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THE USE OF SUPEROXIDE DISMUTASE IN ACCELERATING SYMPTOM RELIEF IN ASTHMATIC AND HOUSE DUST MITE ALLERGIC CHILDREN RECEIVING HOUSE DUST MITE IMMUNOTHERAPY: DOUBLE BLIND RANDOMIZED CONTROLLED CLINICAL TRIAL

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Objective: To evaluate the efficacy of superoxide dismutase (SOD) in lung function (FEV1 reversibility) and respiratory symptoms (drug scores, symptoms scores) in asthmatic and house dust mite allergic children receiving house dust mites immunotherapy. Methods: Forty subjects aged 6–17 years old with asthma, tested positive for house dust mite allergy on skin prick test, and received immunotherapy were enrolled in this study. All subjects completed clinical based assessments and diary-based assessments for drug and symptom scores. Following a four-week baseline assessment, all subjects were randomized to receive SOD or placebo. Respiratory symptoms (drug and symptoms score) and FEV1 were evaluated at the end of the 1st, 2nd, 3rd, and 4th weeks after randomization. Drug score, symptoms score, and FEV1 reversibility test results were analyzed using a Paired t test and repeated measure of ANOVA. Results: There was a significant difference in drug scores, symptoms score, and FEV1 reversibility test outcomes between SOD and placebo. SOD group showed a significant decrease in all outcome measures compared to those in placebo group. Conclusions: The use of SOD as antioxidants is effective in accelerating symptom relief for children with asthma and house dust mite allergy receiving house dust mite immunotherapy.
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72
International Journal of Integrated Health Sciences. 2015;3(2)
Original Article
Use of Superoxide Dismutase in Accelerating Symptom Relief in
Asthmatic and House Dust Mite Allergic Children Receiving House Dust
Mite Immunotherapy
Correspondence:
Anang Endaryanto, Allergy Immunology Division,
Department of Child Health, Faculty of Medicine,
Airlangga University-Dr. Soetomo General Hospital
Jl. Mayjen Prof. Dr. Moetopo 6–8, Surabaya, Indonesia
e-mail: aendaryanto@yahoo.com
Anang Endaryanto, Zahrah Hikmah, Ariyanto Harsono
Allergy Immunology Division, Department of Child Health, Faculty of Medicine, Airlangga University-
Dr. Soetomo General Hospital
Abstract Objective:          
function (FEV1 reversibility) and respiratory symptoms (drug scores,
symptoms scores) in asthmatic and house dust mite allergic children receiving
house dust mites immunotherapy.
Methods: Forty subjects aged 6–17 years old with asthma, tested positive for
house dust mite allergy on skin prick test, and received immunotherapy were
enrolled in this study. All subjects completed clinical based assessments and
diary-based assessments for drug and symptom scores. Following a four-week

Respiratory symptoms (drug and symptoms score) and FEV1 were evaluated
at the end of the 1
st
, 2
nd
, 3
rd
, and 4
th
weeks after randomization. Drug score,
symptoms score, and FEV1 reversibility test results were analyzed using a

Results: 


placebo group.
Conclusions:          
symptom relief for children with asthma and house dust mite allergy receiving
house dust mite immunotherapy.
Keywords:      
symptoms score
IJIHS. 2015;3(2):72–8
Introduction
Asthma is one of the common health problems
in almost all countries in the world. Asthma
prevalence appears to have peaked or reached
a plateau in countries with a high prevalence,
while it is still rising in many Asian cities.
1
In Indonesia, the prevalence of allergic
asthma in school aged children is 2.1%.
2
The prevalence is increasing each year and
reached 6.9% in 2008.
3
Secondary prevention
of asthma allergy through house dust mite
(HDM) immunotherapy has been shown
to improve the natural course of allergic
disease. Immunotherapy is more effective
     
a minimum of 14 weeks; however, dropping
out is still inevitable.
4
In the outpatient allergy
clinic of Dr. Soetomo Hospital, 19.8% patients
dropped out of the scheduled immunotherapy
program in 2006 and 25.3% in 2007.
5
To

therapies should be considered to compliment
the desired outcomes.
      
adjuvant therapy in allergic asthma children
treated with house dust mite immunotherapy.
6,7
 
    
     
     
and DNA.
6,8

Received:
May 6, 2015
Revised:
August 9, 2015
Accepted:
August 28, 2015
:72–8
International Journal of Integrated Health Sciences. 2015;3(2)
73
given concurrently with house dust mite
immunotherapy as a complementary and
alternative medication has not yet been well-


in children with allergic asthma and house
dust mite allergy receiving house dust mite
immunotherapy in a double blind randomized
controlled clinical trial.
Methods
The interventional study was a randomized
double-blinded, placebo-controlled design.
       
      
placebo once daily for a period of 4 weeks. The
protocols of subject selection were followed
and immunotherapy commenced as in the
hospital guidelines. The study included a nurse
to witness the administration of 250 mg oral
   
placebo as the control group, while parents of
the subjects were instructed to continue giving
the supplementation as per advise.
Data collection includes several clinical
assessments, lung function (FEV1 reversibility)
and respiratory symptoms (drug scores,
symptoms scores) at the randomization
period and at 1
st
, 2
nd
, 3
rd
, and 4
th
week following
randomization. Supplementation is given for 4

and third weeks of run in (two diaries of seven

diaries of seven days) after randomization.
Subsequently, the subjects were randomly
assigned into 2 groups. For allocation of the
subjects, a computer-generated list of random

gliadin combination of 250 mg and the other
group a placebo. Each supplement was given
once daily for 4 weeks. During the intervention
period, measures taken for FEV1 reversibility
once a week and all subjects were to complete
a written-diary recording asthma symptom
scores, asthma drug scores, questions on
tolerance and acceptance of the product, and
gastrointestinal complaints.
Concurrent medication for all disorders,
including asthma, was not changed. Subjects
with moderate or severe persistent asthma
attack or with a history of respiratory failure
     
smoking, history of oral steroid intake, rectal,

or at any time during the study. In addition,
subjects suffering from mental retardation,
congenital heart disease, malignancies or
having poor nutritional status were also

written informed consent was taken. Ethical
approval was obtained from Dr. Soetomo
General Hospital Research Ethics Committee.
Subjects with asthma were obtained from
      
     
sensitized to house dust mite, as determined
by skin prick test, and receiving house dust
mite immunotherapy. We included only those
subjects with a positive result to house dust
mite (wheal diameter 3 mm greater than
Anang Endaryanto, Zahrah Hikmah, et al.
Table 1 Baseline Values Before Randomization Period for All Subjects
Variable
Supplement Group
p Value
SOD (n=20) Placebo (n=20)
Age, mean (SD) yrs. 9.55 (2.19) 9.00 (1.49) 0.385

male 10 13 0.990
Female 10 7
Body weight, mean (SD) kg 31.00 (11.52) 26.55 (7.97) 0.163
Body height , mean (SD) cm 133.40 (13.47) 131.35 (12.01) 0.286
FEV
1 reversibility
pre, mean (SD) 23.52 (14.65) 23.22 (11.64) 0.944
Medication (asthma drug) scores 7.05 (6.78) 7.75 (6.97) 0.749
Symptom scores 11.65 (11.98) 13.85 (10.49) 0.540

:72–8
74
International Journal of Integrated Health Sciences. 2015;3(2)
control) and greater than other aeroallergen
 
were enrolled into the baseline recording
period. Forty subjects aged 6–17 years
old with intermittent to mild persistent
asthma, according to GINA 2006 criteria,
were included.
9
Diagnosis of asthma were
determined by the level of FEV1 reversibility

after administration of inhaled salbutamol
during the 1
st
visit.
During the clinical trials, the variability in
asthma symptoms such as improvement and
deterioration were considered important to
     
clinical trials when there was an evidence of
a decreasing quality of life according to their
diaries, or if subjects failed to complete the
diary for at least ten days during the study.
     
were known to participate in other clinical trial
for other drugs in the previous 30 days, recent
    
suffering from respiratory tract infections in
the past three weeks, or change the asthma
medication that has been programmed in the
two weeks prior to clinical trial.
Several independent pharmacists in the
Pharmaceutical Unit Dr. Soetomo General
     
and saccharum lactis-consisted placebo. The
placebo was matched to the study drug for
taste, color, and size. Drugs were stored in a
secured area in accordance with the standard
operating procedures of good clinical practice.
The individual treatment drugs were decoded
as A or B by independent researchers who
were blinded to the designated drugs given.

sealed envelope. All subsequent subjects were
allocated to A or B by a process of minimization
    
assessed on the diaries.
10
The subjects and
research nurses recorded whether treatment
A or B had been given the day after dosing.
The randomization codes were revealed when
the study had been completed.
Measures taken were recorded in the clinic
and on diary cards. At baseline, results FEV1
reversibility, the subject’s attitude to other
medicine, and the results of routine blood
screening for undetected systemic illness were
Use of Superoxide Dismutase in Accelerating Symptom Relief in Asthmatic and House Dust Mite
Allergic Children Receiving House Dust Mite Immunotherapy
Table 2 Variables Measured at Clinic Visits (FEV1 Reversibility) and from Diaries (Drug Score and
Symptoms Score) at the Randomization Period (Week 0) and at 1
st
, 2
nd
, 3
rd
, and 4
th
Week
after Randomization
Outcomes
Variables and
Treatment
Group
Time of Assessment for Outcome Variables
p Value
Week 0 Week 1 Week 2 Week 3 Week 4
FEV
1 reversibility
, mean
(SD)
 23.52 (14.65) 9.57 (6.73) 9.85 (6.74) 6.95 (5.51) 7.49 (7.36) 0.000*)
Placebo Group 23.22 (11.64) 18.94 (11.06) 22.75 (23.10) 18.48 (10.32) 21.25 (18.34) 0.000*)
P 0.944**) 0.002**) 0.022**) 0.000**) 0.003**) 0.020***)
Medication
scores(SD)
 7.05 (6.78) 1.50 (2.40) 1.00 (2.00) 0.40 (1.10) 0.25 (1.12) 0.000*)
Placebo Group 7.75 (6.97) 8.30 (7.53) 7.20 (7.47) 4.80 (5.21) 5.60 (5.47) 0.000
P 0.749**) 0.000**) 0.001**) 0.001**) 0.000**) 0.009***)
Symptom scores
(SD)
 11.65 (11.98) 3.30 (3.25) 3.00 (5.65) 2.30 (2.76) 3.05 (4.08) 0.000*)
Placebo Group 13.85 (10.49) 13.05 (7.91) 14.85 (12.05) 11.05 (6.44) 8.60 (5.28) 0.000*)
P 0.540**) 0.000**) 0.000**) 0.000**) 0.001**) 0.005***)
*): differences between the group treatments for outcome variables
**): differences between the week of assessment for outcome variables
***): interactions between the group treatments and week of assessment for outcome variables
:72–8
International Journal of Integrated Health Sciences. 2015;3(2)
75
    
one day after randomization, when subjects
and investigators were asked separately to

gliadin or placebo.
At randomization, FEV1 were recorded as
      
FEV1 was calculated using the formula. Drug
and symptoms scores were recorded on diary.
Mean scores were calculated for the run-in
         
assessment after randomization. Subjects
were assessed on the symptoms at night,

The frequency of symptoms and the drug
consumed were calculated for each assessment
period. Subjects used inhaled bronchodilator
as required. Bronchodilator consumption was
assessed by the frequency of daily use of the
prescribed bronchodilator during each of the
assessment periods.
An initial sample size of 40, with a 0%
        
would give a power of 80% for detecting a
30% difference in proportion of subjects
who receive house dust mite immunotherapy

the cure rate of allergic children who received
      
previous research and a two tailed test at the
5% level.
FEV1 and quality of life from diaries, in
the form of drug and symptom scores, were
the outcome variables. The primary endpoint
was the proportion of subjects achieving
an improvement in FEV1 reversibility from
baseline to 4 weeks. All outcome measures
such as lung function (FEV1 reversibility) and
respiratory symptoms (drug scores, symptoms
     
    
by comparing the two treatment groups (at
the randomization period and at 1
st
, 2
nd
, 3
rd
,
and 4
th
week after randomization). Asthma
symptom scores, asthma drug scores, and
FEV1 reversibility test results were analyzed
using a paired t test and repeated measure of

were kept blinded to the allocation. The
analysis was involved all subjects who were
randomly assigned.
Results
Baseline data were recorded from fourty
asthmatic children allergic to house dust mite
who received house dust mite immunotherapy.
       
gliadin and saccharum lactis-consisted
placebo as control, and all fourty subjected
completed all clinical assessments. No subject
reported adverse drug reaction due to 250 mg

Baseline details of the two groups were similar
(Table 1).
      
     
improvements were shown in symptom score,

      
difference between the groups in terms of all
outcome variables (Table 2).
Mean improvement in FEV1 reversibility
compared to the baseline value was 1.97%
     
group, with a mean difference of -9.46 (95%
     
-4.89). Mean improvement in medication
(drug) scores from baseline was 2.15 for

     
difference -7.12 to -2.26).
Mean improvement in symptom scores
compared to the baseline value was 5.25 for
    
      
interval for difference -11.12 to -4.124) (Fig.1).

treatment and week of assessment for FEV1
reversibility (P=0.020), asthma symptom
scores (P=0.009), and asthma drug scores
(P=0.005), indicating differences between the
two therapy groups over the course of the study

change in bronchodilator use in either group,
  
using less bronchodilator than the placebo
group in the last four weeks of the study. There
      
of symptoms in asthmatic children allergic to
house dust mite who received house dust mite
immunotherapy.
Discussion
This randomized double-blinded placebo
      
than placebo in terms of assisting relief of
symptoms in asthmatic children allergic to
house dust mite receiving house dust mite
immunotherapy. A study stated that the
      
role on the pathophysiology of airway
remodeling hyperactivity and subsequently
Anang Endaryanto, Zahrah Hikmah, et al.
:72–8
76
International Journal of Integrated Health Sciences. 2015;3(2)
Variables Measured at Clinic Visits [FEV
1
Reversibility (Fig. 1a)] and from Diaries
[Drug Score (Fig. 1b)] and Symptoms Score (Fig. 1c)]) at the Randomization
Period (Week 0) and at 1
st
, 2
nd
, 3
rd
, and 4
th
Week after Randomization
Fig. 1
a
b
c
:72–8
Use of Superoxide Dismutase in Accelerating Symptom Relief in Asthmatic and House Dust Mite
Allergic Children Receiving House Dust Mite Immunotherapy
International Journal of Integrated Health Sciences. 2015;3(2)
77
Anang Endaryanto, Zahrah Hikmah, et al.
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     
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    
    
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      
    

induce apoptosis and cell shedding of airway
epithelial cells.
11
Another study also stated that


group.
12


FEV1/FVC and FEV1 reversibility. Asthma
       

      

was inversely related to airway hyperactivity
determined by FEV1reversibility measured
after ß2-agonist administration. This study
supports previous research by Sackesen et al.
13
     
  
asthma compared to healthy controls.
Several previous studies have shown

and Shanmugasundaram
14
conducted a study
of 60 children aged 5–18 years old.
The
sample was divided into 2 groups: the group
with asthma and healthy children as control
      
supplements 250 mg Amrita Bindu twice daily
for 12 months. The results showed an increase

rate (PER) in the asthma group was almost
similar to the control group. This study
     
     
     

15
who
    
     
demonstrated by the decrease in cell numbers
of eosinophils, neutrophils and lymphocytes in

     
       
reversibility and in a faster time period
when compared to placebo administration
in children aged 6–17 years old with
allergic asthma who received house dust
      

       
immunotherapy, by accelerating the onset of
therapeutic effect; hence, the drop out rate
can be reduced. This research informs that
       
the immunotherapy program, because multi-
year immunotherapy regimen has been shown
problematic, only about 16% adherences at
year 3.
16,17
  
symptom relief in asthmatic children allergic
to house dust mite receving house dust mite
immunotherapy.
:72–8
78
International Journal of Integrated Health Sciences. 2015;3(2)
9.       
stress in the pathogenesis and treatment of

8: 49-56.
10. Bateman ED, Hurd SS, Barnes PJ, Bousquet
J, Drazen JM, FitzGerald M, et al. from the
Global Strategy for Asthma Management and
Prevention, Global Initiative for Asthma (GINA)

www.ginaasthma.org.
11. Comhair SAA, Ricci KS, Arroliga M, Lara AR,
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:72–8
Use of Superoxide Dismutase in Accelerating Symptom Relief in Asthmatic and House Dust Mite
Allergic Children Receiving House Dust Mite Immunotherapy
... Regarding antioxidant defenses, despite increased levels of GSH in the airways, the ratio of oxidized to reduced GSH also increases [57]. Other antioxidants such as ascorbate and alpha-tocopherol decrease [122,123], and SOD activity, but not SOD quantity [39], is likewise diminished [124][125][126][127][128][129]. Catalase activity is suppressed [130,131]. ...
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Studies all over the world on the therapeutic use of antioxidants as supplements has revealed their capacity to control inflammatory processes. Amrita Bindu an Ayurvedic health food supplement has already shown to be an antioxidant inducer and to combat free radical-mediated tissue damage studied in rats. Amrita Bindu is a salt-spice herbal mixture designed for positive health. It was tested as a supplement to therapy for a period of 12 months in 36 children suffering from asthma. Asthma is a chronic inflammatory disease with excessive free radical generation in lungs and blood cells. The patients were followed up by monitoring their clinical conditions, therapeutic doses of anti-asthmatic drugs, free radical generation, lipid peroxidation (LPO) and antioxidants in blood. At the end of 3 months of Amrita Bindu supplementation, the patients had stopped all anti-asthmatic medications and were free from attacks of asthma.
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Data for trends in prevalence of asthma, allergic rhinoconjunctivitis, and eczema over time are scarce. We repeated the International Study of Asthma and Allergies in Childhood (ISAAC) at least 5 years after Phase One, to examine changes in the prevalence of symptoms of these disorders. For the ISAAC Phase Three study, between 2002 and 2003, we did a cross-sectional questionnaire survey of 193,404 children aged 6-7 years from 66 centres in 37 countries, and 304,679 children aged 13-14 years from 106 centres in 56 countries, chosen from a random sample of schools in a defined geographical area. Phase Three was completed a mean of 7 years after Phase One. Most centres showed a change in prevalence of 1 or more SE for at least one disorder, with increases being twice as common as decreases, and increases being more common in the 6-7 year age-group than in the 13-14 year age-group, and at most levels of mean prevalence. An exception was asthma symptoms in the older age-group, in which decreases were more common at high prevalence. For both age-groups, more centres showed increases in all three disorders more often than showing decreases, but most centres had mixed changes. The rise in prevalence of symptoms in many centres is concerning, but the absence of increases in prevalence of asthma symptoms for centres with existing high prevalence in the older age-group is reassuring. The divergent trends in prevalence of symptoms of allergic diseases form the basis for further research into the causes of such disorders.