doxovent m medical ppt

8/13/2019 Doxovent M Medical Ppt

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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

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