New Evidence in Acute Asthma Treatment

8/13/2019 New Evidence in Acute Asthma Treatment

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Definition

Asthma is a chronic inflammatorydisorder of the airways in which manycells and cellular elements play a role.

The chronic inflammation is associatedwith airway hyperresponsiveness thatleads to recurrent episodes of wheezing,

breathlessness, chest tightness, andcoughing, particularly at night or in themorning.

Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma, updated 2009


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Epithelial

damage

Inflammatory

cell infiltration

Vascular

dilation

Mucous gland

hypertrophy

Edema

Mucus

Thickeningof basement

membrane

Adapted from National Asthma Education and Prevention Program. Expert PanelReport. Guidelines for the Diagnosis and Management of Asthma. August 1991.

Changes in Airway Morphology in

Asthma

Airway smooth

muscle


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These episodes are usually associated

with widespread, but variable, airflow

obstruction within the lung that is often

reversible either spontaneously or with

treatment. Clinical manifestations of

asthma can be controlled withappropriate treatment.

When asthma is controlled, there shouldbe no more than occasional flare-ups

and severe exacerbations should be

rare.



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Asthma Prevalence, 2004

Global burden of Asthma, 2004


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7/43Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma, updated 2009


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Treatment Cycle, GINA, updated 2009

Assessingasthma control

Treating to

achieve control

Monitoring to

maintain control


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reliever

Rapid acting B2-

agonist inhaledand oral

Systemic steroid

Anticholinergics

Xanthines

controller Inhaled and systemic

glucocorticosteroid

Leukotriene modifiers Inhaled LABA

Theophylline

Cromones Oral LABA

Asthma Medication


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Medication Routes

1. Inhalation

2. Orally

3. Injection

Benefits:

Delivered directly into the airwaysProducing higher local concentrations

Significantly less systemic side effects


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Inhalation Medications


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Quick Relief Medicines

(Rapid Acting 2-Agonist)

Act fast, generally within 15-20 minutes

Relaxes the smooth muscles around the bronchial

tubes Must have available at all times

Is only medicine that helps breathe quickly


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BETA2AGONIST

ACTION

IN ASTHMA

BRONCHODILATATION

INCREASED

MUCOCILIARYCLEARANCE

DECREASEDNEUTROPHILFUNCTION

DECREASED

BACTERIALADHERENCE

DECREASEDCHOLINERGIC

NEUROTRANSMISSION

DECREASEDPLASMA

EXUDATION


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Onset of Action

Rapid or Slow

Duration of Action

Short or Long

Efficacy at Receptor Site

Partial or Full Agonist

CHARACTERISTICS OF 2AGONIST


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Full-agonist Fast-onset Long-duration

Salbutamol - + -

Terbutaline - + -

Fenoterol - + -

Salmeterol - - +

Formoterol + + +

Procaterol + + +

Fast onset and full-agonis for relieverLong duration for add on controller

Choosing Beta-2 agonist


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PROCATEROL

Was found by Yoshizaki et al. at Japan

in 1976

Procaterol is a potent bronchodilator

even on a low dose

Has the effect of ten times stronger than

salbutamol and terbutalline


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PROCATEROL

TABLET (ORAL)

METERED DOSE INHALER (MDI)

SOLUTIO (NEBULIZED)


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Mean % FEV1 - Change from baseline (Initial Dosage)

35%

15%

0

M5 M30 H1.0 H2.0 H3.0 H4.0 H5.0 H6.0 H7.0 H8.0

Double-blind, randomized, 2 weeks study in 40-80% from predicted FEV-1 patients

M = minute H= hour

Ref: Storm; W,at.al.1985.Annals of Allergy, 55: 476-478

20 gMeptinair tid,n=71

10 gMeptinair tid,n=68

Placebo, n=67

:p< 0.05

PROCATEROL has fast bronchodillating effect


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Fast onset of action and longer duration than salbutamol

Comparative study of Meptinair vs salbutamol inhaler

Initial dose Week 12

50

40

30

20

10

Meptinair20 g tid,n=171

Salbutamol 200 g tid,n=162

0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8

Duration of Action (Hours) Duration of Action (Hours)

50

40

30

20

10

The horizontal (dashed) line represent 15% clinical improvement in FEV1from baseline.

Ref: Mazza J.A,et.al. 1992. Annals of Alergy, 68: 267-273


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Faster and longer duration of action than fenoterol

= P< 0.05 P vs F= P< 0.05 P vs S

= P< 0.05 S vs F

Fenoterol (F), n=35

Meptinair (P), n=35

Salmeterol (S), n=35

2000

1800

1600

1400

1200

0 5 15 30 300 540 (minute)

Change of FEV1value

Ref: Yunus F.,et.al. 2001. Indonesia Allergologist Association. 4 th National Congress Medan


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The Utility of a Long-Acting

Sympathomimetic Agent, Procaterol, for

Nocturnal AsthmaR. P. Baughman and R. G. Loudon. Chest February 1988

Ten patients with nocturnal asthma

Procaterol 0.1mg at night

Measured FEV1 every 2 hours from10PM to 8AM


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The use of long-acting -adrenergic

sympathomimetic agent reversed the

obstruction of the airway seen in

nocturnal asthma


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Twenty (20) asthmatic patients

Two puffs of procaterol (20g) or two

puffs of salbutamol (200g) MDI

PEF, FVC and FEV1were measured

after 5, 15, 30, 60, 120 and 180 min


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Pengaruh pemberian prokaterol dibandingkan

dengan salbutamol secara inhalasi dosis terukur

terhadap gejala klinis dan faal paru pada penderita

asmaMaimunah, T. Syafiuddin. Jurnal Respirologi Indonesia, 1999

Thirty (30) asthmatic patients

Procaterol 20g TID and Salbutamol

200g TID

PEFR, FEV1, FVC, bronchodilator test

every 2 weeks for 8 weeks


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Within the first two weeks, both drugs

showed equal efficacy dan clinical

improvements

After 2 weeks, the salbutamol group

showed deterioration while theprocaterol group still showed some

improvements

The decline in spirometry was greater in

salbutamol group than in procaterol


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A long-term trial of procaterol in

steroid-dependent patientsD.P. Tashkin. Journal of Respirology 1997

Seventy five (75) cocticosteroid-

dependent with moderate to severeasthmatic patients

Oral or inhaled corticosteroid andprocaterol for 28 weeks in five centers


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Procaterol has corticosteroid-sparing

effect of procaterol without a

compensatory increase in bronchodilator

use


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PURPOSE

The present study aimed to compare the

efficacy of nebulized procaterol with

nebulized salbutamol in the treatment of

moderate acute asthma


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METHODS

This was a randomized, double-blind, parallel group

study in 140 patients with moderate acute asthmaaccording to modified GINA 1998

Patients visiting the Emergency Room of PersahabatanHospital - Jakarta, male or female, aged 15 to 60 years,

were eligible for entry into this study

Excluded from the study were pregnant or lactatingwomen, smokers, patients with chronic obstructivepulmonary disease (COPD), heart disease,

hyperthyroidism, diabetes mellitus, severe infections, orother chronic diseases


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METHODS

Patients were randomly assigned to receive three

doses of either nebulized procaterol or salbutamol

The primary efficacy variable was the

improvement in predicted PEFR, while the

secondary efficacy variable was the improvement

in asthma score and the incidence and severity ofadverse events


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A total of 156 patients were screened and

there were 140 patients eligible for safety

evaluation, 137 patients eligible for ITTevaluation and 133 patients eligible for PP

analysis (Figure 1)

RESULT

P t l S lb t l


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Procaterol

(n=68)

Salbutamol

(n=69)

VITAL SIGNS

Temperature (0C) mean (SD)

Heart rate (beats/min) mean (SD)

Blood pressure (mm Hg) mean (SD)

SystolicDiastolic

Respiratory rate (resp/min) mean (SD)

36.9 (0.36)

104.2 (11.7)

121.5 (10.8)77.9 (8.9)

27.3 (2.6)

36.8 (0.48)

102.9 (12.7)

120.0 (9.7)75.2 (7.0)

27.4 (2.2)

PHYSICAL EXAMINATIONSn (%)

Normal

Abnormal (hyperemic pharynx)

64 (94.1)

5 (5.9)

66 (95.7)

3 (4.3)

ASTHMA SCOREmean (SD) 8.8 (1.5) 8.4 (1.6)

PEFRmedian (range)

PEFR value (L/min)

% predicted

< 25% - n(%)

125 (70 - 300)

30.5 (12 - 57)

19 (27.9)

120 (80 - 320)

26.0 (15 - 64)

32 (46.4)

ARTERIAL BLOOD GAS ANALYSESmean (SD)

PaO2 (mm Hg)

PaCO2 (mm Hg)

SaO2 (%)

HCO3-(mEq/L)

pH

LABORATORY ABNORMALITIESn (%)

ECG ABNORMALITIESn (%)

75.8 (16.28)

33.9 (6.67)

94.4 (4.37)

22.4 (3.84)

7.4 (0.06)

23 (33.8)

18 (26.5)

79.8 (22.18)

32.8 (5.46)

95.3 (2.66)

21.8 (2.64)

7.4 (0.06)

23 (33.3)

14 (20.3)


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PEFR (% predicted) improvements in each

group

Mean PEFR (% predicted) was markedly improved

compared with baseline value at every timepoint (20,

40, 60 and 120 minutes) in both groups (Figure 2).

Procaterol was statistically better in improving PEFR

value at 120 minutes compared with salbutamol but notclinically significant. The minimum clinically significant

difference in PEFR improvements between procaterol

and salbutamol groups according to the investigators

judgment as defined in the protocol was 5%. At othertimepoints, PEFR improvements by procaterol was

similar to salbutamol


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PEFR(%

predicted)

Procaterol (n=68) Salbutamol (n=69)

Timepoints(minutes)

Figure 2. PEFR (% predicted) values at different timepoints in procaterol and salbutamol groups, ITT population.

The improvements from baseline were significant at all timepoints (**p


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Asthma score improvements from baselinein procaterol and salbutamol groups

The asthma scores in procaterol and salbutamol groupswere markedly improved at every timepoint (20, 40, 60and 120 minutes) (Figure 3). At 120 minutes, meanasthma score in procaterol group was 2.0 and insalbutamol group was 2.1. Asthma score improvementsin procaterol group were compared with those insalbutamol group. It was shown that procaterol gavegreater improvements in asthma scores at the first 40minutes (20 and 40 minutes, p


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Time (minutes)

Procaterol (n=68) Salbutamol (n=69)

Figure 3. Asthma scores at several timepoints in procaterol and salbutamol groups, ITT population.

The improvements from baseline were significant at all timepoints (** p


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Arterial blood gas analyses

Arterial blood gas analyses at 120 minutes aresummarized in Table 2. Number of patients analyzed forblood gas was 62 patients in procaterol group and 65patients in salbutamol group. Six patients in procaterolgroup and 3 patients in salbutamol group could not be

included in the blood gas analysis due to the missingdata on either at baseline or at 120 minutes. Overall,PaO2 in procaterol group was slightly increased, while itwas slightly decreased in salbutamol group. SaO2 wasunchanged in procaterol group and slightly decreased in

salbutamol group, while PaCO2 slightly decreased inboth procaterol and salbutamol groups


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Blood Gas Analysis

PP analysis

Procaterol

(n=62)

Salbutamol

(n=65)

PaO2 (mmHg) 0 minutes

120 minutes

76.8

81.4

80.0

76.2

SaO2 0 minutes

120 minutes

95.0

95.0

95.3

94.3

PaCO2

(mmHg)

0 minutes

120 minutes

33.4

31.6

32.8

31.7

Table 2. Mean PaO2, PaCO2and O2saturation (SaO2)

before and after treatment (120 minutes)in procaterol

and salbutamol groups, PP analysis


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Adverse events

Incidences of adverse events were very low in thepresent study. Adverse events recorded were sinustachycardia and palpitation, which were common after2agonist administration. Palpitation was recorded as asubjective symptom.

There were 2 subjects in salbutamol group experienced

palpitation, and no one in procaterol group. Thepalpitation was considered as mild.

Sinus tachycardia was found during electrocardiographyat 120 minutes, which was recorded and analyzed forany changes from baseline. There were 2 (2.9%) cases

of changes in ECG recordings in procaterol group and 6(8.6%) cases in salbutamol group.

No serious adverse event was found in the presentstudy


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CONCLUSIONS

Beta 2 agonists have been used as reliever inasthma management

In moderate acute asthma, nebulized procateroland nebulized salbutamol were both effective in

improving PEFR and decreasing asthma score.

Both treatments were well tolerated, and adversereactions were rare, lower incidence with procaterolthan with salbutamol


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New Evidence in Acute Asthma Treatment

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