ArticlePDF Available

Abstract and Figures

This research aims at discovering dietary supplements which may show comparable or even stronger beneficial effects (with less or none adverse effects) than corticosteroids in children with Duchenne Muscular Dystrophy (DMD). This paper presents a case report on the effects of an ionized "saline water" called "ASEA redox Supplement®" (ARS) oral solution in a ~2-year-old boy with DMD from Bucharest, Romania. In vitro studies showed that ARS is a very potent selective NRF2 activator, thus a very potent (indirect) antioxidant: the studies conducted in vivo also support this main pharmacological mechanism of ARS, with no toxicity up to high doses, in contrast with the much more toxic corticosteroids. From the first months of ARS treatment all the rhabdomyolysis markers (with very high initial serum levels) dropped significantly, with no found toxicity. The main conclusions of this paper are: (1) ARS has remarkable antioxidant and immunomodulatory effects and should be studied on larger groups of children with DMD under the age of 4 years old (but also on other age groups of children and even young adults), as an alternative to early corticosteroids; (2) Given its immunomodulatory effect (NRF2 selective activation and NF-kB inhibition), ARS deserves future cohort studies on its potential to replace corticosteroids and other non-steroidal immunosuppressants (at least partially) in many types of pulmonary/renal/hepatic/ articular/skin autoimmune autoimmune and even malignant diseases of both children and adults; (3) Given its very strong antioxidant effects (by highly selective NRF2 potent activation), ARS deservesfuture cohort studies on acute/chronic diseases that imply high levels of tissular oxidative stress, especially some acute/chronic cardiovascular and respiratory diseases like acute myocardial infarction with acute/chronic heart failure, stroke, Chronic Obstructive Pulmonary Disease (COPD), asthma etc. of both children and adults (so that ARS may help millions and even billions worldwide). https://biomedress.com/volume1-issue4.php https://biomedress.com/pdf/CJBRT-19-04-018.pdf https://biomedress.com/pdf/CJBRT-19-04-018-01.pdf (the extensive table containing all the consults and paraclinical investigations of this child-patient) This paper belongs to a series of three cases on Asea effects in DMD children-patients: https://www.researchgate.net/publication/325371161 (1st case - preprint), https://www.researchgate.net/publication/334596031 (1st case - CJBRT article), https://www.researchgate.net/publication/334773748 (1st case - periodic updates), https://www.researchgate.net/publication/335502350 (2nd case - preprint), https://www.researchgate.net/publication/340902127 (3rd case - preprint); See also: https://www.researchgate.net/publication/336990483 and https://www.researchgate.net/publication/337026408 (ppt on Asea), https://www.researchgate.net/publication/339592997 (on possible testing of NRF2 activators in COVID-19)
Content may be subject to copyright.
Citation: Andrei-Lucian Drăgoi. The Remarkable Effects of “ASEA redox Supplement” In A Child with Duchenne Muscular Dystrophy A Case Report2019;1(4): 11.
© All rights are reserved by Andrei-L ucian Drăgoi. Page 1 of 11
Can J Biomed Res & Tech
July 2019 Vol:1, Issue:4
© All rights are reserved by Andrei-Lucian Drăgoi
The Remarkable Effects of “ASEA
redox Supplement” In A Child with
Duchenne Muscular Dystrophy A
Case Report
Abstract
This research aims at discovering dietary supplements which
may show comparable or even stronger beneficial effects (with
less or none adverse effects) than corticosteroids in children
with Duchenne Muscular Dystrophy (DMD). This paper
presents a case report on the effects of an ionized “saline water”
called “ASEA redox Supplement®” (ARS) oral solution in a
~2-year-old boy with DMD from Bucharest, Romania. In vitro
studies showed that ARS is a very potent selective NRF2
activator, thus a very potent (indirect) antioxidant: the studies
conducted in vivo also support this main pharmacological
mechanism of ARS, with no toxicity up to high doses, in
contrast with the much more toxic corticosteroids. From the
first months of ARS treatment all the rhabdomyolysis markers
(with very high initial serum levels) dropped significantly, with
no found toxicity. The main conclusions of this paper are: (1)
ARS has remarkable antioxidant and immunomodulatory
effects and should be studied on larger groups of children with
DMD under the age of 4 years old (but also on other age groups
of children and even young adults), as an alternative to early
corticosteroids; (2) Given its immunomodulatory effect (NRF2
selective activation and NF-kB inhibition), ARS deserves
future cohort studies on its potential to replace corticosteroids
and other non-steroidal immunosuppressants (at least partially)
in many types of pulmonary/renal/hepatic/ articular/skin
autoimmune autoimmune and even malignant diseases of both
children and adults; (3) Given its very strong antioxidant effects
(by highly selective NRF2 potent activation), ARS
deservesfuture cohort studies on acute/chronic diseases that
imply high levels of tissular oxidative stress, especially some
acute/chronic cardiovascular and respiratory diseases like acute
myocardial infarction with acute/chronic heart failure, stroke,
Chronic Obstructive Pulmonary Disease (COPD), asthma etc.
of both children and adults (so that ARS may help millions and
even billions worldwide).
Keywords: ASEA redox supplement (ARS) oral solution, 3-
year-old boy, Duchenne muscular dystrophy (DMD), NRF2
selective activation, corticosteroids
Main abbreviations: DMD: Duchenne Muscular Dystrophy;
ARS: ASEA redox Supplement®; NF-κB: nuclear factor
kappa-light-chain-enhancer of activated B cells; NRF2: Nuclear
factor erythroid 2-related factor 2; COPD: Chronic Obstructive
Pulmonary Disease
Main Text
An introduction to DMD
Duchenne Muscular Dystrophy (DMD) [1,2] is the most
common type of muscular dystrophy and has an incidence of
~1/3600 born male infants. DMD is a severe X-linked recessive
muscular dystrophy caused by a mutation (inherited from a
person's parent in ~2/3 of DMD cases and non-inherited de novo
mutation in ~1/3 of DMD cases) in the gene encoding dystrophin
(dys) (located on the short [p] arm of X chromosome, at locus 21
[Xp21]), which dys is a cytoplasmic protein and an essential
component of a protein complex (with many subunits) that
connects the myocyte cytoskeleton to the surrounding basal
lamina of the extracellular matrix through the muscular cell
membrane (sarcolemma). Normal skeletal myocytes contain
small amounts of dys but its total/partial absence or abnormal
length leads to excess calcium cations penetrating the
sarcolemma and causing excess water to enter into all
mitochondria which then burst, causing intracellular oxidative
stress, sarcolemma permanent damage and
myocytes/cardiomyocytes necrosis. Progressive rhabdomyolysis
causes muscular fibers to be progressively replaced by adipose
and connective tissue (pseudohypertrophic muscular dystrophy
or muscular pseudohypertrophy). Muscle weakness associated
with progressive muscle atrophy (with secondary fatigability,
frequent falls and progressive difficulty in walking and getting
up from lying or sitting position) usually begins around the age
of 4 years and worsens rapidly in boys with DMD, so that most
of them become unable to walk by the age of 12 years. In
advanced stages, DMD patients may have respiratory disorders
(due to respiratory muscles damage), swallowing difficulties
(with high risk of aspiration pneumonia) etc. Due to
rhabdomyolysis (including myocardium cytolysis), DMD
patients have extremely high Creatine Kinase (CK) and possibly
(very) high CK-MB isomer (CK-MB) serum levels: the serum
levels of Aspartate Transaminase (AST) and Alanine
Transaminase (ALT) are also very increased. Consequently,
Andrei-Lucian Drăgoi*
Independent MD pediatrician specialist, Romania
*Address for Correspondence
Aleea (Alley) Arinii Dornei, nr. 11, bloc i9, scara A, et. 1, ap. 4, Bucuresti, sector 6;
cod postal (postal code) 060797; Email: dr.dragoi@yahoo.com
Submission: June 26, 2019
Published: July 20, 2019
Copyright: © This work is licensed under Creative Commons
Attribution4.0 License
Open Access Case Report
Citation: Andrei-Lucian Drăgoi. The Remarkable Effects of “ASEA redox Supplement” In A Child with Duchenne Muscular Dystrophy A Case Report2019;1(4): 11.
© All rights are reserved by Andrei-L ucian Drăgoi. Page 2 of 11
Myoglobin (MG) (produced by rhabdomyolysis) also attains
high concentrations in serum and urine. Electromyography
(EMG) distinguishes the weakness caused by destruction of
muscle tissue. Echocardiography may show dilative
cardiomyopathy secondary to myocardial fibrosis (which can
occasionally lead to congestive heart failure and/or cardiac
arrhythmias). DNA testing demonstrating mutation(s) in one or
more of the 79 exons of dys-gene can often make the diagnosis
at birth or confirm the diagnosis in most suspected cases. DMD
doesn’t have a curative treatment, but only a pathophysiological
and symptomatic treatment which may delay the onset of
symptoms and increase the quality of life. Several types of
medications were proved to be relatively useful in the treatment
of DMD and its complications, such as: steroids such as
prednisolone and deflazacort (which were demonstrated to
slow muscle degeneration and to produce short-term
improvements in muscle strength and function up to 2 years,
including walking period prolongation according to some
reports); β2-agonists such as salbutamol (which were
demonstrated to increase muscle strength, but don’t modify
disease progression), anticonvulsants (for possible seizures
control), ataluren (which is indicated for DMD patients that
can walk and are more than 5 years old; ataluren probably
makes ribosomes less sensitive to premature stop codons,
especially for the 'UGA' stop codon, by promoting insertion of
certain near-cognate transfer RNA at the site of nonsense
codons, with no apparent effects on downstream mRNA
transcription, processing, stability nor on the resultant protein),
sildenafil (which was also demonstrated to improve the
muscular blood flow in DMD boys) etc. There are also several
new genetic treatment approaches to DMD patients. The exon-
skipping gene therapy (ESGT) with antisense oligonucleotides
(oligos/AONs like eteplirsen or drisapersen) triggers skipping
of an exon (adjacent to the exon affected by mutation) so that to
restore the reading frame and production of a (still-truncated
but) more functional version of dys. For ESGT to be efficient
on medium and long term, AONs must be periodically
redelivered into muscles. Stem cell replacement therapy
(SCRT) was also proposed. SCRT is a therapy using pericytes
(a type of multipotent stem cells which have the ability to be
delivered systemically and uptaken by crossing the vascular
barrier, then to fuse and form myotubes): pericytes are injected
arterially, crossing through arterial walls into muscles, where
they can differentiate into potentially functional myocytes.
CRISPR/Cas9-mediated genome editing (not currently feasible
in humans, but potentially feasible in the future) is the most
ambitious hope in the treatment of DMD: this is a technique
which can precisely remove a targeted mutation of dys-gene, by
allowing the DNA repair mechanisms of myocytes to replace
that mutant dys-gene with a normal dys-gene. Despite all these
efforts in finding new and more efficient treatments, the
average life expectancy of DMD patients is ~ 26 years (with a
maximum between 30-50 years in rare cases who benefit from
excellent care). Most DMD patients become wheelchair-
dependent early in life and the gradual development of cardiac
hypertrophy and/or restrictive respiratory insufficiency
typically results in premature death between ages of 20-30
years. Important note. Among the differential diagnosis of
DMD are other genetic/non-genetic muscular dystrophies
(MDs), from which the more rare (1.5-6/100 000 male births)
(X-linked recessive) Becker muscular dystrophy (BMD) is
similar to DMD (regarding etiology and pathogenesis which
include less severe mutations of the same dys-gene [thus making
BMD a dystrophinopathy too]) but with less affected (“milder”)
phenotypes.
An introduction to ARS, NF-kB and NRF2
ARS is produced by an international direct selling and multi-
level marketing company called “ASEA, LLC” [1] founded in
2007 and headquartered in Salt Lake City, Utah, USA. The
present ARS is based on a technology initially created,
developed and patented [2] by a former company called “Medical
Discoveries Inc.” and was previously called “MDI-P”. ARS is a
clear, colorless liquid generated by electrolysis of a highly
purified sterile saline. ARS is distributed in ~1 liter plastic
bottles/vials. ARS has a saline concentration of ~0.27g NaCl
/100ml (0.27%) and additionally contains (in a total
concentration of ~1%) highly reactive (but stabilized) chlorine
and oxygen species (see ARS patent previously referenced as a
footnote):
The Oxidant (OX) Species from ARS mainly include hydrogen
peroxide (H2O2), superoxide anions species (O2- and HO2-),
hypochlorous acid (HOCl), hydronium cation (H3O+),
hypochlorite radical (OCl*), singlet oxygen 1[O2], (partially
soluble) oxygen biatomic molecules (in triplet ground state) and
oxygen triatomic molecules (O3) (ozone);
The Reductive (RED) Species from ARS mainly include:
hypochlorite anions (ClO) (also paired as sodium hypochlorite
Na+ClO [NaOCl]), chlorine anions (Cl), chlorine biatomic
molecules (Cl2), (partially soluble) hydrogen biatomic molecules
(H2) and hydrogen anions (H-). In contrast with ARS, MDI-P had
a relatively high concentration (~25-50%) of those reactive
(mainly OX) species and was initially tested for its microbicidal
properties: it was found to be a very fast- acting, broad-spectrum
microbicidal solution effective against Staphylococcus aureus,
Pseudomonas aeruginosa, Legionella pneumophila and Candida
albicans [3]. ARS was launched by ASEA LLC in 2009 as
dietary supplement certified for oral consuming safety by the
Department of Agriculture and Food, State of Utah, USA [3].
ARS is currently produced in a production facility which is FDA
registered, NSF certified and GMP compliant. In 2015, ASEA
partnered with BioAgilytix Labs [4] (specialized in biomarker
testing) which periodically validates (as also monitored by FDA)
the existence of reactive oxygen species in the ARS solution [5].
After ARS being officially registered in the European Union
(EU) (with number “NUT 1936” [6]), the first European country
in which ARS was also registered and launched as a dietary
supplement was Italy (a founding member of EU), under the
name “ASEA advancing life” (with index number 54229 in the
official list of dietary supplements approved in Italy [7]).
A secondary introduction to the nuclear factor kappa- light-
chain-enhancer of activated B cells (NF-kB) NF-kB is a
ubiquitous DNA transcription factor that “governs” the Phase I
cellular stress response, implying cytokine production and cell
Citation: Andrei-Lucian Drăgoi. The Remarkable Effects of “ASEA redox Supplement” In A Child with Duchenne Muscular Dystrophy A Case Report2019;1(4): 11.
© All rights are reserved by Andrei-L ucian Drăgoi. Page 3 of 11
survival when exposed to free radicals, heavy metals,
ultraviolet irradiation, oxidized LDL, bacterial or viral antigens
etc. NF-κB essentially regulates the immune response to
infection: incorrect NF-κB regulation has been linked to cancer,
inflammatory and autoimmune diseases, septic shock, viral
infection and improper immune development.
A secondary introduction to the (erythroid-derived 2)-like 2
nuclear factor (NRF2) NRF2 is a ubiquitous DNA
transcription factor (usually activated after NF-kB activation)
which “governs” the Phase II cellular stress response, so that
NRF2 activation can induce an over-expression of more than
150 genes (which are all involved in the Phase II cellular stress
response), many of these genes encoding antioxidant
proteins/enzymes (like superoxide dismutase [SOD],
glutathione peroxidases [GPx], catalases etc) and tissular
lipases (which supply higher amounts of fatty acids as “fuels”
for cell repairing) that protect cells against oxidative damage
triggered by injury and inflammation.
The demonstrated biological activity of ARS ARS was tested
in vitro and in vivo on animals and humans too. In vitro studies
on various human cells showed that ARS is a very potent (but
transient) selective NRF2 activator (by increasing 5 to 8 times
the cytoplasmatic concentrations of SOD and GPx, even at low
ARS in vitro concentrations), avoiding the activation of NF-kb
(thus having interesting favorable immunomodulating
properties) [4]: the studies conducted in vivo (on both animals
and humans) also support this main pharmacological mechanism
of ARS, with no toxicity (as previously presented) up to high
doses (calculated per kilogram of body mass) and a satisfactory
bioavailability (which assures the strong effect demonstrated in
vivo); all studies on ARS until present are briefly presented in
one official brochure published by ASEA LLC on its official
website [8]. ARS oral consumption was already demonstrated in
vivo to over-express by 20-30% five protein-coding genes
(Potassium Channel Tetramerization Domain Containing 12 gene
[KCTD12], Early Growth Response 1 gene [EGR1], Pyridine
Nucleotide-Disulphide Oxidoreductase Domain 1 [PYROXD1],
Interleukin 1 Receptor Associated Kinase 3 [IRAK3], C-C Motif
Chemokine Receptor 10 [CCR10]), all implicated in various
genetic signaling pathways, including regulatory network
pathways (the inflammation pathway reduction [the NRF2
pathway], the innate immune system function pathway, vascular
integrity signaling pathways, digestive enzymes signaling
pathways and hormone modulation pathways) [9]. As NRF2 is
ubiquitously expressed with the highest concentrations in the
cytoplasm of cells from the vital organs (in descending order of
NRF2 cytoplasmic concentrations: kidneys, muscles, lungs,
heart, liver and brain), it is expected that ARS to mainly protect
human vital organs (with the additional argument that these vital
organs have the largest blood supply, which is directly
proportional with the concentration that ARS may reach in these
vital organs). ARS was also shown to induce apoptosis in
cultures of dysfunctional, stressed or damaged cells [4].
Additionally, ARS activates human tissular lipases (most
1For more information and verifications, the page dedicated to the (redox) science behind ARS can be accessed at this URL:
aseaglobal.com/science/ (see all the sections from the “Science” meniu tab)
2One of the main ASEA patents (patent no. 8367120) can be accessed at this URL: www.patentgenius.com/patent/8367120.html
3The ARS certificate of safety for oral consuming can be accessed at this URL (saved by A. L. Drăgoi in 2016 in his personal
database and stored on his personal domain dragoii.com, as this certificate isn’t publicly accessible in the present on ASEA LLC
company official site): asea.dragoii.com/ASEA_certificate_of_safety_for_human_consumption.jpg. The other documentation
demonstrating ARS oral consumption safety can be also accessed on ASEA LLC official website or on www.dragoii.com at
URLs:
(1)
asea.dragoii.com/Asea_Safety_Studies_from_2002_to_2006_Collection_brochure.pdf (a list of endotoxicity and
cytotoxicity studies abstracts,a list which is not accessible from ASEA LLC official website in the present); (2)
mediafilelibrary.myasealive.com/src/media/xmfl/file/ASEA%20REDOX%20Safety%20&%20Classification%20Summary.pdf
(alternative source URL: asea.dragoii.com/Asea_Safety_Classification_Summary_brochure.pdf)
4For more information and verifications, the official website of BioAgilytix Labs can be accessed at this URL:
www.bioagilytix.com
5ARS redox certification by BioAgilytix Labs has a dedicated page on ASEA LLC official website that can be accessed at this
URL: aseaglobal.com/science/bioagilytix-redoxcertified/
6For more information and verifications, the official list of all the dietary supplements approved in EU can be accessed at this
URL (for ARS entry, see page 842 of the linked pdf list):
asea.dragoii.com/ASEA_Registration_In_UE_NUT1936_see_pag_842.pdf
7For more information and verifications, the official list of all the dietary supplements approved in Italy can be accessed at this
URL (for ARS entry, see page 149 of the linked pdf list):
asea.dragoii.com/ASEA_Registration_In_Italy_No54229_see_pag_149_.pdf
Citation: Andrei-Lucian Drăgoi. The Remarkable Effects of “ASEA redox Supplement” In A Child with Duchenne Muscular Dystrophy A Case Report2019;1(4): 11.
© All rights are reserved by Andrei-L ucian Drăgoi. Page 4 of 11
probably via NRF2 pathway) and significantly increases the
fatty acids serum levels that are further internalized by skeletal
muscles and myocardium and used as “fuels” by myocytes and
cardiomyocytes, partially sparing the glycogen reserves of
myocytes/cardiomyocytes and so raising the resistance of
skeletal muscles to effort and possibly the resistance and
contractility myocardium: see prof. D.C. Nieman’s first
metabolomics study on ARS [10]. Based on this first
metabolomics study on ARS (and its encouraging results)
conducted by prof. D.C. Nieman, the University of North
Carolina (Chapel Hill) also started a second trial on ARS called
Effect of ASEA on Energy Expenditure and Fat Oxidation in
Humans [11] with results summarized in ARS “all main
studies” brochure at page 2, in a rubric entitled “Influence of
ASEA redox supplement ingestion on oxidative stress [12].
Given its antidoping certification [13], ARS is also widely used
in the present by various athletes around the world [14]. ARS
can be thus considered a potentially valuable nutrigenomic
treatment resource which deserves extended studies on
progressively larger cohorts. There are many known natural
molecules (especially flavonoids) and plant extracts that were
demonstrated to be natural NRF2 activators in vitro and/or in
vivo: sulforaphane, resveratrol, quercetin, curcumin, Ginkgo
biloba plant extract, ginseng plant extract, catechins etc. There
are also some synthetic NRF2 activators like: dimethyl
fumarate, monomethyl fumarate, metformin etc. However, all
these molecules have demonstrated tissular toxicity (especially
liver toxicity) at high doses, in high contrast with ARS which
was demonstrated to have an excellent safety profile (as
previously presented in this paper). Caloric restriction (which
was demonstrated to prolong life span in humans and animals)
was also demonstrated to also imply a significant NRF2
activation effect (due to induced oxidative stress in caloric
restricted cells): physical exercise has a similar activation
effect on NRF2 by (“naturally”) producing a large palette of
reactive oxygen species (ROS) which ROS (in some specific
amounts) were proved to be essential to muscle fibers survival
and development, by activating the endogenous antioxidant
enzymes via NRF2 pathway (inversely explaining the high
health risks of sedentary).
The main scope of this case report study is to emphasize the
multiple advantages that ARS has over corticosteroids and the
potential or ARS (if extensively studied in the future) to fully
replace corticosteroids in children with DMD, given the
remarkable (and very promising) biological effects of ARS in
this Romanian boy with DMD and also given the absence of
ARS adverse reactions until present.
Other authors have also focused on the importance of NRF2
pathway activation in the treatment of DMD (5, 6, 7, 8, 9).
The Detailed Description of this DMD Case Report
The first consult of the DMD boy in my pediatric
office (from January 11th 2018, at 2 years and 8
months of age). The DMD diagnosed boy first came to my
pediatric office for consult on January 11th 2018 when he was
aged approximately 2 years and 8 months. Anamnesis
(including familial history). When he was ~1-year-old (in the
summer of year 2016), the boy had a high fever episode and he
was suspected for high risk bacterial infection, so that he was
hospitalized in “Victor Gomoiu” Children Hospital from
Bucharest where he received a short cure (7 days) with
antibiotics for urinary tract infection (UTI) with urine culture
positive for Escherichia coli(with a slight enlargement of the
left kidney, but no other abnormalities on the abdominal
ultrasound): with that hospitalization, the boy was discovered
to have high serum levels of AST,
8This brochure can be accessed using these URLs:
(1)
mediafilelibrary.myasealive.com/src/media/xmfl/file/ASEA%20REDOX%20Scientific%20Validation%20Summary.pdf
(2)
asea.dragoii.com/ASEA_All_studies_Until_Present_Summary_Brochure.pdf
9The main results of this genetic study on ARS are briefly presented in a brochure that can be accessed at these URLs:
(1)
aseascience.com/asea-science/initial-gene-study-showed-asea-redox-affected-important-signaling-pathway-genes/
(2)
mediafilelibrary.myasealive.com/src/media/xmfl/file/ASEA%20REDOX%20Gene%20Study%20Summary.pdf
(3)
asea.dragoii.com/ASEA_First_Gene_Study_Summary_brochure.pdf
10The results of this study are contained in a pdf brochure (Microsoft PowerPoint Presentation) can be freely accessed using this
URL (recovered and available on dragoii.com domain): asea.dragoii.com/ASEA_Prof_Nieman_Metabolomics_study_results.pdf
11The details of this trial study can be accessed at this URL: clinicaltrials.gov/ct2/show/record/NCT01884727
12This ARS “all main studies” pdf brochure can be accessed at these URLs:
(1)
mediafilelibrary.myasealive.com/src/media/xmfl/file/ASEA%20REDOX%20Scientific%20Validation%20Summary.pdf
(official URL)
Citation: Andrei-Lucian Drăgoi. The Remarkable Effects of “ASEA redox Supplement” In A Child with Duchenne Muscular Dystrophy A Case Report2019;1(4): 11.
© All rights are reserved by Andrei-L ucian Drăgoi. Page 5 of 11
the boy was redirected to the children neurology ward of
“Alexandru Obregia” Hospital from Bucharest, for further
investigations and diagnosis: the DNA testing (ready on
September 12th 2016) of both the child and the mother showed
the same mutation in the 52nd exon of dys-gene (a duplication
of its 7547th nucleotide) which very probable implies a
premature interruption of dys-gene reading from exon 53 to its
last exon 79. Based on this genetic result, the boy was then
diagnosed by the neurologist with “oligosymptomatic
progressive muscular dystrophy” and was recommended
physical therapy and periodic control (at every 6 months) in the
children neurology ward (but with no reassessment of the
muscle damage biological markers at that time). The mother
also gave information about her brother (the maternal uncle of
her boy) who “couldn’t walk and was immobilized to bed from
~7 years of age until his death at ~18 years of age”, which is
very suggestive for a DMD phenotype, thus for positive history
of familial DMD (but the boy’s mother couldn’t show any
medical documents of her brother and his diagnosis). As
expected, the dys-mutation-carrier mother has no biological or
clinical signs of muscle damage (including no biological
markers of heart muscle damage and normal
electrocardiography (ECG). The parents were told by the
neurologist to wait until the boy will be 4-year-old, for him to
start a cure with prednisone P.O, to delay the progress of the
disease: this (quite long) prednisone P.O, temporization
(decided by the neurologist) and the symptoms/signs of the boy
at that time (impaired extension of the right limb when walking
and running plus calves enlargement) worried parents and these
were the main reason which determined the parents to ask a
second medical opinion from me, as an MD pediatrician
specialist.
Physical examination. The main clinical signs found were:
impaired extension of the right limb (when walking), calves
pseudo hypertrophy (with 23/23 cm maximum circumference
of both calves), slight tonus deficit of the axial/spinal muscles,
extreme anxiety at the physical exam, hyperkinetic child,
moderate language delay (he only used ~20 correctly
pronounced words at that age and only used pairs of words, but
rarely sentences with verbs). The rest of the physical (including
neurological) examination results were normal: cranial nerves
tests in normal limits, normal breath rate and normal
pulmonary sounds, normal heart rate (with no heart murmurs),
normal abdomen (without clinically detectable
hepato/splenomegaly), but with increased consistency stools
(with defective discomfort), normal diuresis and urination
(with no kidney pain/sensibility), normal genital apparatus.
Body mass: 14 kg (Age: 2y8m) (in the normal range for sex
and age). Body height: 91 cm (Age: 2y8m) (in the normal
range for sex and age). Based on diagnosis, anamnesis and
physical examination (previously presented), I have requested
some basic imaging and laboratory exams (see next).
Medical imaging exams of the DMD boy (in
chronological order): see next. Heart ultrasound
(January 28th 2018): echographically normal (with the
reserve that the child was very anxious and hyperkinetic during
this examination). Abdominal ultrasound (*April 10th 2018;
*parents delayed this exam because of objective reasons):
minimal hepatomegaly; all the other examined organs were
echographically normal (with the reserve that the child was
very anxious and hyperkinetic during this examination).
Laboratory exams (rhabdomyolysis and inflammatory markers
serum levels) of the DMD boy (in chronological order: blood
probes taken on January 16th 2018 and January 22nd 2018): see
next. Gamma-glutamyl-transferase (GGT) (GGT was
periodically used as a liver toxicity marker): 10 U/ml (within
the normal range [wnr]); AST serum level: 473 U/L (~10 times
the normal superior limit [nsl] [~10 x nsl]; of muscle origin,
given the GGT wnr); ALT serum level: 558 U/L (~17 x nsl; of
muscle origin, given GGT wnr); CK: 34 453 U/L (~200 x nsl;
of muscle origin, given the GGT wnr); CK-MB: 1241 U/L
(~52 x nsl; myocardial origin). MG (22.01.2018): 2006 ng/mL
(~28 x nsl; of muscle [including myocardial] origin) (the MG
serum level was chosen, because the child didn’t want to
cooperate for determining the urinary concentration of MG by
urine sampling). C-reactive protein (CRP) serum level
(22.01.2018): 0.61 mg/L (wnr). Erythrocyte sedimentation rate
(ESR) (22.01.2018): 9 mm/h (wnr).
Treatment (from ~ January 22nd 2018) Given all the
DMD patient information previously given (plus the
argumentative notes on giving ARS orally to a child under 12
years of age), I have decided to give the following
recommendations (including medical treatment): ARS
solution, P.O. 30+30+0 ml/day (~4 ml/body_kg/day) (started
from ~22.01.2018); L- carnitine oral solution (in concentration
1g/10 ml, 10 ml vials), P.O. 0+½+0 vials/day (500 mg/day ~
36 mg/body_kg/day) (after lunch, with fruit juice) (also started
from ~22.01.2018).
(2)
asea.dragoii.com/ASEA_All_studies_Until_Present_Summary_Brochure.pdf (alternative URL)
13The antidoping certificate of ARS can be accessed at this URL (as recovered on author’s dragoii.com personal site):
asea.dragoii.com/ASEA_antidoping_certificate.pdf
14The site of ASEA LLC dedicated to the most known athletes around the world consuming ARS can be accessed at this URL:
aseaathletes.co
Citation: Andrei-Lucian Drăgoi. The Remarkable Effects of “ASEA redox Supplement” In A Child with Duchenne Muscular Dystrophy A Case Report2019;1(4): 11.
© All rights are reserved by Andrei-L ucian Drăgoi. Page 6 of 11
Important argumentative note on L-carnitine
prescription L-carnitine acts as a transporter of long-chain
fatty acids into the mitochondria (where to be oxidized for
energy production): given the anticipated high serum levels of
fatty acids produced by ARS (as previously mentioned by
citing the metabolomics study conducted by prof. D. C.
Nieman on ARS), I have used L-carnitine as an adjuvant for
ARS. I have also included omega-3 fatty acids plus
multivitamins oral supplement as syrup (conc. ~8 mg DHA/ml,
1.8 mg EPA/ml; also containing vitamins A, D, C, E, B1
(thiamine), B2 (riboflavin), B6, B12 (cobalamin), niacin
[vitamin B3], pantothenic acid [vitamin B5], biotin [vitamin
B7]) (started from 22.01.2018) 1.5+1.5+1.5 ml/day (4.5 ml/day
in total).
Important argumentative note on omega-3 plus
vitamins prescription. I have chosen this DHA-EPA-
multivitamin mix especially for the boy’s language delay: I
have chosen however a very small dose (4.5ml/day) given the
age and the possibility that the multivitamin (antioxidant) mix
may inhibit ARS effect (by partially/totally neutralizing the
free radicals from the ARS solution already absorbed in the
blood). I have also (re)prescribed physical therapy (reinforcing
the same recommendation given by the neurologist, as
previously mentioned): however, the parents weren’t compliant
to this recommendation, with their argument that the boy “is
already very active and full of energy”. I have also prescribed a
psychological consult: the parents weren’t compliant to this
recommendation either, because of some prejudices on this
kind of consult, as they consider their boy psychologically
“normal”.
Important note (interpretation) Given the small age of the
boy, the small number of signs/symptoms up to present, the
fact that there is no “cut-off” exon number for a dys-gene
mutation to exactly predict when an affected boy will develop a
DMD phenotype and when he will develop a milder BMD
phenotype, the diagnosis of DMD isn’t 100% sure yet:
however, the severe form of MD of his maternal uncle (with
loss of walking from 7 years of age until his death at 18 years
of age) indicates this boy’s duplication of the 7547th nucleotide
(from 52nd exon of dys-gene, which is probably shared with his
maternal uncle and surely inherited from his maternal
grandmother [also mother of his maternal uncle]) will more
probably generate a DMD phenotype: additionally, there is a
study in which a targeted disruption of exon-52 in the mouse
dys-gene had induced muscle degeneration similar to that
observed in DMD [10]. The extremely (initial) high CK and
CK- MB serum levels also indicate/suggest a DMD phenotype
found in a clinically oligosymptomatic initial stage. That is
why we have decided to start an aggressive therapy with ARS
at least one year before the age of 4 years (when he was
temporized to begin a corticosteroid treatment or other
treatment like ataluren or even experimental treatments with
AONs or stem cell [pericytes] replacement therapy).
All the pediatric consults (including this previously described
initial pediatric consult given to this boy with DMD), imaging
and labs were condensed in the next
(Table 1: https://biomedress.com/pdf/CJBRT-19-04-018-
01.pdf);the significant decrease of all the rhabdomyolysis
markers (in the period in which this boy with DMD received
ARS P.O.) was also quantized in the next figures.
Figure 1a: The significant global decrease of all the
rhabdomyolysis markers serum levels (expressed
adimensionally, as multiples of their normal superior limits), in
the period in which this boy with DMD received ARS P.O
Figure 1b: The significant global decrease of some
rhabdomyolysis markers (CK, CK-MB and MG) serum levels
plus GGT serum level showing no liver toxicity (expressed
adimensionally, as multiples of their normal superior limits), in
the period in which this boy with DMD received ARS P.O.
0
50
100
150
200
Jan-18
Feb-18
Mar-18
Apr-18
May-18
Jun-18
Jul-18
Aug-18
Sep-18
Oct-18
Nov-18
Dec-18
Jan-19
Feb-19
Mar-19
Apr-19
May-19
GGT
CK
CK-MB
MG
Citation: Andrei-Lucian Drăgoi. The Remarkable Effects of “ASEA redox Supplement” In A Child with Duchenne Muscular Dystrophy A Case Report2019;1(4): 11.
© All rights are reserved by Andrei-L ucian Drăgoi. Page 7 of 11
Figure 1c: The significant global decrease of some
rhabdomyolysis markers (AST, ALT and MG) serum levels
plus GGT serum level showing no liver toxicity (expressed
adimensionally, as multiples of their normal superior limits), in
the period in which this boy with DMD received ARS P.O.
Results and Interpretations
a. At my request, the parents send some movies (filmed with
a phone in mp4 format) with their boy climbing stairs,
walking and running; short selected sequences from these
movies (so that the face of the child to not be visible
frontally) were uploaded on author’s personal site
(www.dragoii.com) and are available at the following
URLs:
i. www.dragoii.com/ARSinDMD_HighStairStepsClimb_
6sec.mp4 (the boy climbing stairs with high steps 6
seconds movie selection)
ii. www.dragoii.com/ARSinDMD_LowStairStepsClimb_
9sec.mp4(the boy climbing stairs with low steps 9
seconds movie selection)
iii. www.dragoii.com/ARSinDMD_HorizontalWalk_4sec.
mp4 (the boy walking on a horizontal plane - 4 seconds
movie selection)
iv. www.dragoii.com/ARSinDMD_HorizontalRunning_4s
ec.mp4 (the boy running on a horizontal plane - 4
seconds movie selection)
b. The ARS-based treatment in the last ~1.5 years,from
22.01.2018 up to 29.05.2019(with ARS P.O. 60 ml/day [~4
ml/body_kg/day]inthefirst~3months, then90ml/day[~6-
6.5ml/body-kg/day]from18.04.2018until17.12.2018, then
100ml/day[~7ml/body-kg/day]from18.12.2018until
29.05.2019)was associated with a slightALT serum level
total increase of~22% (despite a significant decrease of
ALT serum levels from ~17 nsl on January 2018 to 14 nsl
on December 2018), an AST serum level total decrease
of~22% (with normal GGT serum levels in all this ~1.5
years interval, thus no detectable liver toxicity of ARS), a
marked CK serum level total decrease of ~46%, a very
significant CK-MB serum level decrease of ~61% and a
quite spectacular MG serum level total decrease of ~86%
(with CK, CK-MB and MG being actually the main target
of my ARS recommendation and which may be explained
by the fact that ARS has stronger NRF2 activation effect
on the myocardium, where the expression of NRF2 is
larger than in skeletal muscles, an additional indirect subtle
potential “proof” that ARS acts via NRF2 pathway). This
results suggest that ARS may have very potent muscular
(including myocardial) protective effects, significantly
limiting the muscular damage in DMD patients, with the
potential of even stronger effects in (milder) BMD
phenotypes: this comes in the “same pack” with no liver
toxicity, no adverse effect on growth and development of
the child and no other adverse effects in other clinical
spheres until the present. The slight increase of AST, ALT,
CK and CK-MB in the last year (from July 2018 until
present, as seen in the previous graphics, but only a small
increase when compared to the significant drop of these
rhabdomyolysis markers in the first ~6 months of ARS)
has many possible explanations: (i) it is plausible that ARS
dosage of 4-7 ml/body-kg/day to have progressively
generated a phenomenon of ARS-resistance in myocytes
(which is possible, as in the case of many other
pharmacological agents): however, the spectacular drop of
MG serum levels (which continued to decrease despite the
slight increase of all the other markers in the last ~1 year)
appears to contradict this hypothesis (because MG is the
most specific muscular marker, with the highest eloquence
in this set of markers); (ii) At doses of 4-7 ml/body-
kg/day, it’s also possible that ARS may sustain the
myocytes (including cardiomyocytes) and keep them
functional, but at their “limits” of survival, so that
myocytesmay continue to lose CK, CK-MB, AST and
ALT through their celular membranes, but without
apoptosis and thus keeping MG in the intracellular
medium; (iii) There’s also the possibility that ARS may
accelerate the clearance of red blood cells (RBCs) (and
their rate of renewal implicitly) so that AST and ALT may
(at least) partially be produced by this higher rate of RBCs
replacement; (iv) it is also possible that ARS to have
produced a greater number of young myocytes (including
cardiomyocytes) (by some ARS-specific mechanisms, that
are detailed in the next paragraphs), which myocytes may
still lose CK, CK-MB, AST and ALT (through their
celular membranes) but maintain their viability so that not
to lose MG too; (iv) the muscular mass of this DMD boy
has surely increased in the last 1.5 years and the present
ARS doses may not be adequate anymore (for this
increased muscular mass) so that larger doses up to 10
ml/body-kg/day (and even higher) may be needed in the
future (doses which may however exceed the financial
possibilities of the family and this may also be a problem
in the future, especially if ataluren won’t show any clinical
and paraclinical benefits); (v) the slight increase of CK,
CK-MB, AST and ALT in the last ~1 year also superposed
to the temporary removal of L-carnitine and omega-3 plus
multivitamin supplements (because we had the suspicion
that A, D and E vitamins may have generated that
hyperechogenicity of the liver and its moderately
increased dimensions as shown by the abdominal
ultrasound from December 2018): this may indicate that
omega-3, multivitamins and L-carnitine may yet have a
synergic effect with ARS and may help ARS in decreasing
the global rhabdomyolysis rate of this boy affected by
DMD; however, the normalization of the abdominal
ultrasound from June 2019 indicates that L-carnitine
and/or omega-3 plus multivitamins may have exposed the
liver to a (obviously reversible) pharmacological stress,
which suggests that L-carnitine and omega-3 plus
multivitamins may be reintroduced (given their possible
beneficial synergic effects with ARS), but in shorter cures
of 1-2 months (given their possible hepatotoxicity when
given in cures of 3 to 6 months);
c. The significant decrease of both CK and CK-MB serum
levels may be explained by a (significant) decrease of the
Citation: Andrei-Lucian Drăgoi. The Remarkable Effects of “ASEA redox Supplement” In A Child with Duchenne Muscular Dystrophy A Case Report2019;1(4): 11.
© All rights are reserved by Andrei-L ucian Drăgoi. Page 8 of 11
oxidative stress in DMD myocytes, a decrease produced by
ARS via NRF2 pathway (and more pronounced in the
myocardium). Similarly to steroids, it is not excluded that
ARS may also induce additional over expression of UTRN
gene and utrophin synthesis subsequently [11]. ARS may
act on UTRN gene via NRF2 pathway or, more probably
(and also by NRF2-pathway), by upregulating sarcospan
(SSPN) (a 25-kDa transmembrane protein located in the
dystrophin-associated protein complex of skeletal muscle
cells; SSPN depends on dys for its proper transmembrane
localization). SSPN up regulates the levels of Utrophin-
glycoprotein complex (UGC) to compensate dys loss in the
neuromuscular junction of DMD patients [12,13]: utrophin
expression is extremely increased in DMD patients (and
also female carriers) as a compensatory mechanism, both
in dys- lacking muscle fibers and in rare (revertant) fibers
that express dys, as a small proportion of muscle fibers of
DMD patients continue to show strong dys staining (and
these "revertant fibers" are thought to arise by a
mechanism that restores the reading frame [14,15].
Normally, SSPN upregulates both UGC and Dystrophin-
associated Glycoprotein Complex (DGC), which DGC has
the very important role to form a critical link between the
(intracellular) cytoskeleton and the extracellular matrix.
SSPN regulates the amount of utrophin produced by the
UGC to restore laminin binding due to dys absence or
inefficiency (of too-short dys isoforms from DMD
phenotypes): if laminin binding is not restored by SSPN,
the cell membrane diminishes its surface and its adherence
to the extracellular matrix. In dystrophic mdx mice (mice
with various artificially induced point mutations in their
dys-gene [producing early artificial STOP codons in the
dys-gene, which will produce various small non-functional
dys variants], used as an experimental model to study
DMD), SSPN increases levels of utrophin (by inducing
UTRN gene over expression) and restores the levels of
laminin binding, reducing the symptoms of DMD. SSPN is
also an essential regulator of Akt/PKB signaling pathway
(a signal transduction pathway with protein kinase B [Akt]
and phosphatidylinositol 3-kinase [PI3K] as key-
components, a pathway that promotes survival and growth
in response to extracellular signals): this signaling pathway
will be hindered and muscle regeneration will not occur in
the absence of SSPN.
d. There is also a small probability for ARS to modify the
sensibility of ribosomal protein synthesis (translation) to
stop codons, so that ARS may also induce other DMD
isoforms (based on the skipping of reading stop codons)
like ataluren is hypothesized to act.
e. It is not excluded that ARS may also (directly or
indirectly) partially restore the reading frame of dys- gene
and so to increase the percent of "revertant fibers" in DMD
patients: only an immunohistological study on a DMD
child (or adult) treated with ARS could confirm or infirm
such a hypothesis.
Discussions
a. This specific DMD case (treated with ARS P.O.) may
inspire new possible future studies based on ARS. Given
its clinical and biological effects in this DMD child case
and its “prototype” selective NRF2 activator features,
ARS and all the other known NRF2 activators may be
tested in DMD and BMD patients (in future blinded [b]
randomized controlled trials [bRCTs]). RCTs on NRF2
activators versus steroids in DMD/BMD cases (started
before OR after 4 years of age) may also be conducted.
DMD patients treated with ARS can be verified for UTRN
gene over expression and utrophin high cellular levels.
MD patients treated with ARS can also be verified for
intracellular existence of DMD isoforms other the DMD
pathological isoform expected in the specific exon-52
mutation (or other dys-exons mutations) of each DMD
patient in part. Immunohistological studies can also
demonstrate various muscular effects of ARS, to check if
ARS actually increases the percent of "revertant fibers" in
DMD patients.
b. Only 4-5% of DMD patients have exon-52 dys mutations
[16], so that ARS may have a great potential to be tested
in all types of mutations on all dys-gene exons, including
in the patients with milder BMD phenotype.ARS may be
an important potential tool to test for and combat cellular
oxidative stress in vital organs (where NRF2 reaches its
highest concentrations) and muscles (including the heart
muscle, of course) in a large spectrum of acute and
chronic adult and child diseases: myocardial infarction,
stroke, chronic liver disease, chronic kidney disease,
cancers (including protective effects for healthy cells in
various [highly toxic] chemotherapy regimens) etc.
c. Given the estimated DMD prevalence worldwide
(4.78/100 000 males), the estimated BMD prevalence
worldwide (1.53/100 000 males) [17] and the present
human population on Earth (~7.7*109 persons, from which
~50%~3.85*109 males, according to April 2019 real-time
statistics15), we predict ~242 935 cases worldwide of
DMD and BMD together. Extrapolating the estimated
average frequency of DMD (1/3600 male births) and the
estimated minimum frequency of BMD (1.5/100 000 male
births) to the global human birth rate on Earth of 386 000
births/day (from which ~50% are male births, according to
the last estimation from 2015 16), we estimate that ~57
new cases (of DMD and BMD together) appear every day
on Earth (corresponding to ~20625 new “DMD+BMD”
cases per year). ARS may thus have significant potential
in helping in all these old and new cases. Given its
extrapolated strong antioxidant effect in other child/adult
high-oxidative stress acute and chronic diseases (as
previously discussed), ARS may help millions and even
billions worldwide.
d. Corticosteroids were proven to ameliorate both the motor
and intellectual functions in children with DMD, but with
modest decrease of the rhabdomyolysis markers (and even
increasing the CK serum level in some studies, without a
clear explanation yet) and with a very large palette of side
effects on children with DMD (treated with
corticosteroids) [18-20]: in contrast, we have
Citation: Andrei-Lucian Drăgoi. The Remarkable Effects of “ASEA redox Supplement” In A Child with Duchenne Muscular Dystrophy A Case Report2019;1(4): 11.
© All rights are reserved by Andrei-L ucian Drăgoi. Page 9 of 11
demonstrated (at least in this presented case) that ARS
P.O. at doses 4-6.5 ml/body kg/day has the same
ameliorative effects (as corticoids have) plus significant
reductions of rhabdomyolysis markers plus no
demonstrated side effect after ~1 year of treatment with
ARS.
e. This boy has the right to receive ataluren starting from the
age of 5 (because the Romanian law doesn’t allow yet the
initiation of ataluren earlier than this age, but supports the
expenses in DMD boys with non-sense mutations after this
age): we predict that ARS may act synergically with
ataluren either by producing even more revertant
muscular fibers or by significantly diminishing the
oxidative stress in myocytes (by producing longer/heavier
dys isoforms together with protecting myocytes from
oxidative stress and intracellular irreversible damage
implicitly). ARS generally increases the capacity of animal
cells to defend from various toxic agents (including
pharmacological agents), that is why ARS has also the
potential to decrease the rate of adverse effects of ataluren
(especially nausea and vomiting).
Conclusions
a. ARS has remarkable antioxidant and immunomodulatory
effects and should be studied on larger groups of children
with DMD under the age of 4 years old (but also on other
age groups of children and even young adults), as an
alternative to early corticosteroids.
b. Given its immunomodulatory effect (NRF2 selective
activation and NF-kB inhibition), ARS deserves future
cohort studies on its potential to replace corticosteroids and
other non-steroidal immunosuppressants (at least partially)
in many types of pulmonary/renal/hepatic/ articular/skin
autoimmune autoimmune and even malignant diseases of
both children and adults;
c. Given its very strong antioxidant effects (by highly
selective NRF2 potent activation), ARS deserves future
cohort studies on acute/chronic diseases that imply high
levels of tissular oxidative stress, especially some
acute/chronic cardiovascular and respiratory diseases like
acute myocardial infarction with acute/chronic heart
failure, stroke, Chronic Obstructive Pulmonary Disease
(COPD), asthmaetc. of both children and adults (so that
ARS may help millions and even billions worldwide).
Acknowledgments
a. Funding: All the pediatric consults given to this child
were supported by the National Health System (based on
articles no. 34 and no. 49 of the Romanian Constitution
and also based on our contract as a pediatric cabinet with
the Romanian National Health Insurances System
(RNHIS); however, all the expenses with ARS, L-carnitine
and omega-3 fatty acids (plus vitamins) were supported by
the parents of the child, because these substances are not
supported by the RNHIS; a part of the rhabdomyolysis
markers (which were sampled periodically, but not
supported by RNHIS) were also paid by the parents;
b. Author contributions: The conceptualization, data
curation, formal analysis, investigation, methodology,
project administration, software (used for keeping the
evidence of all patients, including this boy), supervision,
validation, visualization, writing (the original draft plus
review & editing) were all done by dr. Andrei-Lucian
Drăgoi, the single author of this article. Funding
acquisition and resources were mainly supported by the
parents of this boy and secondarily supported by RNHIS;
we have also obtained the oral consent of both parents to
publish this medical case in both English and Romanian,
with the only condition to not mention the names of the
boy, parents or other relatives;
c. Competing interests: the author of this paper was
invited a couple of times to present ARS and his clinical
experience with ARS, but with no financial remuneration
and no competing interests.
d. Data and materials availability: we have initially
published this case report as a simple preprint (DOI:
10.13140/rg.2.2.21420.36486) entitled “(ASEA in DMD -
version 1.1 - 1.08.2018 - 13 pages) The remarkable
clinical and biological effects of ASEA ionized water
/"redox supplement" (co- administered with L-carnitine
and omega-3 fatty acids plus multivitamins dietary
supplements) in a ~3-year- old boy with Duchenne
muscular dystrophy (DMD) from Romania - a case report”
on: Research Gate platform (see URL:
www.researchgate.net/publication/325371161),
Academia.edu platform (see URL:
www.academia.edu/36909338), Vixra platform (see URL:
http://rxiv.org/abs/1806.0354) and GSJournal platform
(see URL: http://gsjournal.net/Science-
Journals/Research%20Papers/View/7338); we have also
created a simple webpage about ARS (asea.dragoii.com),
in the purpose of extensively informing the parents of
children-patients on ARS, when we have recommended
ARS to specific patients; this preprint was also taken over
by other platforms like:Data city(see Url:
https://search.datacite.org/works/10.13140/rg.2.2.21420.3
6486). This present article is an updated and revised
version of that initial preprint: a great part of that preprint
was rewritten for this paper. All data is available in the
main text of this present article.
References
1. Katharine Bushby, Richard Finkel, David J Birnkrant,
Laura E Case, Paula R Clemens, et al. (2010) Diagnosis
and management of Duchenne muscular dystrophy, part 1:
diagnosis, and pharmacological and psychosocial
management. The Lancet Neurology 9(1): 77-93.
2. Maggie C Walter, Peter Reilich (2017) Recent
developments in Duchenne muscular dystrophy: facts and
numbers. J Cachexia Sarcopenia Muscle 8(5): 681-685.
3. Aldona L Baltch, Raymond P Smith, Mary A Franke,
William J Ritz, Phyllis Michelsen, et al. (2000)
Microbicidal activity of MDI-P against Candida albicans,
Citation: Andrei-Lucian Drăgoi. The Remarkable Effects of “ASEA redox Supplement” In A Child with Duchenne Muscular Dystrophy A Case Report2019;1(4): 11.
© All rights are reserved by Andrei-L ucian Drăgoi. Page 10 of 11
Staphylococcus aureus, Pseudomonas aeruginosa and
Legionella pneumophila. American Journal of Infection
Control 28(3): 251-257.
4. Gary L Samuelson (2010) White paper on in-vitro
bioactivity of ASEA™ related to toxicity, glutathione
peroxidase, superoxide dismutase efficacy and related
transcription factors. (a preprint with 28 [A4] pages written
and disseminated online by PhD Gary L. Samuelson as an
“independent science advisor”).
5. Sara Petrillo, Pelosi L, Piemonte F, Travaglini L, Forcina L,
et al. (2017) Oxidative stress in Duchenne muscular
dystrophy: Focus on the NRF2 redox pathway. Human
Molecular Genetics 26(14): 2781-2790.
6. HG Radley, A De Luca, GS Lynch, Miranda D Grounds
(2007) Duchenne muscular dystrophy: focus on
pharmaceutical and nutritional interventions. The
International Journal of Biochemistry & Cell Biology 39(3):
469-477.
7. Jessica Terrill, Hannah G Radley-Crabb, Tomohito Iwasaki,
Frances Lemckert, et al. (2013) Oxidative stress and
pathology in muscular dystrophies: focus on protein thiol
oxidation and dysferlinopathies. FEBS Journal 280(17):
4149-4164.
8. Cheng-Cao Sun, Jing-Yu Pan, Shu-Jun Li, De-Jia Li (2015)
The role of sulforaphane on Duchenne muscular dystrophy
by activation of Nrf2. International Journal of
Inflammation, Cancer and Integrative Therapy (previously
known as “Interdisciplinary Journal of Microinflammation
3(1).
9. Vinod Malik, Louise Rodino-Klapac, Jerry R Mendell
(2012) Emerging drugs for Duchenne muscular dystrophy.
Expert Opinion on Emerging Drugs 17 (2): 261-277.
10. E Araki, Nakamura K, Nakao K, Kameya S, Kobayashi O,
et al. (1997) Targeted disruption of exon 52 in the mouse
dystrophin gene induced muscle degeneration similar to that
observed in Duchenne muscular dystrophy. Biochemical
and Biophysical Research Communications 238(2): 492-
497.
11. A Clerk, Morris GE, Dubowitz V, Davies KE, Sewry CA
(1993) Dystrophin-related protein, utrophin, in normal and
dystrophic human fetal skeletal muscle. The Histochemical
Journal 25(8): 554-561.
12. JL Marshall, E Chou, J Oh, A Kwok, DJ Burkin, et al.
(2012) Dystrophin and utrophin expression require
sarcospan: loss of α7 integrin exacerbates a newly
discovered muscle phenotype in sarcospan-null mice.
Human Molecular Genetics 21(20): 4378-4393.
13. AK Peter, JL Marshall, RH Crosbie (2008) Sarcospan
reduces dystrophic pathology: stabilization of the utrophin-
glycoprotein complex. Journal of Cell Biology 183(3): 419-
27.
14. V Arechavala-Gomeza, Kinali M, Feng L, Guglieri M,
Edge G, et al., (2010) Revertant fibers and dystrophin
traces in Duchenne muscular dystrophy: implication for
clinical trials. Neuromuscular Disorders 20(5): 295-301.
15. L T Thanh, T M Nguyen, T R Helliwell, G E Morris
Characterization of revertant muscle fibers in Duchenne
muscular dystrophy, using exon-specific monoclonal
antibodies against dystrophin. The American Journal of
Human Genetics 56(3): 725-731.
16. CL Bladen, D Salgado, S Monges, ME Foncuberta, Kyriaki
Kekou, et al. (2015) The TREAT-NMD DMD Global
Database: analysis of more than 7,000 Duchenne muscular
dystrophy mutations. Hum Mutat 36(4): 395-402.
17. JK Mah, L Korngut, J Dykeman, L Day, T Pringsheim, et
al. (2014) A systematic review and meta‐analysis on the
epidemiology of Duchenne and Becker muscular
dystrophy. Neuromuscular Disorders 24(6): 482-491.
18. Y Sato, A Yamauchi, M Urano, E Kondo, K Saito (2014)
Corticosteroid Therapy for Duchenne Muscular Dystrophy:
Improvement of Psychomotor Function. Pediatric
Neurology 50(1): 31-37.
19. K Cxyzewski (1997) The effect of hydrocortisone on the
serum creatine kinase activity of muscle diseases. Journal
of Neurology 216(Issue 4): 283-287.
20. J Dubow, S Wanaski, T Cunniff, J Meyer (2016) Effect of
Deflazacort and Prednisone on Muscle Enzymes in the
Treatment of Duchenne Muscular Dystrophy. Neurology
86(sup 16).
15For real-time statistics on world’s human population see URL: www.worldometers.info/world-population
16See the website “Our World in Data” page at URL: https://ourworldindata.org/fertility-rate#empirical-view (subchapter “Births
and the birth rate - Births Globally”)
Citation: Andrei-Lucian Drăgoi. The Remarkable Effects of “ASEA redox Supplement” In A Child with Duchenne Muscular Dystrophy A Case Report2019;1(4): 11.
© All rights are reserved by Andrei-L ucian Drăgoi. Page 11 of 11
Assets of Publishing with us
Global archiving of articles
Immediate, unrestricted
online access Rigorous Peer
Review Process Authors
Retain Copyrights
Submission Link: https://biomedress.com/online-submission.php
https://www.biomedress.com
ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
Sulforaphane (SFN) possesses powerful chemo-preventive effects and plays a crucial role on oxidative stress and inflammatory. In our recent study, SFN treatment could relieve muscular dystrophy in mdx mice by activating Nrf2 (NF-E2 related factor 2). Moreover, our findings indicated that SFN-activated Nrf2 alleviated muscle inflammation in dystrophin-deficient mdx mice through suppressing NF-κB signaling pathway. Collectively, SFN-induced Nrf2 molecular pathway might be a promising approach for treatment of the patients with Duchenne muscular dystrophy.
Article
Full-text available
Analysing the type and frequency of patient specific mutations that give rise to Duchenne Muscular Dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning and improved clinical care. Locus specific databases (LSDBs) allow for the collection, organization, storage and analysis of genetic variants of disease. Here we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analysed genetic data for 7149 DMD mutations held within the database. 5682 large mutations were observed (80% of total mutations), of which 4894 (86%) were deletions (1 exon or larger), and 784 (14%) were duplications (1 exon or larger). There were 1445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Article
Full-text available
The muscular dystrophies comprise more than 30 different clinical disorders that are characterised by progressive skeletal muscle wasting and degeneration. Although the genetic basis for many of these disorders has been identified, the exact mechanism for pathogenesis generally remains unknown. It is considered that disturbed levels of Reactive Oxygen Species (ROS) contribute to the pathology of many muscular dystrophies. Reactive oxygen species and oxidative stress can cause cellular damage by directly and irreversibly damaging macromolecules such as proteins, membrane lipids and DNA; another major cellular consequence of ROS is the reversible modification of protein thiol side chains that can affect many aspects of molecular function. Irreversible oxidative damage of protein and lipids has been widely studied in Duchenne Muscular Dystrophy (DMD), and we have recently identified increased protein thiol oxidation in dystrophic muscles of the mdx mouse model for DMD. This review evaluates the role of elevated oxidative stress in DMD and other forms of muscular dystrophies and presents new data that show significantly increased protein thiol oxidation and high levels of lipofuscin (a measure of cumulative oxidative damage) in dysferlin-deficient muscles of A/J mice at various ages. The significance of this elevated oxidative stress and high levels of reversible thiol oxidation, yet minimal myofibre necrosis, is discussed in the context of disease mechanism for dysferlinopathies, and critically compared with the situation for dystrophin-deficient mdx mice. © 2013 The Authors Journal compilation © 2013 FEBS.
Article
Dystrophin is the product of the Duchenne muscular dystrophy (DMD) gene. Dystrophin-related protein (utrophin), an autosomal homologue of dystrophin, was studied in skeletal muscle from normal fetuses aged 9-26 weeks and one stillbirth of 41 weeks' gestation, and compared with low- and high-risk DMD fetuses aged 9-20 weeks. Utrophin was present at the sarcolemma from before 9 weeks' gestation, although there was variability in intensity both within and between myotubes. Sarcolemmal immunolabelling became more uniform, and levels of utrophin increased to a maximum at approximately 17-18 weeks. Levels then declined, until by 26 weeks sarcolemmal labelling was negligible and levels were similar to adult control muscle. By 41 weeks there was virtually no sarcolemmal labelling, although immunolabelling of capillaries was bright. Similar results were obtained with normal and DMD fetal muscle. Utrophin is therefore expressed in the presence and absence of dystrophin and down-regulated before birth in normal fetal muscle fibres. Samples were not available to determine whether or when, utrophin levels decline in DMD fetal muscle. On Western blots, utrophin was shown to have a smaller relative molecular mass than adult dystrophin, but similar to the fetal isoform. Blood vessels were brightly immunolabelled at all ages, although utrophin immunolabelling of peripheral nerves increased with gestational age.
Article
Oxidative stress is involved in the pathogenesis of Duchenne muscular dystrophy (DMD), an X-linked genetic disorder caused by mutations in the dystrophin gene and characterized by progressive, lethal muscle degeneration and chronic inflammation. In this study, we explored the expression and signaling pathway of a master player of the anti-oxidant and anti-inflammatory response, namely NRF2, in muscle biopsies of DMD patients. We classified DMD patients in two age groups (Class I, 0-2 years and Class II, 2-9 years), in order to evaluate the antioxidant pathway expression during the disease progression. We observed that altered enzymatic antioxidant responses, increased levels of oxidized glutathione and oxidative damage are differently modulated in the two age classes of patients and well correlate with the severity of pathology. Interestingly, we also observed a modulation of relevant markers of the inflammatory response, such as heme oxygenase 1 and IL-6, suggesting a link between oxidative stress and chronic inflammatory response. Of note, using a transgenic mouse model, we demonstrated that IL-6 overexpression parallels the antioxidant expression profile and the severity of dystrophic muscle observed in DMD patients. This study advances our understanding of the pathogenic mechanisms underlying DMD and defines the critical role of oxidative stress on muscle wasting with clear implications for disease pathogenesis and therapy in human.
Article
The muscular dystrophies are a broad group of hereditary muscle diseases with variable severity. Population-based prevalence estimates have been reported but pooled estimates are not available. We performed a systematic review of worldwide population-based studies reporting muscular dystrophies prevalence and/or incidence using MEDLINE and Embase databases. The search strategy included key terms related to muscular dystrophies, incidence, prevalence and epidemiology. Two reviewers independently reviewed all abstracts, full text articles and abstracted data using standardized forms. Pooling of prevalence estimates was performed using random effect models. 1104 abstracts and 167 full text articles were reviewed. Thirty-one studies met all eligibility criteria and were included in the final analysis. The studies differed widely in their approaches to case ascertainment, resulting in significant methodological heterogeneity and varied data quality. The pooled prevalence of DMD and BMD was 4.78 (95% CI 1.94-11.81) and 1.53 (95% CI 0.26-8.94) per 100,000 males respectively. The incidence of DMD ranged from 10.71 to 27.78 per 100,000. This is the first meta-analysis of worldwide prevalence estimates for muscular dystrophies. There is a need for more epidemiological studies addressing global estimates on incidence and prevalence of muscular dystrophies, utilizing standardized diagnostic criteria as well as multiple sources of case ascertainment.
Article
Of the numerous clinical trials for Duchenne muscular dystrophy, only the corticosteroid prednisolone has shown potential for temporal improvement in motor ability. In this study, the effects of prednisolone on intellectual ability are examined in 29 cases of Duchenne muscular dystrophy because little information has been reported. And also, motor functions and cardiac functions were evaluated. The treated group was administered prednisolone (0.75 mg/kg) orally on alternate days and the compared with the untreated control group. Gene mutations were investigated. The patients were examined for intelligence quotient adequate for age, brain natriuretic peptide, creatine kinase, and manual muscle testing before treatment and after the period 6 months to 2 years. Intelligence quotient scores of the treated increased to 6.5 ± 11.9 (mean ± standard deviation) were compared with the controls 2.1 ± 4.9 (P = 0.009). Intelligence quotient scores of the patients with nonsense point mutations improved significantly (21.0 ± 7.9) more than those with deletion or duplication (1.9 ± 9.0; P = 0.015). Motor function, such as time to stand up, of those treated improved significantly and brain natriuretic peptide level was reduced to a normal level after treatment in 15 patients (73%). Our results demonstrate the effectiveness of prednisolone in improving intellectual impairment as well as in preserving motor function and brain natriuretic peptide levels. We presume that prednisolone has a read-through effect on the stop codons in the central nervous systems of Duchenne muscular dystrophy because intelligence quotient of point mutation case was improved significantly.
Article
Sarcospan (SSPN) is a core component of the major adhesion complexes in skeletal muscle, the dystrophin– and utrophin (Utr)–glycoprotein complexes (DGC and UGC). We performed a rigorous analysis of SSPN-null mice and discovered that loss of SSPN decreased DGC and UGC abundance, leading to impaired laminin-binding activity and susceptibility to eccentric contraction-induced injury in skeletal muscle. We show that loss of SSPN increased levels of α7β1 integrin. To genetically test whether integrin compensates for the loss of DGC and UGC function in SSPN-nulls, we generated mice lacking both SSPN and α7 integrin (DKO, double knockout). Muscle regeneration, sarcolemma integrity and fibrosis were exacerbated in DKO mice and were remarkably similar to muscle from Duchenne muscular dystrophy (DMD) patients, suggesting that secondary loss of integrin contributes significantly to pathogenesis. Expression of the DGC and UGC, laminin binding and Akt signaling were negatively impacted in DKO muscle, resulting in severely diminished specific force properties. We demonstrate that SSPN is a necessary component of dystrophin and Utr function and that SSPN modulation of integrin signaling is required for extracellular matrix attachment and muscle force development.