Hydrogen- Clinical use and future prospects
In this presentation we will show how hydrogen can have a positive effect on:
Cancer Inflammation/pain killer
Diabetes Atopic dermatitis
The Problem
Every single day we are exposed to the harmful effect of our environment. Pollution, sun exposure and various toxins from a broad range of sources damage our cells. Science is starting to understand the biology behind this damage. One of the main reasons is caused by the molecules known as ‘free radicals’ or Reactive Oxidative Species (ROS). Typically, molecules have two electrons to keep them stable. The free radicals, however, only have one electron due to the harmful environmental impact, which makes them unstable and a contributing factor to the breakdown of our bodies.
The unstable free radical are always seeking to become stabilised by pulling in an additional electron from healthy molecules. This process sets off a chain reaction and more molecules become imbalanced and thus unhealthy. A damaging process known as oxidative stress. Persistent oxidative stress is one of the major causes of most lifestyle-related diseases, cancer and the ageing process.
Everyday we are exposed to cell-damaging free radicals
The Solution
Antioxidants are substances that protect your cells from oxidative stress and inflammation by removing the harmful free radicals. The amount of free radicals in the body must be in balance to maintain a good health. Certain vitamins are known as antioxidants and are believed to counteract oxidative stress by reducing the formation of free radicals. Nevertheless, vitamins and nutrients are linked to a limited therapeutic success. On the other hand, molecular hydrogen has potential as a novel antioxidant in preventative and therapeutic applications.
Hydrogen readily gives up electrons to ROS, which stabilises them and stops them in their tracks. Hydrogen shows not only effects against oxidative stress, but also various anti-inflammatory and anti-allergic effects. Hydrogen holds advantages over other antioxidants because it is such a tiny molecule: it is able to penetrate cell membranes, and can easily enter deep into cell components, where other antioxidants are not able to reach. Also, hydrogen boosts the body’s defences by increasing production of natural antioxidants. No adverse effects of consuming hydrogen exist.
Molecular Hydrogen eliminates free radicals.
ROS and their potential implications
ROS
DNA Oxidation
Protein oxidationLipid oxidation
Cancer
Cell ageing
Tissue ageing/dedegeneration
Proliferation / metastasis
Disease/ageing
Intracellular organ degeneration
Oxidative deterioration
AGE production
Inflammation promotion
Immune system cell growth
Osteoclasts promote
Intracellular progression
Acidification Enzyme Synthesis
Growth factor stimulus
Physiological ActivityCytotoxic Action
ROS
Two types of ROS
Hydrogen as a selective antioxidant
Selective, clean, and safe. While taking high doses of supplemental antioxidants has negative health effects, it is impossible to take too much H2. Molecular Hydrogen ONLY scavenges and neutralises the harmful free radicals, leaving the beneficial ones alone. Many antioxidants leave behind toxic byproducts, but the only byproduct of H2 is water.
Therapeutic target
Physiological activity: Low
Cytotoxic activity: high
TROSToxic ROS
Adverse effects due to removal
Target selectivity is important for antioxidant therapy
BROSBiological ROS
stimulationStrong
weak
ROS activity and physiological activity/cytotoxicity
Scientific?The wide-ranging therapeutic and preventative benefits of molecular hydrogen have been evidenced in over 850 peer-reviewed, scientific articles, encompassing over 170 disease models including: type 2 diabetes, rheumatoid arthritis and other autoimmune diseases, metabolic syndrome, Parkinson’s & Alzheimer’s disease, heart disease, numerous forms of cancer
Major papers/clinical trials since 2007
Immune activation / inflammation and ROS
• Block TNFα induction in the NFκB pathwa• NO suppression by inhibition of iNOS activity• Suppress IL-6 mRNA expression• Suppression of ICAM-1 mRNA expression• Maintaining mitochondrial function
TNFα NFκB
ROS
Cytokine
COX
Cytotoxicity
iNOS
TNFα
2013: hydrogen molecule suppresses TNFα induced cell damage
2014: Effect of inhalation of hydrogen gas after cardiac arrest
· Suppression of decline in behaviour/cognitive function.· Neuronal cell death/inflammatory response decreased markedly.
By hydrogen inhalation
· Neuronal cell necrosis decreases.· Suppress hippocampal / cerebral cortex microglial activity.
2015: Hydrogen drip suppressed intestinal mucosal damage due to hemorrhagic shock
· Administration of hydrogen to the ischemic injury of the digestive tract mucosa caused by hemorrhagic shock· Histologically, reduction of intestinal villous damage, reduction of neutrophil infiltration· Reduction of MDA, MPO, IL-6, TNFα (increase of inflammatory cytokines) in the hydrogen administration group· Increase in SOD, IL-10 (antiinflammatory cytokine / increase in antioxidant substance) in hydrogen administration group
Appendix 2016: Onset of Parkinson's disease by mutation of DJ-1 gene
DJ-1
O2
Mitochondria
ROS
Cell/DNA
ROS
AntioxidantDJ-1
O2
Mitochondria
ROS
Cell/DNA
ROS
Antioxidant
Oxidative damage
Oxidative damage: Acquired Genetic mutation: Familiar
SignalStress
H2?
2016: Multi-center double-blind study on Parkinson's disease
Confirm effectiveness with large-scale double-blind trial conducted on Parkinson's disease• H 2 Hydrogen water containing 5 mM 1 L / day 8 weeks
Evaluation:• UPDRS (unified Parkinson 's disease rating scale)
Confirmed effect in: Hydrogen administration can inhibit the progression of Parkinson's disease
Clinical UseFrom basic medicine to clinical medicine
Exploring administration methods considered from previous papers
1: Dissolved in liquid before administration
2: Gas administered, dissolving in the body
* Water (digestive tube) * drip * injection *
* Inhalation (lung) * Dermal Injection*
3: Generated in the gastrointestinal tract, dissolved in the body
* Hydrogen body occlusion (oral administration) * Acceleration of development by intestinal bacteria (Acarbose etc.)
Drip Injection
Infusion/injection solution Hydrogenated physiological saline
Gas concentration in cylinder Filled gas concentration Humidity Filling pressure
: >99.999% : 99.9999% : 0% : 0~100kPa
Hydrogen dissolution
• Henry's law • Boyle/Charles' law • Intermolecular force of hydrogen gas • Intermolecular force of liquid • Presence in the nano bubble state
(Ppm measurement)
Dissolution limit ≒1.57ppm
Dissolved hydrogen concentration in drip bag
0.0
0.6
1.2
1.8
2.4
3.0
Fill straight up Immediately after Shake After 5 minutes After 10 minutes After 15 minutes After 20 minutes After 50 minutes After 60 minutes After 24 hours After 48 hours
0
2.1
1.6
1.8
2.4
2.2
1.9
1.71.6
1.4
0
1.9
1.51.6
2.1
1.7
1.5
1.31.2
1.1
0
1.4
1.21.3
1.5
1.3
1
0.7
0.50.4
Atmospheric pressure filling shake 10 seconds 90kpa filling - Shake 10 seconds 90 kpa filling - shake 15 seconds
ppm Dissolution limit (1.57 ppm) hyper phenomena due to pressurised dissolution
Water drip
Hydrogen gas injection
Perform various inspections before and after
What is 8-OHdG?Steady-state levels of DNA damages represent the balance between formation and repair. Average frequencies of steady state endogenous DNA damages in mammalian cells. The most frequent oxidative DNA damage normally present in DNA is 8-oxo-dG, occurring at an average frequency of 2,400 per cell. When 8-oxo-dG is induced by a DNA damaging agent it is rapidly repaired.
Increased levels of 8-oxo-dG in a tissue can serve as a biomarker of oxidative stress.
Oxidative DNA damage, such as 8-oxo-dG, likely contributes to carcinogenesis (cancer)
The contribution happens via two different mechanisms. The first mechanism involves modulation of gene expression, whereas the second is through the induction of mutations.Thus 8-oxo-dG, if not repaired, can directly cause frequent mutations, some of which may contribute to cancer.
Oxidative stress and 8-OHdG
8-OHdG 8-hydroxy-2’-deoxyguanosine
Normal deoxyguanosine (dG)
HO
Oxidative stress
Urine
Elimination by repairing enzymes
This process is constantly occurring tens of thousands of times per cell/day
· Genetic damage is 5 to 500,000 per day (× 60 trillion) per cell· Detect damage due to oxidation· 8-OHdG test ≈ oxidative stress speed to genes
Relationship between administration and 8-OHdG
OH DNAdamage
repair
ApoptosisCell death / destruction
Cell ageing
Cancer
8-OHdG
Nuclear membrane
Cell membrane
H2O
H2
H2
H2
In the blood
Interstitial
in the cell
In the nucleus
Reduction of 8-OHdG by administration≈ nuclear migration of hydrogen molecules≈ Protection action of DNA
Regeneration by stem cells
Changes of 8-OHdG by hydrogenated physiological saline infusion
Reference value4~13
• 32 patients treated with hydrogen saline infusion• In nearly all cases, a decrease in 8-OHdG is observed• Braking the oxidation damage speed of DNA
Changes in TARC due to hydrogen drip infusion
Changes in TARC due to infusion
0
750
1500
2250
3000
Start End
Patient A Patient B Column 1
<450pg/ml 450~700pg/ml
>700pg/ml
:Normal :Mild :Moderate or higher
TARC (Thymus and activation-regulated chemokine) It is a type of chemokine with leukocyte chemotaxis, and when overproduced, it is believed that Th2 cells are attracted to the lesion locus, production of IgE antibody and activation of eosinophils occur, and an allergic inflammatory reaction is caused. Specificity is seen in atopic dermatitis, it increases markedly as severe, and it decreases with lightening.
Currently accumulating more data
Injection
Hydrogen (nano bubble) injection and its possibilities
Intramuscular injection Tendon sheath injection
Intra-articular injection
Action of physiological saline Research as an analgesic mechanism of trigger point from previous study Used for pain relief at the Study Meeting of Fascial Pain Syndrome (MPS) Fascial exfoliation with physiological saline is analgesic The analgesic effect is stronger for hydrogen (bubble) water
Dissolved water (water molecules) role Suppression of hydrogen NFκB?
Action of hydrogen nano bubbles The action varies depending on the type of gas in the bubble There is no announcement of hydrogen nano bubbles Anti-inflammatory effects of nano bubbles? Other action? Possibility of unknown action
NFκB
TNFα
OH COX Inflammation
Cytokine/iNOS
Acute irritation
Nano bubble action?Other action?
Adhesion peeling action
Consideration of intra-articular injection· Shoulder periarthritis· Osteoarthritis of the knee· Rheumatoid arthritis· Hip acetabular dysplasia· Ankle sprain sequelae· Temporomandibular disorders
Intra-articular injection
Pain reliefReduction of pain during motion/walkingReduction of joint swellingExpansion of range of motion
Age-related changeAthleteCollagen diseaseAfter trauma etc.
Oral Hydrogen Administration
Hydrogen Water
• Water containing molecular hydrogen • Ingested as "hydrogen" • Hydrogen molecular weight that can be administered is small • Hydrogen intake of 11.5 cc / l as 1.5 ppm upper limit • It is unstable and easy to come off
Hydrogen Capsules
• Substances that generates molecular hydrogen in the body • MgH 2, flanagan, coral calcium etc. exist • The most amount generated per gram is MgH 2 • The theory of generation (chemical formula) is clear: MgH 2 • Amount generated per hour> is unknown (fluctuation) • MgH 2 is prescribed as "research reagent" because food is unauthorized
Carbohydrate absorption retarder
• Encourage the generation of hydrogen gas by intestinal bacteria • There is a paper bonacarbose • Different amounts depending on intestinal bacterial load/type
Types of oral hydrogen administration
What are AGEs?Advanced glycation end products (AGEs) are proteins or lipids that become glycated as a result of exposure to sugars. They can be a factor in ageing and in the development or worsening of many degenerative diseases, such as diabetes, atherosclerosis, chronic kidney disease, and Alzheimer's disease
Changes in subcutaneous AGEs by long-term oral administrationAGEs
1.5
1.8
2
2.3
2.5
13.6,3 13.10.2913.11.2613.12.31 14.1.28 14.2.25 14.3.15 14.4.22 14.6.2 14.6.24 14.7.15 14.8.15 14.11.15
AGEs
Hydrogen Gas Inhalation
H2
H2
H2
H2
H2
H2 H2
Inhalation H2 concentrationTemperature (body temperature)
Suction pressureContact area
1 60% O2 21% Is necessary 37℃ 1 α CPAP/Positive pressure breathing etc. The alveolar area about 70m2
H 2 concentration in blood/interstitial fluid/intracellular fluidWhat is the saturation limit?How long will it take to reach the limit?
Body Fluid Volume of body weight: 60% Intracellular fluid: 40%Tissue liquid: 15%Plasma · Lymph fluid: 4.5%Cavity fluid: 0.5%
Alveolus of inhaled hydrogen gas → vascular migration
H2
H2
Interstitial
Intracellular
Hydrogen inhalation: still at the research stage
Exhalation ppm
0
100
200
300
400
Before inhalation 3 min 10 min 20 min 30 min
ppm Hydrogen concentration in expired gas
Inhalation for 60 minutes 3 minutes After atmospheric spontaneous breathing
Suction gas composition: Hydrogen: 60% Oxygen: 30% Water vapor: 10% + Fresh air
It is at present unknown whether it is free from blood or residual hydrogen of dead space
Hydrogen Gas Injection
Injection of intracutaneous/subcutaneous hydrogen gas
H2 gas (van der Waals force)
Due to the presence of intermolecular forces, it is not absorbed immediately
Diffusion to body fluid / interstitial fluid (molecular hydrogen): Transition part: 1.6 ppm? effect
Transition into the blood / lymph fluid: Transition part: 1.6 ppm effect
Subcutaneous emphysema condition
Hydrogen Gas injection
Gas concentration in cylinderFilled gas concentrationHumidityFilling pressureDose
: >99.999% : 99.9999% : 0% : 0~100kPa : Xml
· Cell/tissue damage due to filling pressure· Dosage by region
OH NFκB↓ COX2↓ Inflammation↓☓
TNFα/IL-1
Sterile H2 gas
Inflammation and reactive oxygen
TNFα
UV/Ra
LPS
CD40/RANKLT-β
IL-1
NFκB COX2 Inflammatory response
Nrf2
H2
NOX ↓ O2
-
↓ H2O2
Fe Cu Sterilization
Intra-articular injection
Hypothesis of pain relief
Aseptic 100% hydrogen gas administration into the joint space(Administration to closed space in joint)
↓Dissolution in synovial fluid/synovial fluidInvasion into the joint capsule
↓Reduction of inflammation/pain relief
Transdermal absorbent bath agent/external medicine
Percutaneous absorption external use/bath preparation
O2 gasH2
waterEpidermis
Dermis
Subcutaneous tissue
Muscle tissue
Blood
Hydrogen molecules dissolved/reserved in water pass through
In the gaseous state, by intermolecular force H2 do not break through the skin because they are bonded
H2 gasH2 gas
Dissolution treatment
Hydrogen gas dynamics in the body by bathingChange in hydrogen concentration in exhalation gas by bathing
(15)
10 20 30 40 5010
14
16
18
20
beforeafter
ppm
min
12control
Hydrogen bath agent
Medical Corporation Medical Association Medical Association Tsuji Clinic
Thank you
HyCare Akarui Ltd
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