in pathophysiology of Asthma

In an open label study on 14 asthmatic subjects who were administered 80mg of Seratrodast once a day for 4 weeks significantly decreased Airway hyperresponsiveness by antagonizing TXA2 released from the inflamed airways.

Figure 13: The value of PD35-Grs before & after the Seratrodast treatment. PD35-Grs significantly increased after the Seratrodast treatment (P<0.05).[25] PD35-Grs 35% decrease in respiratory conductance after Methacholine

Respiratory conductance (Grs) was measured by the forced oscillation method and airway responsiveness was evaluated as the inhaled dose of methacholine, which induced 35% decrease in Grs (PD35-Grs). Increase in PD35-Grs indicates a decrease in airway hyperresponsiveness.[25] Decrease in Airway Inflammation Administration of Seratrodast decreased the concentration of ECP in sputum significantly (p < 0.05), and sputum ECP significantly increased again after withdrawal of (p < 0.05). The results suggest that Seratrodast improves clinical [15] symptoms and airway hyperresponsiveness by reducing airway inflammation.

Figure 14: The effect of Seratrodast on the concentration of ECP in induced sputum. Administration of Seratrodast decreased the concentration of ECP in sputum significantly (p<0.05), and its withdrawal caused a significant increase of sputum ECP (p<0.05).[15]

Decreases Sputum Production & Changes Physicochemical properties of Sputum In a Multicenter, double-blind, randomized, placebo-controlled study Forty-five patients with mild to moderate asthma who had been continuously expectorating sputum of > 20 g/d were assigned to receive Seratrodast, 40 mg/d, or placebo for 6 weeks. Seratrodast treatment decreased the amount of sputum (p = 0.005), dynamic viscosity (p = 0. 007), and albumin concentration (p = 0.028). Nasal clearance time of a saccharin particle was shortened in the Seratrodast group at week 4 (p = 0.031) and week 6 (p = 0.025), compared with the placebo group.

Figure 15: Time course of the amount of daily production of sputum in asthma patients with airway hypersecretion. Seratrodast (closed circles) or placebo (open circles).[26]

Blockade of TXA2 receptor by Seratrodast decreased the amount of sputum along with alterations in its physicochemical properties, and caused an improvement in nasal mucociliary clearance.[26] Increases Cough Threshold in Chronic Bronchitis patients Increased eicosanoid synthesis has been suggested as the underlying mechanism of chronic productive cough in patients with chronic bronchitis. The effects of Seratrodast and pranlukast on cough response to inhaled capsaicin were examined in sixteen patients with stable chronic bronchitis. Table 5: Pulmonary function and capsaicin cough threshold on Seratrodast, pranlukast and placebo treatment in chronic bronchitis patients.
Control
FVC as % pred. (%) FEV1 as % pred. (%) Cough threshold (M) 97.9 + 4.1 102.4 + 4.6 17.3 (1.3)

Placebo
99.4 + 3.8 103.9 + 4.2 20.5 (1.4)

Seratrodast
98.8 + 3.9 105.3 + 4.1 38.6 (1.4)*

Pranlukast
94.2 + 7.4 103.0 + 9.5 31.5 (1.4)

Data are shown as standard error of the mean for FVC (forced vital capacity) and FEV (forced expiratory volume in one second) and as geometric mean value (geometric standard error of the mean) for capsaicin cough threshold. *P<0.05 compared with placebo treatment (Wilcoxonsigned-ranks test).

The cough threshold was significantly increased compared with placebo after four week treatment with Seratrodast, but not after treatment with Pranlukast.[27]
(Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or [27] more coughs, was measured as an index of airwaycough sensitivity.)

Seratrodast: Decreases EAR & LAR Relieves Airway Hyperresponsiveness Decreases Airway Inflammation Decreases Sputum Production Changes Physiochemical properties of Sputum (Decreases sputum albumin & fucose levels) Increases Cough Threshold in Chronic Bronchitis patients

INDICATIONS Prophylactic management of asthma [28] OTHER USES Allergic rhinitis [33] Treatment of chronic productive cough in chronic bronchitis [27] DOSAGE AND ADMINISTRATION Adults (18 years and above) In the prophylactic management of bronchial asthma, a dose of 80 milligrams (mg) once daily in the evening after food is recommended. Seratrodast has been shown to be well-tolerated following repeated once daily oral doses of up to a maximum of 320 milligrams. In elderly patients the treatment should be started with a lower dose of 40mg/day.[28] ADVERSE REACTIONS Adverse reactions are generally rare, but if present, range from mild to moderate in severity. [28]

Table 4: Adverse Reactions

0.1 to 5%
Hypersensitivity Hepatic Rash, Itching Elevated AST (GOT), ALT (GPT), AL-P, LDH, of Y-GTP Vomiting Thrombocytopenia, epistaxis, subcutaneous bleeding Insomnia, tremor, numbness Hot flashes, edema

Less than 0.1% (rare)

Nausea, loss of appetite, stomach discomfort, abdominal pain, diarrhea, Gastrointestinal constipation, dry mouth, taste disturbance Hematologic Neuropsychiatric Other Anemia, eosinophilia Drowsiness, headache, dizziness Palpitations, malaise

CONTRAINDICATIONS Seratrodast is contraindicated in patients who are hypersensitive to the drug and in patients with hepatic failure.
[28] It is not suitable for the treatment of an acute asthmatic attack.

PRECAUTIONS Seratrodast has a tendency to bring about an elevation in the levels of the hepatic enzymes. Therefore, it has to be administered with caution in patients with hepatic impairment, and continuous monitoring of the hepatic enzyme levels should be carried out (once a month). If there is a clinically significant elevation in the enzyme levels, Seratrodast should be discontinued. No clinical data are available with respect to use in pregnant and lactating women or children. Seratrodast should be administered with caution in geriatric patients, preferably starting with a lower dose.
[28]

OVERDOSAGE There have been no reports of overdosage with Seratrodast. In cases of overdosage, the stomach should be emptied by aspiration and lavage. Vital parameters should be managed symptomatically.[28]

SERATRODAST: CLASSIFIED AS CONTROLLER MEDICATION IN GINA AND JAPANESE GUIDELINES

GINA GUIDELINES CONTROLLER MEDICATIONS: Several Oral anti allergic drugs have been introduced in some countries for the treatment of mild to moderate asthma:

Seratrodast Tranilast Repirinast Tazanolast

Pemirolast Ozagrel Ibudilast Amlexanox

Seratrodast can be given as a controller medication from step 1 as per Japanese guidelines for adult asthma management.

Japanese guidelines for adult asthma Controllers (Agents for long-term management)
5. Theophylline sustained release preparation 6. Anti IgE antibody Omalizumab

1. Corticosteroids 1) Inhaled corticosteroids I) Beclomethasone dipropionate ii) Fluticasone propionate iii) Budesonide iv) Ciclesonide v) Mometasone furoate 2) Oral corticosteroids

2. Long-acting 2 agonists 1) Inhalants Salmeterol xinafoate 2) Patch-Tulobuterol 3) Oral Medicines Procaterol Hydrocloride Clenbuterol Hydrocloride Formoterol fumarate Tulobuterol hydrochloride Mabuterol hydrochloride

7. Antiallergics other than leukotriene receptor antagonists 1) Mediator antireleasers Sodium cromoglicate, tranilast, amlexanox, repirinast, ibudilast, tazanolast and pemirolast potassium 2) Histamine H1 receptor antagonists Ketotifen fumarate, azelastine hydrochloride, oxatomide, mequitazine and epinastine hydrochloride 3) Thromboxane Inhibitors i) Thromboxane A2 synthesis inhibitor Ozagrel hydrochloride ii) Thromboxane-A2 receptor antagonist Seratrodast 4) Th2 cytokine inhibitor Suplatast tosilate 8) Other agents and therapies (Chinese medicines, specific immunotherapy and non specific immunotherapy

3. Combination inhaler of corticosteroid/ long acting 2 agonist 1) Combination inhaler of fluticasone propionate / salmeterol xinafoate 2) Combination inhaler of budesonide / formoterol 4. Leukotriene receptor antagonists I) Pranlukast hydrate ii) Zafirlukast iii) Montelukast sodium

Treatment steps for Asthma (Japanese guidelines for Adult Asthma)

Treatment step 1 Inhaled corticosteroids (low dose) Inhaled corticosteroids (low to medium doses) If the above agent is ineffective, concomitantly use one of the following agents LABA (a compounding agent can be used) LTRA Theophylline sustained release preparation LTRA Theophylline sustained release preparation LABA (a compounding agent can be used) Concomitantly use one or more of the agents below Inhaled corticosteroids (Medium to high doses) Treatment step 2 Treatment step 3 Treatment step 4 Inhaled corticosteroids (high dose)

If the above agent cannot be used, use one of the following agents LTRA Theophylline sustained release preparation (unnecessary for rare symptoms)

Concomitantly use multiple agents of those below

Long- term management agents Basic treatment

LABA (a compounding agent can be used) LTRA Theophylline sustained release preparation if poorly controlled with all of the above agents add either or both of the agents below Anti IgE antibody** Oral corticosteroid***

Additional treatment

Antialiergics other than LTRA* (Seratrodast) Inhaled SABA

Antialiergics other than LTRA* (Seratrodast) Inhaled SABA

Antialiergics other than LTRA* (Seratrodast) Inhaled SABA

Antialiergics other than LTRA* (Seratrodast) Inhaled SABA

Exacerbation treatment #

LTRA : leukotriene receptor antagonists, LABA : Long-acting b2 agonist, SABA : Short-acting b2 agonist. *Antiallergics refer to mediator anti releasers, histamine H1 antagonists, thromboxane A2 inhibitors, and Th2 cytokine inhibitors. **Anti-IgE antibody is indicated for patients who are positive for perennial inhaled allergen with serum total IgE value of 30-700 IU/mL. ***Oral corticosteroids are intermittent administration for a short period. Keep the minimum maintenance dose if a patient cannot be controlled by enhanced treatment with other agents short intermittent administrations. # Management against mild exacerbations are shown.

CLINICAL STUDIES

INDIAN EXPERIENCE WITH SERATRODAST

Bioequivalence study The pharmacokinetics of Seratrodast was determined in Indian population by conducting a bioequivalence study in which the test product SERETRA (Seratrodast 80 mg manufactured by Zuventus Healthcare Ltd.) was compared against the reference product (Bronica of Takeda Pharmaceuticals). The study was conducted on 26 healthy human volunteers in an open label, balanced, randomized, single dose, two treatment, two sequence, two period, crossover, oral Bioequivalence study.

Parameter Tmax (hr) Cmax (g/l) Half life (hr)

SERETRA (Test product) 3.48 5.38 22.66

Seratrodast (International Pack Insert) 2.75 7.40 25.03

Figure 16: Comparative Linear Plot: Average Seratrodast conc. vs. time

The formulations were well tolerated in the Indian population since there were no significant changes in the post study evaluation (hematology and biochemistry) and no serious adverse events recorded. The results of the study showed that SERETRA was [48] Bioequivalent to the test product BRONICA and suitable for use in Indian population.

Clinical Trial
A Multi-centric, Double blind, Double Dummy Randomized, Comparative Clinical trial of Seratrodast 80 mg vs Montelukast 10 mg in the treatment of Asthma was conducted in Indian patients (n=205). (Clinical Trial Registry of India, Reg. No: REF/2011/07/002531). The objective of the study was to compare the treatments in terms of improvement from the baseline values, based on the change in asthma symptom score (wheezing, shortness of breath, expectoration, cough and chest tightness), lung function parameters (PEF, FVC and FEV1), and sputum (Fucose test, Eosinophil Cationic Protein and Albumin) and mucociliary clearance score.

Results
Asthma symptom score: Although, both the treatments significantly improved the symptom score for all five major symptoms (wheezing, shortness of breath, expectoration, cough and chest tightness) from the baseline after a 4 week treatment period (P< 0.05), the reduction in expectoration score was found to be significant in Seratrodast group as compared with montelukast treated patients (P<0.05) as shown below in Table 7.

Table 7: Change in mean symptom scores from baseline, at day 14 and day 28 in both study groups.
Montelukast 10mg (n=102)
Treatment Groups

Seratrodast 80mg (n=103)

p value for difference in mean changes

Baseline Day 14 Day 28 Mean Change Baseline Day 14 Day 28 Mean Change from baseline from baseline (0-28; 95% CI) (0-28; 95% CI)

Wheezing

1.4 0.7

1.1 0.7

0.9 0.6

-0.5 (-0.7 to -0.4)

1.4 0.8

1.0 0.7

0.9 0.7

-0.5 (-0.6 to -0.4)

NS

Shortness of breath

1.5 0.8

1.3 0.8

1.1 0.7

-0.4 (-0.5 to -0.2)

1.5 0.7

1.2 0.7

1.1 0.7

-0.4 (-0.5 to -0.2)

NS

Expectoration

1.5 0.6

1.2 0.7

1.0 0.7

-0.5 (-0.8 to -0.4)

1.5 0.6

1.2 0.6

0.9 0.5

-0.7 (-0.8 to -0.5)

Cough

1.6 0.6

1.2 0.7

1.1 0.6

-0.6 (-0.7 to -0.4)

1.6 0.6

1.2 0.6

1.0 0.6

-0.6 (-0.7 to -0.5)

NS

Chest Tightness

1.4 0.7

1.1 0.8

0.9 0.7

-0.5 (-0.6 to -0.3)

1.3 0.8

1.0 0.7

0.9 0.7

-0.4 (-0.5 to -0.2)

NS

7.5 Total Asthma Score 2.5

5.9 3.0

5.0 2.6

2.5 (-3.1 to -1.9)

7.3 2.8

5.6 2.7

4.6 2.6

-2.8 (-3.4 to -2.2)

NS

NS - P > 0.05; S - P < 0.05 After 28 days, significant improvement from baseline was observed in wheezing, shortness of breath, expectoration, cough and chest tightness for both the treatments.

Lung function parameters The effect of Seratrodast and Montelukast on lung function tests is shown in Table 8. Both the treatments significantly increased mean values for FVC, FEV1 and PEF from the baseline after a 4 week treatment period (P<0.05). The difference in mean changes of FVC and FEV1 was -0.004 (95% CI:-0.065 to 0.073) and -0.029 (95% CI: -0.106 to 0.048) respectively, which was not significantly different between the two groups (P>0.05) at the end of the study. However, Seratrodast treatment significantly improved PEF as compared to Montelukast, wherein mean difference between two groups was 0.416 (95% CI: 0.015 to 0.682; P<0.05) which is equivalent to 24.9L/min higher PEF with Seratrodast. The increase in PEF from baseline was more than 36 L/min in Seratrodast group. Table 8: Lung function tests after 28 days of Montelukast and Seratrodast treatment.
Parameter Montelukast 10mg (n=102) Seratrodast 80mg (n=103) Difference in Mean Changes (95% CI) -0.004 (-0.065 - 0.073) -0.029 (-0.106 - -0.048) 0.416 (0.15 - 0.682) p value of mean changes

Mean Change from Mean Change from baseline (day 0-28, 95% CI) baseline (day 0-28, 95% CI)

FVC (L) FEV1 (L) PEF (L/sec)

0.177 (0.134 - 0.221) 0.217 (0.168 - 0.308) 0.199 (0.135 - 0.606)

0.181 (0.128 - 0.235) 0.188 (0.138 - 0.239) 0.614 (0.397 - 0.832)

NS NS S

NS- P>0.05; S- P<0.05; FVC= Forced vital capacity; FEV1 = forced expiratory volume in 1 second; PEF= Peak expiratory flow After 28 days, significant improvement from baseline was observed in FVC, FEV1 and PEF for both the treatments.

Figure 16: Increase in PEF (L/Sec) from baseline after 28 days of Montelukast & Seratrodast treatment

Sputum & mucociliary clearance score After 28 days of treatment, the mean change in nasal clearance time (NCT) from baseline was found to be -2.506 (95% CI: -3.31 to -1.70) and -2.12 (95% CI: -2.920 to -1.32) in Montelukast and Seratrodast treated group, respectively. Both the groups showed similar improvement in the NCT and sputum characteristics at 28th day of the study and there was no statistical difference observed between these treatment groups (P>0.05). Interestingly, in sputum laboratory tests, there was a significant difference observed between the groups with respect to the change from the baseline values of ECP and albumin, favoring Seratrodast (P<0.05;Table 9).

Table 9: Summary of sputum analysis

Parameters Montelukast 10mg (n=102) Seratrodast 80mg (n=103) Difference in Mean Changes (95% CI) P value for difference in Mean Changes

Mean Change from Mean Change from baseline (day 0-28, 95% CI) baseline (day 0-28, 95% CI)

Fucose (mg/ml) ECP (ng/ml) Albumin (mg/dl)

-0.025 (-0.03 to -0.01) -23.55 (-24.64 to -22.47) -32.82 (-34.09 to -31.55)

-0.022 (-0.026 to -0.019) -27.20 (-28.38 to -26.01) -37.51 (-39.20 to -35.81)

-0.003 (-0.0046 to -0.0091) 3.64 (5.24 to 2.04) 4.68 (6.79 to 2.57)

NS S S

NS- P>0.05; S-P<0.05; NCT- nasal clearance time; NSC- nasocilliary clearance score; ECP- eosinophil cationic protein

Efficacy Parameters

Figure 17: Superior efficacy of Seratrodast compared to Montelukast in reducing Expectoration score, Sputum ECP and Albumin after 28 days of treatment

Conclusion Seratrodast, a TXA2 receptor antagonist, was found to be better in the improvement of PEF, expectoration score, ECP and albumin level as compared to Montelukast justifying preference of Seratrodast as a controller medication in mild to moderate asthma patients.[49]

Seratrodast was found to be better in the improvement of PEF, expectoration score, ECP and albumin level as compared to Montelukast in Indian patients.

Preclinical Study
Acute toxicity Study Forty eight male and 48 female Wistar rats and Swiss albino mice aged 8 9 weeks were administered with single oral dose of Seratrodast at dosage levels of 6.75, 14.50 and 45.50mg/kg. The number of deaths (mortality) was recorded during 7 days of observation period. General behavior and local reactions (if any) were noted throughout the treatment period. On all days the body weight, food intake and water intake of the animals were noted. We observed that, Seratrodast did not produce any mortality in rats or mice at the given dosage levels. No significant changes were noted in the food intake or water consumption in any of the groups. Necropsy examination after 7 days showed that, treatment with Seratrodast induced non significant changes in the organ-body weight ratio of animals except in liver, spleen and intestines. These changes were largely confined to high dose group ( 45.5 mg/kg).Liver seems to be the target organ that is most affected after Seratrodast administration at higher doses. Subacute Toxicity Study Forty eight male and 48 female Wistar rats and Swiss albino mice aged 8 9 weeks were administered with single oral dose of Seratrodast at dosage levels of 3.25, 8 and 17 mg/kg. The number of deaths (mortality) was recorded during 7 days of observation period. General behavior and local reactions (if any) were noted throughout the treatment period. On all days the body weight, food intake and water intake of the animals were noted. We observed that, Seratrodast did not produce any mortality in rats or mice at the given dosage levels. No significant changes were noted in the food intake or water consumption in any of the groups. Necropsy examination showed that, treatment with Seratrodast induced non significant changes in the organ-body weight ratio of animals except in liver, kidney and stomach. These changes were largely confined to high dose group.( 17 mg/kg)treated at17mg/kg. Kidney seems to be the target organ that is most affected after Seratrodast administration at higher doses.

CLINICAL REFERENCES
Test drug N
Conclusion

SN

Author year Patients

Study Design

Duration of the study

1. 8 weeks Asthma

LI Xin, ZHAO Jian-ping etal. 2006 Double-blind, randomized 213

Seratrodast 80mg Vs Montelukast 10mg

Seratrodast is a new, safe, and effective drug in treating patients with asthma and possesses reliable efficacy and less adverse reaction as compared to montelukast.[29]

2. 6 weeks Asthma

YIN Kai-sheng etal. 2004 220

Seratrodast 40mg Vs zafirlukast 20mg Double-blind, randomized, Multi centric

I. The control rate of seratrodast (71.68%) was significantly higher than that of zafirlukast (62.62%, P 0.05). II. Seratrodast, a thromboxane A2 receptor antagonist, appeared to be effective and safe in the treatment of asthma.[30] The cough threshold was significantly increased compared with placebo after four-week treatment with seratrodast, but not after treatment with pranlukast. Thromboxane antagonism may be considered to be one of the therapeutic options for the treatment of chronic productive cough.[27]

3. 4 weeks 16

Seratrodast 80mg Ishiura Y, OD Vs Placebo Fujimura M, vs Pranlukast Yamamori C, et al. 112.5mg tid 2003 Randomized cross- over trial Chronic Bronchitis

4.

Fukuoka T, etal. 2003 Seratrodast Seratrodast 80mg OD 12 weeks

open-label, crossover design study

10

Asthma

I. Seratrodast decreased the concentration of ECP in sputum significantly (p < 0.05), and sputum ECP significantly increased again after withdrawal of (p < 0.05). II. Seratrodast improves clinical symptoms and airway hyperresponsiveness by reducing airway inflammation. III. Seratrodast may be useful as an anti-inflammatory agent and beneficial when added to inhaled corticosteroids in the treatment of bronchial asthma.[15] I. The results revealed significant improvement of respiratory distress, evaluated on both the HughJones classification and the Borg scale, at week 8.

5.

Horiguchi T.etal. 2002 Seratrodast Seratrodast 80mg OD

Open label study

8 weeks

14

Chronic Pulmonary Emphysema

II. Among the respiratory function parameters examined, only FVC was significantly improved. III. These results indicated that seratrodast is useful for the improvement of respiratory distress in patients with chronic pulmonary emphysema in the stable phase.[31]

CLINICAL REFERNCES
Test drug N
Conclusion

SN

Author year Patients

Study Design

Duration of the study

6. Asthma

Baba K.etal. 2002 35

Seratrodast 80mg OD

The exacerbation rate in group C after 12 months tended to be lower than in the other two patient groups (P = 0.0743). In group C (seratrodast), the average dose of iBDP from 9 to 24 months after the initial step down was significantly lower than before the step down (P < 0.0001) and was not significantly different from the mean dose of iBDP in groups A or B.[32] I. For sputum analysis, seratrodast treatment decreased the amount of sputum (p = 0.005), dynamic viscosity (p = 0. 007), and albumin concentration (p = 0.028).

7. 6 weeks

Tamaoki J.etal.2000 45

Seratrodast 40mg OD Or placebo Mild to moderate Asthma

Double blind, randomized, Multi center, Placebocontrolled parallel group trial

II. Nasal clearance time of a saccharin particle was shortened in the seratrodast group at week 4 (p = 0.031) and week 6 (p = 0.025), compared with the placebo group. III. Blockade of TxA(2) receptor causes an improvement in mucociliary clearance by decreasing the viscosity of airway secretions.[26]

I. Improvement of nasal obstruction was considered as the characteristic effect of Seratrodast.

8.

Yasuo. S.Etal 1999

Seratrodast 80mg/d Vs Terfenadine 120mg/d Double-blind Multi-center Comparative Study

23 4

Perennial Allergic Rhinitis

II. The improvement rate of nasal obstruction at the final evaluation in the seratrodast group was significantly superior to Terfenadine group, 51.4% vs. 34.7% (p=0.016). III. Improvement rates of nasal discharge and sneezing were also higher in seratrodast group than in Terfenadine group.[33]

9.

Tanaka. H. etal. 1999

Seratrodast 40mg OD

Open label study

4 weeks (11 patients continued the drug for 6 months)

45

Asthma

Responders and non-responders to TXA2 receptor antagonist existed in patients with asthma, and it suggests that the ratio of urinary eicosanoids might be a possible predictor of the effects of TXA2 receptor antagonist.[34]

CLINICAL REFERNCES
Test drug N Conclusion Patients Study Design Duration of the study Seratrodast 80mg OD Or placebo 4 months 31 Asthma Double blind, randomized, Placebomatched parallel group trial
Seratrodast treatment of patients with asthma may inhibit activated eosinophil infiltration in part by modulating the expression of chemokines in bronchial tissues.[35]

SN

Author year

10.

Hoshino M.etal. 1999

11. 4 weeks 14 Asthma

Aizawa. H. etal 1998

Seratrodast 80mg OD Open label study

Blockade of TxA2 receptor causes an improvement in mucociliary clearance by decreasing the viscosity of airway secretions.[25]

12. 8 weeks

Samara E etal. 1998

Seratrodast, 80mg/d or 120mg/day 183 Mild to Moderate Asthma

Double blind, randomized, Multi center, Placebocontrolled parallel group trial

I. The pharmacokinetics of seratrodastwere linear after single and multiple dosing for 8 weeks. II. Seratrodast at a dose of 120 mg daily produced an increase in forced expiratory volume in 1 second (FEV1) from baseline that was linearly correlated with its plasma concentrations III. A lower percentage of predicted FEV1 (i.e., more severe obstruction) was associated with higher slopes, and greater increases in FEV1.[18]

13. Randomized

Takeru I et al. 1999

Seratrodast, 20/40/80mg/d

4 weeks

155

Perennial Allergic Rhinitis

I. Improvement rates for nasal obstruction, nasal discharge and sneezing showing "marked improvement" or better in the 20mg, 40mg, and 80mg daily doses. II. All the three symptoms showed higher improvement rates dose-dependently. III. Compared with published data for terfenadine and epinastine, recently developed anti-allergic agents, improvement rates in nasal discharge and sneezing of the 20mg group were lower, but the 40mg and 80mg groups showed equal or higher improvement rates in all three symptoms. Notably, improvement in nasal obstruction in the 40mg and 80mg groups was higher than that of terfenadine & epinastine.[36]

SN

Author year N Patients

Test drug

Study Design

Duration of the study Conclusion

14. 2 weeks 142

TOKUJI U et al. 1999

Seratrodast and Mequitazine Or Both Perennial Allergic Rhinitis

1] Improvement rate in nasal symptoms: "moderately improved" or better were 64.3% in the concomitant use group, 57.5% in the Seratrodast group & 32.6% in the mequitazine group, showing no difference between the concomitant use group and the Seratrodast group; however, improvement in the concomitant use group was higher than that of the mequitazine group. 2] Improvement rate classified by symptoms nasal obstruction, nasal discharge and sneezing were higher in Seratrodast & concomitant use group than that of the mequitazine group.[37]

15. Seratrodast 1

Fujimori Katsuya et al. 1999 Case Report

Chronic Cough

Coughing was reduced in this case by a thromboxane A2 receptor antagonist, Seratrodast is clinically important.[38]

SAKAKURA YASUO 16. et al. 1999

Seratrodast 4mg/day, 40mg/day or 80mg/day Multi-center, Double-blind Comparative Study

4 weeks

224

Perennial Allergic Rhinitis

1) In final improvement rate evaluation of nasal symptoms, primary end point, moderate improvement or better was 36.8% (28/76) in the 4mg/day group, 38.4% (28/73) in the 40mg/day group, and 45.3% (34/75) in the 80mg/day group, demonstrating increasing improvement rate dose-dependently. 2) In the subject group whose main complaint was nasal obstruction & duration of disease was one year or longer, improvement rate in nasal symptoms (final evaluation) was similarly dose-proportional, demonstrating efficacy in treating nasal obstruction. 3) Safety evaluation: No serious events were observed in any of the groups. 4) Based on the above results, it is suggested that 80mg of Seratrodast may be the daily dose for treating perennial allergic rhinitis.[39]

SN Conclusion

Author year N Patients

Test drug

Study Design

Duration of the study

17. 4 weeks

UNNO TOKUJI et al. 1999 53

Seratrodast 80mg & 120mg daily Open Label Study Perennial Allergic Rhinitis

I. In a dose finding study using 4, 40 and 80mg/day, which was conducted in parallel with this study, 80mg/day was suggested to be optimal for clinical use. II. Considering the results of the two studies together, it was concluded that 80mg/day is the most appropriate clinical dosage of the agent for the [40] treatment of perennial allergic rhinitis.

18. 12- 24 weeks

YAJIN KOJI. 1999 19

Seratrodast 80mg/day

Open Label Study

Perennial Allergic Rhinitis

The results suggest that Seratrodast appears to be highly effective in treating perennial allergic rhinitis [41] and safe in a long-term period.

19. 4 weeks

SAKAKURA YASUO et al. 1999. 38

Seratrodast 20 or 80mg/day

Perennial Allergic Rhinitis

1) In the 80mg/day group, changing rates of nasal volume and minimum cross section showed significant improvement after 4 weeks. 2) Improvement rate in nasal obstruction in the 80mg/day group was higher than that in the 20mg/day group. 3) Correlation with nasal obstruction was relatively higher among nasal obstruction, nasal discharge, and paroxysmal sneezing. 4) No clinically significant side effects were found in any subjects in the 20 or 80mg/day group.[42]

20.

MASUDA YU et al. 1999.

Seratrodast 80mg/day

12 weeks

14

Perennial Allergic Rhinitis

These results suggest that Seratrodast is markedly effective in treating the patients with perennial allergic rhinitis, and has no safety problems in a [43] long-term administration.

Takahashi T, 21. Takishima T, Shida T etal. 1993 Seratrodast 80mg/day

24- 48 weeks

103

Bronchial Asthma

The rate of moderate or severe asthma improvement was 48.5 % (47/97). Out of the 25 patients evaluated for dose reduction of glucocorticoids, dose reduction was possible in [44] 22 (88%) patients.

SALIENT FEATURES SALIENT FEATURES

Seratrodast is a potent, long-acting, stereospecific, thromboxane A2/ prostaglandin endoperoxide receptor antagonist. In addition, Seratrodast has PGF2, PGD2 and 9a, 11-PGF2 antagonistic effects. Seratrodast is rapidly and dose - dependently absorbed. The peak plasma concentrations decline bi-exponentially with an average half-life of 20 hours after single administration. Seratrodast inhibits activated eosinophil infiltration by modulating the expression of chemokines in bronchial tissues. It contributes to the suppression of sECP (serum eosinophilic cationic protein) levels, resulting in successful step down of inhaled steroids therapy in patient. It is the first thromboxane receptor antagonist that was developed as an anti-asthmatic drug and received marketing approval in Japan in 1997. It has been studied in approximately 5000 patients across the world and used by millions. Improves PEF by more than 36 L/min. Seratrodast showed 3 times higher increase in PEF than Montelukast. Seratrodast significantly reduces Airway Hyperresponsiveness in asthma patients It shows marked improvement in clinical symptoms, muco-ciliary clearance and lung function parameters in clinical trials. Seratrodast is better in efficacy than Montelukast, Pranlukast and Zafirlukast in asthma. Seratrodast is better in efficacy than terfenadine and mequitazine in Seasonal and Perennial Allergic Rhinitis. Seratrodast is well tolerated and has been given safely for 24 months in bronchial asthma patients.

REFERENCES REFERENCES
1. Anon. Chronic respiratory diseases. In J. Bousquet & N. Khaltaev (Eds.). Global surveillance, prevention and control of chronic respiratory diseases: A comprehensive approach. WHO library Publication. 2007. 2. Pocket Guide for Asthma Management and Prevention. Available at http://www.ginasthma.org/uploads/users/files/GINA_PocketGuide_2011.pdf. 3. Ishimura M etal. Effects of KP-496, a novel dual antagonist at thecysteinyl leukotriene receptor 1 and thethromboxane A(2) receptor, on airway obstructionin guinea pigs. Br J Pharmacol. 2008 Feb;153(4):669-75. Epub 2007 Nov 26. 4. Hansel TT, Barnes PJ (eds): New Drugs for Asthma, Allergy and COPD.Prog Respir Res. Basel, Karger 2001, vol. 31, pp 6. 5. Dogn J M etal. Thromboxane A2 inhibition: therapeutic potential in bronchial asthma. Am J Respir Med. 2002;1(1):11-7. 6. Devillier P, Bessard G. Thromboxane A2 and related prostaglandins in airways.Fundam Clin Pharmacol 1997; 11 (1): 2-18 7. Mizushima Y, Oosaki R. Clinical Potential of Anti-Thromboxane A2 Agents in Bronchial Asthma. BioDrugs. 1997 Feb;7(2):91-8. 8. Rolin S etal. Prostanoids as pharmacological targets in COPDand asthma.Eur J Pharmacol. 2006 Mar 8;533(1-3):89-100. Epub 2006 Feb 3. 9. Cathcart MC, Reynolds JV, O'Byrne KJ, Pidgeon GP. The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer. Biochim Biophys Acta. 2010 Apr;1805(2):153-66. 10. Hamberg M, Svensson J, Samuelsson B. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 1975; 72 (8): 2994-8. 11. Ellis EF, Oelz O, Roberts LJ, et al. Coronary arterial smooth muscle contractionby a substance released from platelets: evidence that it is thromboxane A2.Science 1976; 193 (4258): 1135-7. 12. Pawlowski NA, Kaplan G, Hamill AL, et al. Arachidonic acid metabolism by human monocytes. Studies with platelet-depleted cultures. J Exp Med 1983;158 (2): 393-412. 13. Taylor IK etal. Thromboxane A2 biosynthesis in acute asthma and after antigen challenge. Am Rev Respir Dis. 1991 Jan;143(1):119-25. 14. O'Byrne PM, Fuller RW. The role of thromboxane A2 in the pathogenesis of airwayhyperresponsiveness. Eur Respir J 1989; 2 (8): 782-6 15. Fukuoka T et al. The effect of Seratrodast on eosinophil cationic protein and symptoms in asthmatics. Journal of asthma. 2003; 40(3):257-264. 16. Minoguchi K, Adachi M.Thromboxane A2 synthase inhibitor and receptor antagonist. Nihon Rinsho. 2001 Oct;59(10):1986-91. 17. Kurashima K, Ogawa H, Ohka T, Fujimura M, Matsuda T.Thromboxane A2 synthetase inhibitor (OKY-046) improves abnormal mucociliary transport in asthmatic patients. Ann Allergy. 1992 Jan;68(1):53-6. 18. Samara E, Cao G, Locke C, et al: Population analysis of the pharmacokinetics and pharmacodynamics of seratrodast in patients with mild to moderate asthma. Clin Pharmacol Ther 1997a; 62:426-435. 19. Hussein Z, Samara E, Locke CS, et al: Characterization of the pharmacokinetics and pharmacodynamics of a new oral thromboxane A2-receptor antagonist AA-2414 in normal subjects: population analysis. Clin Pharmacol Ther 1994; 55(4):441-450. 20. Samara EE. Seratrodast (AA-2414)-A Novel Thromboxane-A2 Receptor Antagonist. Cardiovascular Drug Reviews. 1996;14(3):272-285. 21. Kumar GN, Dubberke E, Rodrigues AD, et al: Identification of cytochromes P450 involved in the human liver microsomal metabolism of the thromboxane A2 inhibitor seratrodast (ABT-001). Drug Metab Dispos 1997; 25(1):110-115. 22. Ashida Y, Matsumoto T. Effect of AA-2414. a new thromboxane A, receptor antagonist on experimental allergic asthma. Jpn Pharmacol Ther (suppl. 7) 1993;21:245-254. 23. Matsumoto T, Asbida Y, Tsukuda R. Pharmacological modulation of immediate and late airway response and leukocyte infiltration in guinea pigs. J Pharmacol Exp Ther 1994;269:123&1244. 24. Terao S, Shiraishi M, Matsumoto T, Ashida Y.Thromboxane A2 antagonist--discovery ofseratrodast. Yakugaku Zasshi. 1999 May;119(5):377-90. 25. Aizawa H, Inoue H et al. Effects of thromboxane A2 antagonist on airway hyperresponsiveness, exhaled nitric oxide, and induced sputum eosinophils in asthmatics. Prostaglandins Leukot Essent Fatty Acids. 1998 Sep; 59(3):185-90. 26. Tamaoki.J. et al. Effect of a thromboxane A2 antagonist on sputum production and its physicochemical properties in patients with mild to moderate asthma. Chest 2000; 118:73-79. 27. Ishiura Y et al. Thromboxane antagonism and cough in chronic bronchitis. Ann Med. 2003; 35(2):135-9. 28. BRONICA@ Tablets 40, 80 ? Granules 10?. Takeda Pharmaceutical Company Limited. Revised September 2009 (Tenth Edition) 29. Li X, Zhao J et al. Seratrodast in treatment of 107 patients with asthma. Chin J New Drugs Clin Rem 2006; 25(10): 729-733. 30. Kai-sheng Y, Ying-yun C et al (A Double-Blind Randomized Clinical Study in Multiple-Centre Comparing The Effect Of Seratrodast On Asthma With Zafirlukast. J Jiangsu Clin Med. 2004; Vol. 02. [Cited Dec 2010]. 31. Horiguchi T et al. Study on the usefulness of Seratrodast in the treatment of chronic pulmonary emphysema. Arzneimittelforschung. 2002; 52(10):764-8. 32. Baba K et al. 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. 33. Sakakura Y, Unno T et al. Clinical Evaluation of Seratrodast, a Thromboxane A2 Antagonist, in Patients with Perennial Allergic Rhinitis. Multi-center Comparative Double blind Test with Terfenadine. J Clin Ther Med. 1991; 15(2):267-307 34. Tanaka H. et al. Can urinary eicosanoids be a potential predictive marker of clinical response to thromboxane A2 receptor antagonist in asthmatic patients? Respir Med. 1999 Dec;93(12):891-7. 35. Hoshino M et al. Effect of AA-2414, a thromboxane A2 receptor antagonist, on airway inflammation in subjects with asthma. J Allergy Clin Immunol. 1999; 03:1054-61. 36. Takeru I et al. A Study on Efficacy and Safety of 20mg/day, 40mg/day, 80mg/day of Seratrodast, a Thromboxane A2 Receptor Antagonist on Perennial Allergic Rhinitis Patients. An Early Phase II Study. J Clin Ther Med. 1991; 15(2):147-182 37. Tokuji U et al. Effect of Combination Therapy with Seratrodast and Mequitazine on Perennial Allergic Rhinitis. J Clin Ther Med. 1991; 15(2):309-337.. 38. Katsuya. F. et al. Chronic Cough Successfully Treated with Seratrodast, A Thromboxane A2 Receptor Antagonist. Differential Diagnosis of a Cough. J Clin Ther Med. 1991; 15(2):58-61. 39. Yasuo S et al. Dose Finding Study of Seratrodast, a Thromboxane A2 Antagonist, in Patients with Perennial Allergic Rhinitis. A Multi-center, Double-blind Comparative Study. J Clin Ther Med. 1991; 15(2):213-245. 40. Tokuji U et al. Study on Administration of 80mg/day and 120mg/day of Seratrodast in Perennial Allergic Rhinitis Patients. J Clin Ther Med. 1991; 15(2):213-245. 41. Koji Y et al. Clinical Evaluation on 12-week Administration of Seratrodast, a Thromboxane A2 Antagonist, in Perennial Allergic Rhinitis. J Clin Ther Med. 1991; 15(2):373-388. 42. Yasuo S et al. Evaluation of Effect of Seratrodast on Nasal Passage Patency in Perennial Allergic Rhinitis by Acoustic Rhinometry.. J Clin Ther Med. 1991; 15(2):183-211. 43. Yu .M.et al. Efficacy and Safety on 12-week Administration of Seratrodast, a Thromboxane A2 Antagonist, in Patients with Perennial Allergic Rhinitis. J Clin Ther Med. 1991; 15(2):355-371. 44. Takahashi T, Takishima T, Shida T etal .Clinical evaluation on Long term Treatment of AA-2414, a Thromboxane A2 Receptor Antagonist in adult Patients with Bronchial Asthma. Rinsho Iyaku 1993.9suppl.8:213-55 45. Aizawa H, Hirose T.A possible mechanism of airway hyperresponsiveness induced by prostaglandin F2 alpha and thromboxane A2. Prostaglandins Leukot Essent Fatty Acids. 1988 Sep;33(3):185-9. 46. Tilley SL et al.Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanesJ Clin Invest. 2001 Jul;108(1):15-23. 47. Ohta Ketal.Japanese guideline for adult asthma. Allergol Int. 2011 Mar;60(2):115-45. doi: 10.2332/allergolint.11-RAI-0327. 48. An open-labeled, randomized, cross-over bioequivalence study of Seratrodast 80mg under fasting condition. Data on file 49. A Multi-centric, Double blind, Randomized, Comparative Clinical trial to Evaluate the Efficacy and Safety of Seratrodast 80 mg as compared to Montelukast 10 mg in the treatment of Asthma. Data on file. 50. Greenfield J R, Samaras K. Suppression of HPA axis in adults taking inhaled corticosteroids. Thorax. 2006 March; 61(3): 272273.

Seratrodast 80mg Tablets

COMPOSITION Each uncoated tablet contains: Seratrodast..80 mg DESCRIPTION Seratrodast is an orally active quinone derivative and a potent TXA2 receptor antagonist used in the prophylactic management of asthma and treatment of allergic rhinitis.

CONTRAINDICATIONS Hypersensitivity to Seretra or any of the ingredients. Patients with hepatic failure. USE IN SPECIAL POPULATIONS Pregnancy and Lactation There are no adequate and well controlled studies in pregnant women. Seretra should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Seretra should be avoided during lactation. Pediatric Use (< 18 years of age) The safety and efficacy of Seretra has not been established in children and should not be used in this age group.
CO2H

O H 3C

H 3C O

Ch3

Chemical name: () 7-phenyl-7-(2,4,5-trimethyl-3,6-dioxocyclohexa1,4-dien-1-yl)heptanoic acid Molecular formula: C22 H26 O4 Molecular weight : 354.44 CLINICAL PHARMACOLOGY Pharmacodynamics Seratrodast is a potent, long-acting, stereospecific thromboxane A2/prostaglandin endoperoxide receptor antagonist. The R-(+)enantiomer of Seratrodast is the pharmacologically active moiety. Seratrodast appears to exert its anti-asthmatic effects through antagonism of the thromboxane A2 receptor. In addition, seratrodast blocks the bronchoconstrictor effects of PGF2, PGD2 and 9,1lPGF2 mediated through activation of thromboxane A2 receptor (TP receptor). Pharmacokinetics Following single and repeated oral administration, seratrodast is rapidly and dose- dependently absorbed. The peak plasma concentrations of seratrodast increase proportionally with dose reaching steady-state concentration within 7 days of administration. Following once daily doses of 80mg for 15 days in patients with mild to moderate asthma, the peak plasma concentration of Seratrodast is 8.80 g/ml with an average Tmax of 2.4 hours. The area under the plasma concentration-time curve (AUC) for Seratrodast is 22.96 g.hr/ml, the average apparent volume of distribution is 33 liters and it has high protein binding capacity (more than 99%). Seratrodast is metabolized to 5-methylhydroxyseratrodast and 4hydroxyseratrodast by cytochrome P450 (CYP) isoenzymes. It is also partially (35%) glucuronidated in plasma and may be subject to enterohepatic recycling. Following oral administration of 40 to 120 mg/day in healthy subjects, renal clearance ranged from 5.10 to 8.94 ml/hr (average 7.0 ml/hr) after a single dose and at steady-state respectively. The percentage of the dose excreted as unchanged drug in the urine ranged from 0.42% to 1.37% (average 0.83%) after a single dose and at steady-state. The plasma concentrations decline bi-exponentially with an average half-life of 20 and 36 hours after single and multiple administrations, respectively. INDICATIONS Seretra is indicated in Prophylactic management of mild to moderate asthma. Treatment of allergic rhinitis. DOSAGE AND ADMINISTRATION In the prophylactic management of bronchial asthma, a dose of 80 mg once daily is recommended. Seretra has been shown to be welltolerated following repeated once daily oral doses of up to a maximum of 320 mg. In elderly patients, the treatment should be started with a lower dose of 40mg/day.

WARNINGS AND PRECAUTIONS Acute Asthma: Seretra is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients should be advised to have appropriate rescue medication available. Therapy with Seretra can be continued during acute exacerbations of asthma. Seratrodast may lead to an elevation in the levels of the hepatic enzymes. Therefore, it has to be administered with caution in patients with hepatic impairment. Seratrodast should be discontinued if a hypersensitivity reaction occurs. DRUG INTERACTIONS Use cautiously with other anti-inflammatory analgesics, antipyretic (phenacetin), cephalosporin antibiotics and drugs that has been reported to cause hemolytic anemia. As aspirin can compete for serum protein binding, it may increase the concentration of unbound drug (seratrodast) by 26%. ADVERSE REACTIONS Adverse reactions are generally rare, but if present, range from mild to moderate in severity.
Adverse reactions with Incidence of 0.1 to 5% Hypersensitivity Hepatic Rash, Itching. Elevated AST (GOT), ALT (GPT), AL-P, LDH, of -GTP Nausea, loss of appetite, stomach discomfort, abdominal pain, diarrhea, constipation, dry mouth, taste disturbance Anemia, eosinophilia Vomiting Adverse reactions with Incidence < 0.1% (rare)

Gastrointestinal

Hematologic

Thrombocytopenia, epistaxis, subcutaneous bleeding Insomnia, tremor, numbness Hot flashes, edema

Neuropsychiatric

Drowsiness, headache, dizziness Palpitations, malaise

Other

OVERDOSAGE There have been no reports of overdosage with Seretra. In cases of overdosage, the stomach should be emptied by aspiration and lavage. Vital parameters should be managed symptomatically. STORAGE Store in a cool, dry and dark place.

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