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Doxofylline SR+ Montelukast

(Fixed Dose Combination)

Asthma - Definition
Asthma is a Chronic inflammatory
disease characterized by Airway hyperesponsiveness to a variety of stimuli resulting in Bronchospasm which reverses

spontaneously - on treatment

Prevalence of Asthma  Asthma affects 300 million adults and children worldwide Estimated prevalence of asthma is increasing 50% per decade WHO: 15-20 million asthmatics in India Children: 12% and Adults 5%’    .

Basic Cellular Mechanisms FIRST EXPOSURE  Sensitization process SECOND EXPOSURE  Early allergic reaction  Late allergic reaction .

1st exposure Allergic Response Allergen SENSITIZA TION PHA SE Body produces IgE antibodies Enters the body An tibodies + Allergens Y Y Y Y Y Sensitization Mast cell Y Y Y Y Excess antibodies Bind to mast cells Y Produce Inflammatory mediators (histamine) (not released) Y Y .

Allergic Response 2 n d e x p o s u r e IgE antibody Allergen Chemotactic Factors Histamine 5-30 minutes after exposure EARLY ALLERGIC RESPONSE (EAR) .

SW ELLING } between 3-11 hours after exposure .Allergic Response 2 n d e x p o s u r e C h e m o t a c t i c F a c t o r s Migration & Activation Basophils EOSINOPHILS Neutrophils Secondary Mediators ECP . MBP D a m a g e t o E p i t h e l i a l c e l l s ( t h i s e x p o s e s t h e p a r a s y m p a t h e t i c n e r v e s ) INFLAMMATION Bronchoconstriction Mucus production Ciliary activity V asodilation LATE ALLERGIC RESPONSE (LAR) REDNESS.

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Drugs Relievers  Controllers  For treatment of For long term control bronchospasm and to relieve acute attacks of inflammation and to prevent further attacks .

What Are Relievers? - Rescue medications Quick relief of symptoms(within 2 min) Used during acute attacks Action lasts 4-6 hrs .

Relievers  Short acting beta 2 agonists  Inhaled salbutamol  Inhaled levosalbutamol .

What are Controllers? - Prevent future attacks Long term control of asthma Prevent airway remodeling .

SR Oral prednisolone β2-agonists (LABA) .Controllers Inhaled  Oral  Corticosteroids(ICS) Leukotriene antagonists   Cromolyn sodium Long acting inhaled   Theophylline .

reduce therapy Monitor  -Theophylline-SR .Stepwise Approach to Asthma Therapy .Adults Outcome: Asthma Control Outcome: Best Possible Results Controller:  Controller: Controller: Controller: None Daily inhaled corticosteroid     Daily inhaled corticosteroid Daily long-acting inhaled β2-agonist  Daily inhaled corticosteroid Daily long –acting inhaled β2-agonist plus (if needed)  When asthma is controlled.agonist -Oral corticosteroid Reliever: STEP 1: Intermittent Rapid-acting inhaled β2-agonist prn STEP 2: Mild Persistent STEP 3: Moderate Persistent STEP 4: Severe Persistent STEP Down Alternative controller and reliever medications may be considered .Doxofylline -Anti-Leukotriene -Long-acting inhaled β2.

Doxofylline SR+ Montelukast Compound: Doxofylline SR+ Montelukast Indication: Bronchial Asthma Formulation: Oral tablet preparation Dose: Doxofylline SR 400 mg+ Montelukast 10 mg MOA: Bronchodilator and leukotriene receptor antagonist .

Doxofylline. which needs to be given once daily .Doxofylline SR Doxofylline SR is a sustained release formulation of the newer methylxanthine.

leading to increase in the amount of cAMP in the cells.Mechanism of action Inhibition of phosphodiesterase activity. Adenly cylase ATP Phosphodiesterase cAMP AMP Protein Kinase Decrease intracellular calcium Bronchodilation .

Montelukast  Montelukast is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene (CysLT1) receptor .

Physiology of Inflammation Arachidonic Acid Metabolism Chemical & Mechanical stimuli activates Phospholipase A Harmful Stimulus Cell Perturbation (agitation or disturbance) Liberates Membrane Phospholipids Release ARACHIDONIC ACID (AA) Lipoxygenase Cyclo-oxygenase Endoperoxides PGG2 LEUKOTRIENES PROSTAGLANDINS PGE2 PGD2 PGF2a PROSTACYCLINS PGI2 THROMBOXANE TXA2 PGH2 Hydroperoxides STOMACH. KIDNEYS BLOOD VESSEL WALL PLATELETS .

smooth muscle cell.) . etc. a substance correlated with the pathophysiology of allergic conditions which are associated with the inflammatory process Airway cell (eosinophil.LTD4 LTD4 Montelukast Leukotriene Receptor (CysLT1) LTD4 Montelukast is a selective leukotriene receptor antagonist that blocks LTD4.

.Inflammatory Effects of Leukotrienes in the Airways Increased mucus secretion Decreased mucus transport Cationic proteins (Epithelial cell damage) Airway Epithelium Increased release of tachykinins Eosinophil recruitment Blood vessel CysLTs Sensory C fibres Smooth muscle Oedema Inflammatory Cells (e.111:35S–45S. . Eosinophils) Contraction and proliferation Adapted from Hay DW.g. Mast Cells. Chest 1997.

2% Half life: 2.Pharmacokinetic Properties Doxofylline Oral bioavailability: 62.6% Protein binding: 48% Tmax: 1.5 hrs .19 hrs 90% of drug metabolized in the liver Renal excretion: 4% Half life: 7-10 hrs Montelukast Oral bioavailability: 64% Tmax: 3-4 hrs Metabolized by the liver Renal excretion: < 0.7-5.

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5 2 2. 16(4): 258-268 .Low affinity of Doxofylline for Adenosine receptors In vitro information studies have showed a much lower affinity of doxofylline for Adenosine receptors Enprofylline Bamifylline Theophylline Theophylline Aminophylline Doxofylline 0 0.5 1 1.5 Affinities for adenosine A1 receptors Affinities of various methylxanthines for Adenosine A1 receptors Curr Med Res Opin 2001.

5 2 2.Enprofylline Bamifylline Theophylline Decreased affinities towards adenosine A1 and A2 receptors reduces the unwanted extrapulmonary side effects Aminophylline (accounts for its better safety profile) The A1 and A2 antagonism is 10-20 times lower for doxofylline than theophylline 0 0. 16(4): 258-268 .5 Affinities for adenosine A2 receptors Doxofylline Affinities of various methylxanthines for Adenosine A2 receptors Curr Med Res Opin 2001.5 1 1.

Doxofylline 200 mg.Efficacy of Doxofylline      Study done on 346 patients with bronchial asthma for a duration of 12 weeks Drugs: Doxofylline 400 mg. 8(4): CR 297-304 . There was a significant improvement in FEV1 with doxofylline and theophylline vs placebo There was a remarkable reduction in the asthma attack rate and albuterol use with doxofylline and theophylline Significantly more patients interrupted treatment because of adverse events with theophylline as compared to doxofylline Med Sci Monit. 2002. Theophylline 250 mg and Placebo.

oedema. In the control group (placebo). Results: 57% of patients showed absence of lesions in the doxofylline group.Anti-inflammatory effects of Doxofylline Bronchial biopsies were performed in 14 patients with chronic obstructive bronchitis to assess the presence or absence of neutrophilic infiltration. Eur Rev Med Pharmacol Sci 2000. 4: 15-20 . absence of lesions was observed in 14% of patients. fibrosis and epithelial metaplasia before and after treatment for 3 months with Doxofylline 400 mg bid.

Safety of Doxofylline In a series of 10 patients with COPD. Curr Med Res Opin 2001. no significant changes were noted in heart rate. 98-103 . Mean heart rate rose significantly during treatment with Aminophylline 240 mg IV. compared with baseline values. Monaldi Arch Chest Dis 1995. 16(4): 258-268 Volume of gastric acid output and pepsin output was significantly less with doxofylline IV as compared to aminophylline IV Aliment Pharmacol Therap 1990. Doxofylline had no impact on the sleep arousals or the efficiency. 4: 643-649 The number of arousals per hour during sleep was significantly increased in the theophylline group along with a reduction in the sleep efficiency. 50:2. during or after infusion of Doxofylline 400 mg IV or placebo as assessed by 24 hr Holter monitoring.

56(2): 251-256 .Montelukast in asthma There was a significant improvement in FEV1 and a significant reduction in beta agonist use (puffs/day) during 3 months randomized double blind treatment with montelukast 10 mg/day or placebo in 681 patients with asthma Drugs 1998.

clinically significant tapering of inhaled corticosteroid therapy was possible during treatment with montelukast 10 mg/day as compared to placebo.Reduction of ICS use with Montelukast In a 6 weeks study on 226 patients with stable asthma. Drugs 1998. 56(2): 251-256 .

Ann Allergy Asthma Immunol 2003. double-blind. rhinorrhea. nasal congestion on awakening) Result: Therapy with montelukast significantly improved the overall nasal symptom scores as compared with placebo.90:214-222 . randomized. nighttime awakenings. placebo controlled study in which patients with SAR were randomly assigned to treatment with montelukast 10 mg (n=522) or placebo (n=171) once daily at bedtime for 2 weeks. Outcomes: Daytime nasal symptom score (mean score of congestion. pruritus and sneezing) Nighttime symptoms (mean score of difficulty in going to sleep.Clinical benefits of Montelukast in SAR A Multicenter.

56(2): 251-256 . influenza and abdominal pain All adverse events were considered mild and self limiting and none required active treatment. The most common adverse events were headache. Drugs 1998.Tolerability of Montelukast    Tolerability data are available from 1955 adult patients who participated in placebo controlled clinical trials evaluating montelukast at a dose of 10 mg/kg. cough.

Rationale for combination     Doxofylline is an oral bronchodilator while montelukast is an oral anti-antileukotriene agent Both have separate mode of action and when combined will lead to an additive effect Asthmatic patients have bronchospasm and airway inflammation and this combination will be effective against both the aspects of asthma pathology The combination can be given once daily and hence there is compatibility in dosing .

Indications  Prophylaxis and chronic treatment of asthma in adults 14 yrs of age and older .

Dosage and Administration The oral dose of the fixed dose combination will be Doxofylline SR 400 milligrams (mg) + Montelukast 10 mg to be taken once daily .

Contraindications Hypersensitivity to methylxanthines. nasal congestion. abdominal pain. headache. montelukast and any other component of this product . rash. cramps and palpitations. dizziness.Common adverse events Dyspepsia. Occasionally vomiting and diarrhoea may occur.

USP of Doxofylline SR+ Montelukast          Combination of the safest xanthine bronchodilator with a safe oral anti-inflammatory agent Doxofylline has also shown to have some anti-inflammatory action Both the drugs have shown good efficacy and tolerability in patients with asthma. Once daily dosing Devoid of steroid side effects Drug of choice for patients not willing to take inhaled drugs For asthmatic patients not responding to high dose steroids Can help reduce the dose of inhaled steroids and also lessen the use of inhaled salbutamol. Effective for asthmatic patients with co-existing AR .