Post on 04-Jun-2018
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Doxofylline SR+ Montelukast(Fixed Dose Combination)
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Asthma - Definition
Asthma is a Chronic inflammatory
disease characterized by
Airway hyperesponsivenessto a
variety of stimuli resulting in
Bronchospasmwhich reverses
spontaneously - on treatment
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Prevalence of Asthma
Asthma affects 300million adults andchildren worldwide
Estimated prevalence of asthma isincreasing 50% per decade
WHO: 15-20million asthmatics inIndia
Children: 12% and Adults 5%
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Basic Cellular Mechanisms
FIRST EXPOSURE
Sensitization process
SECOND EXPOSURE
Early allergic reaction
Late allergic reaction
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Allergic Response
SENSITIZATIONPHASE
1st exposure
Enters the body
Allergen Body produces IgE antibodies
Antibodies + Allergens
Excess antibodiesBind to mast cells
Inflammatory mediators (histamine)(not released)
Produce
Y Y
Y
Y
Y
YY
Y
Y
Y
Y
Y
Mast
cell
Sensitization
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Allergic Response
2ndexpos
IgE antibody
Allergen
Histamine
ChemotacticFactors
EARLYALLERGICRESPONSE(EAR)
5-30 minutesafter exposure
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Allergic Response
2ndexpos ChemotactiFactors
Migration&Activation
Basophils Neutrophils
EOSINOPHILS
SecondaryMediators ECP ; MBP
DamagetoEpithelial cells(thisexposestheparasympatheticner
LATE ALLERGIC RESPONSE (LAR)
INFLAMMATION
Mucus productionBronchoconstriction
Ciliary activity
Vasodilation
REDNESS, SWELLIN
between 3-11hours afterexposure
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Drugs
Relievers
For treatment ofbronchospasmand
to relieve acute
attacks
Controllers
For long term controlof inflammation and
to prevent further
attacks
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What Are Relievers?- Rescue medications
- Quick relief of symptoms(within 2 min)
- Used during acute attacks
- Action lasts 4-6 hrs
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Relievers
Short acting beta 2 agonists
Inhaled salbutamol
Inhaled levosalbutamol
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What are Controllers?
- Prevent future attacks
- Long term control of asthma
- Prevent airway remodeling
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Controllers
Oral
Leukotriene antagonists
Theophylline - SR
Oral prednisolone
Inhaled
Corticosteroids(ICS)
Cromolyn sodium
Long acting inhaled
2-agonists(LABA)
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Stepwise Approach to AsthmaTherapy - Adults
Alternative controller and reliever medications may be considered
Reliever: Rapid-acting inhaled 2-agonist prn
Controller:
Daily inhaled
corticosteroid
Controller:
Daily inhaledcorticosteroid
Daily long-actinginhaled 2-agonist
Controller:
Daily inhaledcorticosteroid
Daily longactinginhaled 2-agonist
plus (if needed)
When asthma iscontrolled,reduce therapy
Monitor
STEP 1:
Intermittent
STEP 2:
Mild Persistent
STEP 3:ModeratePersistent
STEP 4:Severe
Persistent
STEP Down
Outcome: Asthma Control Outcome: Best
Possible Results
Controller:
None
-Theophylline-SR
- Doxofylline
-Anti-Leukotriene
-Long-acting inhaled2- agonist
-Oral corticosteroid
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Doxo fyl l ine SR+ Montelukas t
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
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Doxofylline SR
Doxofylline SR is a sustained release formulation of the
newer methylxanthine, Doxofylline, which needs to be
given once daily
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Mechanism of action
Inhibition of phosphodiesterase activity, leading toincrease in the amount of cAMP in the cells.
ATP cAMP AMP
Protein Kinase
Decrease intracellular calcium
Bronchodilation
Adenly cylase Phosphodiesterase
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Montelukast
Montelukast is a selective and orally active
leukotriene receptor antagonist that inhibits the
cysteinyl leukotriene (CysLT1) receptor
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Physiology of Inflammation
ArachidonicAcid Metabolism
Harmful Stimulus
Cell Perturbation (agitation or disturbance)
Liberates
Membrane PhospholipidsChemical & Mechanical stimuli
activates Phospholipase A
Lipoxygenase
Endoperoxides
PGG2 PGH2
PROSTAGLANDINS PROSTACYCLINS THROMBOXANE
PGE2 PGD2 PGF2 PGI2 TXA2
ARACHIDONIC ACID (AA)
STOMACH, KIDNEYS BLOOD VESSEL WALL PLATELETS
Release
Hydroperoxides
LEUKOTRIENES
Cyclo-oxygenase
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Inflammatory Effects of Leukotrienes in the Airways
CysLTs
Airway
Epithelium
Increased
mucussecretion
Decreased mucus
transport
Cationic proteins
(Epithelial cell damage)
Increased release
of tachykinins
Sensory C
fibres
Smooth muscle
Contraction and
proliferation
Inflammatory Cells
(e.g., Mast Cells,
Eosinophils)
Blood
vesselOedema
Adapted from Hay DW. Chest 1997;111:35S45S.
Eosinophil
recruitment
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Doxofylline Montelukast
Oral bioavailability: 62.6%
Protein binding: 48%
Tmax: 1.19 hrs
90% of drug metabolized in the
liver
Renal excretion: 4%
Half life: 7-10 hrs
Oral bioavailability: 64%
Tmax: 3-4 hrs
Metabolized by the liver
Renal excretion: < 0.2%
Half life: 2.7-5.5 hrs
Pharmacokinetic Properties
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Low affinity of Doxofylline for Adenosine receptors
In vitro information studies have showed a much lower affinity of doxofylline for
Adenosine receptors
Curr Med Res Opin 2001; 16(4): 258-268
Theophylline
Affinities of various methylxanthines for Adenosine A1 receptors
0 0.5 1 1.5 2 2.5
Doxofylline
Aminophylline
Bamifylline
Enprofylline
Affinities for adenosine A1 receptors
Theophylline
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Efficacy of Doxofylline
Study done on 346 patients with bronchial asthma for aduration of 12 weeks
Drugs: Doxofylline 400 mg, Doxofylline 200 mg,
Theophylline 250 mg and Placebo.
There was a significant improvement in FEV1 withdoxofylline 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; 8(4): CR 297-304
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Bronchial biopsies were performed in 14 patients with
chronic obstructive bronchitis to assess the presence or
absence of neutrophilic infiltration, oedema, fibrosis and
epithelial metaplasia before and after treatment for 3
months with Doxofylline 400 mg bid.
Results:57% of patients showed absence of lesions in the
doxofylline group. In the control group (placebo), absence
of lesions was observed in 14% of patients.
Eur Rev Med Pharmacol Sci 2000; 4: 15-20
Anti-inflammatory effects of Doxofylline
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Safety of Doxofylline
In a series of 10 patients with COPD, no significant changeswere noted in heart rate, compared with baseline values, duringor after infusion of Doxofylline 400 mg IV or placebo asassessed by 24 hr Holter monitoring. Mean heart rate rosesignificantly during treatment with Aminophylline 240 mg IV.
Volume of gastric acid output and pepsin output wassignificantly less with doxofylline IV as compared toaminophylline IV
The number of arousals per hour during sleep was significantlyincreased in the theophylline group along with a reduction in thesleep efficiency. Doxofylline had no impact on the sleep
arousals or the efficiency.
Curr Med Res Opin 2001; 16(4): 258-268
Aliment Pharmacol Therap 1990; 4: 643-649
Monaldi Arch Chest Dis 1995; 50:2; 98-103
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Reduction of ICS use with Montelukast
In a 6 weeks study on 226 patients
with stable asthma, clinically
significant tapering of inhaledcorticosteroid therapy was possible
during treatment with montelukast
10 mg/day as compared to
placebo.
Drugs 1998; 56(2): 251-256
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Clinical benefits of Montelukast in SAR
A Multicenter, randomized, double-blind, placebo
controlled study in which patients with SAR wererandomly assigned to treatment with montelukast 10 mg(n=522) or placebo (n=171) once daily at bedtime for 2weeks.
Outcomes:Daytime nasal symptom score (mean score ofcongestion, rhinorrhea, pruritus and sneezing)
Nighttime symptoms (mean score of difficulty in going tosleep, nighttime awakenings, nasal congestion on
awakening)
Result:Therapy with montelukast significantly improvedthe overall nasal symptom scores as compared withplacebo.
Ann Allergy Asthma Immunol 2003;90:214-222
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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.
The most common adverse events were headache, cough,
influenza and abdominal pain
All adverse events were considered mild and self limiting
and none required active treatment.
Drugs 1998; 56(2): 251-256
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Indications
Prophylaxis and chronic treatment of
asthma in adults 14 yrs of age and older
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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
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Common adverse events
Dyspepsia, abdominal pain, rash, nasal congestion,
dizziness, headache, cramps and palpitations.
Occasionally vomiting and diarrhoea may occur.
Contra indicat ions
Hypersensitivity to methylxanthines, montelukast and anyother component of this product
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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