# Effects of hydrogen rich water on prolonged intermittent exercise

Peak power output (PPO), also known as “peak work rate” is a common measure of exercise intensity.

The Authors of this 2-weeks ‘ hydrogen /placebo water’ study (a cross over single-blind protocol -see footnotes for references) tested  8 trained male cyclists and measured multiple parameters(including mean and peak power output) on a regular basis(before and after 2 weeks cycle )

Notes:

1 The athletes were given were provided daily with 2 liters of placebo normal water (pH 7.6, ORP +230 mV, H2 0 ppb) or 2 liters hydrogen rich water(pH 9.8, ORP -180 mV, H2 450 ppb)

2  AlkaViva H2 ionizers such as Vesta/Delphy H2 can produce up to 1600 ppb at ph<10  ).

The authors found that while in the placebo group, Peak Power Output  in absolute values decreased significantly at the last couple of sprints and in relative values and ΔPPO decreased significantly  in more than a couple of sprints,  it remained unchanged in the group that drunk hydrogen rich water . Thus they conclude drinking 2  liters of hydrogen rich water per day over a 2 week period may help to maintain peak power output in intense exercise such as repetitive sprints to exhaustion over 30 minutes.

PMID:28474871
DOI:10.23736/S0022-4707.17.06883-9

2018 May;58(5):612-621. doi: 10.23736/S0022-4707.17.06883-9. Epub 2017 Apr 26.

# Protective effect of hydrogen-rich water on liver function of colorectal cancer patients during chemotherapy

The study published in 2017  was conducted to investigate the protective effect of hydrogen-rich water on the liver function of colorectal cancer (CRC) patients treated with mFOLFOX6 chemotherapy.

A controlled, randomized, single-blind clinical trial was designed.

A total of 152 patients with colorectal cancer were recruited by the Department of Oncology of Taishan Hospital (Taian, China) between June 2010 and February 2016, among whom 146 met the inclusion criteria. Subsequently, 144 patients were randomized into the treatment with hydrogen water(n=80) and placebo (n=64) groups. At the end of the study, 76 patients in the hydrogen water treatment group and 60 patients in the placebo group were included in the final analysis.

The 80 patients group started drinking hydrogen-rich water 1 day prior to chemotherapy until the end of the cycle, for a total of 4 days, with a total intake of 1,000 ml hydrogen-rich water per day in 4 doses (250 ml hydrogen-rich water each). Hydrogen-rich water was consumed 0.5 h after a meal and before bedtime.

The patients did not discontinue consuming hydrogen-rich water during the entire course of chemotherapy.

The other 64 placebo patients consumed distilled water, with a daily intake of 1,000 ml in 4 doses (250 ml each).

The changes in liver function after the chemotherapy, such as altered levels of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase, indirect bilirubin (IBIL) and direct bilirubin, were observed. The damaging effects of the mFOLFOX6 chemotherapy on liver function were mainly represented by increased ALT, AST and IBIL levels. The hydrogen-rich water group exhibited no significant differences in liver function before and after treatment, whereas the placebo group exhibited significantly elevated levels of ALT, AST and IBIL. Thus, hydrogen-rich water appeared to alleviate the mFOLFOX6-related liver injury

PMID:29142752
PMCID:PMC5666661
DOI:10.3892/mco.2017.1409
2017 Nov;7(5):891-896. doi: 10.3892/mco.2017.1409. Epub 2017 Sep 1.
###### Protective effect of hydrogen-rich water on liver function of colorectal cancer patients treated with mFOLFOX6 chemotherapy.
Yang Q1Ji G1Pan R1Zhao Y2Yan P3.

### Author information

1
Department of Oncology, Shandong Provincial Taishan Hospital, Taian, Shandong 271000, P.R. China.
2
Department of Pathology, Taishan Medical University, Taian, Shandong 271000, P.R. China.
3
Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China.

# haemodialysis system using dissolved dihydrogen (H2) in water produced by electrolysis: a clinical trial

### Abstract

#### BACKGROUND:

Chronic inflammation in haemodialysis (HD) patients indicates a poor prognosis. However, therapeutic approaches are limited. Molecular hydrogen gas (H(2)) ameliorates oxidative and inflammatory injuries to organs in animal models. We developed an HD system using a dialysis solution with high levels of dissolved molecular hydrogen H(2) and examined the clinical effects.

#### METHODS:

Dialysis solution with molecular hydrogen H(2) (average of 48 ppb) was produced by mixing dialysate concentrates and reverse osmosis water containing dissolved molecular hydrogen H(2) generated by a water electrolysis technique. Subjects comprised 21 stable patients on standard HD who were switched to the test HD for 6 months at three sessions a week.

#### RESULTS:

During the study period, no adverse clinical signs or symptoms were observed.

A significant decrease in systolic blood pressure (SBP) before and after dialysis was observed during the study, and a significant number of patients achieved SBP <140 mmHg after HD (baseline, 21%; 6 months, 62%; P < 0.05). Changes in dialysis parameters were minimal, while significant decreases in levels of plasma monocyte chemoattractant protein 1 (P < 0.01) and myeloperoxidase (P < 0.05) were identified.

#### CONCLUSIONS:

Adding molecular hydrogen H(2) to haemodialysis solutions ameliorated inflammatory reactions and improved BP control. This system could offer a novel therapeutic option for control of uraemia.

2010 Sep;25(9):3026-33. doi: 10.1093/ndt/gfq196. Epub 2010 Apr 12.

### Author information

PMID:
20388631
DOI:
10.1093/ndt/gfq196

https://www.ncbi.nlm.nih.gov/pubmed/20388631

# Molecular Hydrogen as an Emerging Therapeutic Medical Gas for Neurodegenerative and Other Diseases

## Abstract

Effects of molecular hydrogen (water ) on various diseases have been documented for 63 disease models and human diseases in the past four and a half years(by 2012(. Most studies have been performed on rodents including two models of Parkinson’s disease and three models of Alzheimer’s disease. Prominent effects are observed especially in oxidative stress-mediated diseases including neonatal cerebral hypoxia; Parkinson’s disease; ischemia/reperfusion of spinal cord, heart, lung, liver, kidney, and intestine; transplantation of lung, heart, kidney, and intestine. Six human diseases have been studied to date: diabetes mellitus type 2, metabolic syndrome, hemodialysis, inflammatory and mitochondrial myopathies, brain stem infarction, and radiation-induced adverse effects.

Two enigmas, however, remain to be solved. First, no dose-response effect is observed. Rodents and humans are able to take a small amount of hydrogen by drinking hydrogen-rich water, but marked effects are observed. Second, intestinal bacteria in humans and rodents produce a large amount of hydrogen, but an addition of a small amount of hydrogen exhibits marked effects. Further studies are required to elucidate molecular bases of prominent hydrogen (water ) effects and to determine the optimal frequency, amount, and method of hydrogen administration for each human disease

## 1. Introduction

Molecular hydrogen (H2) is the smallest gas molecule made of two protons and two electrons. Hydrogen is combustible when the concentration is 4–75%. Hydrogen, however, is a stable gas that can react only with oxide radical ion (•O) and hydroxyl radical (•OH) in water with low reaction rate constants []:

O+H2H+OHk=8.0×107M1s1OH+H2H+H2Ok=4.2×107M1s1H+OHH2Ok=7.0×109M1s1.
(1)

The reaction rate constants of  •O and •OH with other molecules are mostly in the orders of 109 to 1010 M−1·s−1, whereas those with H2 are in the order of 107 M−1·s−1. Hydrogen, however, is a small molecule that can easily dissipate throughout the body and cells, and the collision rates of hydrogen with other molecules are expected to be very high, which is likely to be able to overcome the low reaction rate constants []. Hydrogen is not easily dissolved in water, and 100%-saturated hydrogen water contains 1.6 ppm or 0.8 mM hydrogen at room temperature( our note: see AlkaViva Vesta H2 water ionizer performance below)

In 1995, hydrogen was first applied to human to overcome high-pressure nervous syndrome in deep sea diving []. Hydrogen was used to reduce nitrogen (N2) toxicity and to reduce breathing resistance in the deep sea. In 2001, being prompted by the radical-scavenging activity of hydrogen, Gharib and colleagues examined an effect of molecular hydrogen on a mouse model of schistosomiasis-associated chronic liver inflammation []. Mice were placed in a chamber with 70% hydrogen gas for two weeks. The mice exhibited decreased fibrosis, improvement of hemodynamics, increased nitric oxide synthase (NOS) II activity, increased antioxidant enzyme activity, decreased lipid peroxide levels, and decreased circulating tumor-necrosis-factor-(TNF-)  α  levels. Although helium gas also exerted some protective effects in their model, the effect of helium gas was not recapitulated in a mouse model of ischemia/reperfusion injury of the liver [].

## 2. Effects of Hydrogen (water ) Have Been Reported in 63 Disease Models and Human Diseases

A major breakthrough in hydrogen research occurred after Ohsawa and colleagues reported a prominent effect of molecular hydrogen on a rat model of cerebral infarction in June 2007 []. Rats were subjected to left middle cerebral artery occlusion. Rats placed in 2–4% hydrogen gas chamber showed significantly smaller infarction volumes compared to controls. They attributed the hydrogen effect to the specific scavenging activity of hydroxyl radical (•OH). They also demonstrated that hydrogen scavenges peroxynitrite (ONOO) but to a lesser extent.

As have been previously reviewed [], effects of molecular hydrogen on various diseases have been reported since then. The total number of disease models and human diseases for which molecular hydrogen has been proven to be effective has reached 63 (by 2012)(Table 1). The number of papers is increasing each year (Figure 1). Among the 87 papers cited in Table 1, 21 papers showed an effect with inhalation of hydrogen gas, 23 with drinking hydrogen-rich water, 27 with intraperitoneal administration or drip infusion of hydrogen-rich saline, 10 with hydrogen-rich medium for cell or tissue culture, and 6 with the other administration methods including instillation and dialysis solution. In addition, among the 87 papers, 67 papers showed an effect in rodents, 7 in humans, 1 in rabbits, 1 in pigs, and 11 in cultured cells or cultured tissues.

Number of papers that report effects of molecular hydrogen since 2007 shown in Table 1.

### Table 1

Sixty-three disease models and human diseases for which beneficial effects of hydrogen have been documented.

Brain
Cerebral infarction [] Rodent, human Gas, saline
Cerebral superoxide production [] Rodent Water
Restraint-induced dementia [] Rodent Water
Alzheimer’s disease [] Rodent Saline
Senile dementia in senescence-accelerated mice [] Rodent Water
Parkinson’s disease [] Rodent Water
Hemorrhagic infarction [] Rodent Gas
Brain trauma [] Rodent Gas
Carbon monoxide intoxication [] Rodent Saline
Transient global cerebral ischemia [] Rodent Gas
Deep hypothermic circulatory arrest-induced brain damage [] Rodent Saline
Surgically induced brain injury [] Rodent Gas
Spinal Cord
Spinal cord injury [] Rodent Saline
Spinal cord ischemia/reperfusion [] Rabbit Gas
Eye
Glaucoma [] Rodent Instillation
Corneal alkali-burn [] Rodent Instillation
Ear
Hearing loss [] Tissue, rodent Medium, water
Lung
Oxygen-induced lung injury [] Rodent Saline
Lung transplantation [] Rodent Gas
Paraquat-induced lung injury [] Rodent Saline
Radiation-induced lung injury [] Rodent Water
Burn-induced lung injury [] Rodent Saline
Intestinal ischemia/reperfusion-induced lung injury [] Rodent Saline
Heart
Acute myocardial infarction [] Rodent Gas, saline
Cardiac transplantation [] Rodent Gas
Sleep apnea-induced cardiac hypoxia [] Rodent Gas
Liver
Schistosomiasis-associated chronic liver inflammation [] Rodent Gas
Liver ischemia/reperfusion [] Rodent Gas
Hepatitis [] Rodent Intestinal gas
Obstructive jaundice [] Rodent Saline
Carbon tetrachloride-induced hepatopathy [] Rodent Saline
Kidney
Cisplatin-induced nephropathy [] Rodent Gas, water
Hemodialysis [] Human Dialysis solution
Kidney transplantation [] Rodent Water
Renal ischemia/reperfusion [] Rodent Saline
Melamine-induced urinary stone [] Rodent Water
Chronic kidney disease [] Rodent Water
Pancreas
Acute pancreatitis [] Rodent Saline
Intestine
Intestinal transplantation [] Rodent Gas, medium, saline
Ulcerative colitis [] Rodent Gas
Intestinal ischemia/reperfusion [] Rodent Saline
Blood vessel
Atherosclerosis [] Rodent Water
Muscle
Inflammatory and mitochondrial myopathies [] Human Water
Cartilage
NO-induced cartilage toxicity [] Cells Medium
Metabolism
Diabetes mellitus type I [] Rodent Water
Diabetes mellitus type II [] Human Water
Metabolic syndrome [] Human, rodent Water
Diabetes/obesity [] Rodent Water
Perinatal disorders
Neonatal cerebral hypoxia [] Rodent, pig Gas, saline
Preeclampsia [] Rodent Saline
Inflammation/allergy
Type I allergy [] Rodent Water
Sepsis [] Rodent Gas
Zymosan-induced inflammation [] Rodent Gas
LPS/IFNγ-induced NO production [] Cells Gas
Cancer
Growth of tongue carcinoma cells [] Cells Medium
Lung cancer cells [] Cells Medium
Radiation-induced thymic lymphoma [] Rodent Saline
Others
UVB-induced skin injury [] Rodent Bathing
Decompression sickness [] Rodent Saline
Viability of pluripotent stromal cells [] Cells Gas
Radiation-induced cell damage [] Cells Medium
Oxidized low density lipoprotein-induced cell toxicity [] Cells Medium
High glucose-induced oxidative stress [] Cells Medium

Two papers, however, showed that hydrogen was ineffective for two disease models (Table 2). One such disease was moderate to severe neonatal brain hypoxia [], although marked effects of hydrogen gas [] and intraperitoneal administration of hydrogen-rich saline [] on neonatal brain hypoxia have been reported in rats [] and pigs []. We frequently observe that therapeutic intervention that is effective for mild cases has little or no effect on severe cases, and hydrogen is unlikely to be an exception. Another disease is muscle disuse atrophy []. Although oxidative stress is involved in the development of muscle disuse atrophy, oxidative stress may not be a major driving factor causing atrophy and thus attenuation of oxidative stress by hydrogen may not be able to exhibit a beneficial effect.

### Table 2

Two disease models for which hydrogen has no effect.

Brain

Moderate to severe neonatal brain hypoxia [] Rodent Gas

Muscle

Muscle disuse atrophy [] Rodent Water

Effects of molecular hydrogen have been observed essentially in all the tissues and disease states including the brain, spinal cord, eye, ear, lung, heart, liver, kidney, pancreas, intestine, blood vessel, muscle, cartilage, metabolism, perinatal disorders, and inflammation/allergy. Among them, marked effects are observed in ischemia/reperfusion disorders as well as in inflammatory disorders. It is interesting to note, however, that only three papers addressed effects on cancers. First, molecular hydrogen caused growth inhibition of human tongue carcinoma cells HSC-4 and human fibrosarcoma cells HT-1080 but did not compromise growth of normal human tongue epithelial-like cells DOK []. Second, hydrogen suppressed the expression of vascular endothelial growth factor (VEGF), a key mediator of tumor angiogenesis, in human lung adenocarcinoma cells A549, which was mediated by downregulation of extracellular signal-regulated kinase (ERK) []. Third, hydrogen protected BALB/c mice from developing radiation-induced thymic lymphoma []. Elimination of radical oxygen species by hydrogen should reduce a probability of introducing somatic mutations. Unlike other disease models, cancer studies were performed only with cells in two of the three papers. Hydrogen is likely to have a beneficial effect on cancer development by suppressing somatic mutations, but an effect on cancer growth and invasion needs to be analyzed further in detail.

## 3. Effects of Molecular Hydrogen on Rodent Models of Neurodegenerative Diseases

Parkinson’s disease is caused by death of dopaminergic neurons at the substantia nigra pars compact of the midbrain and is the second most common neurodegenerative disease after Alzheimer’s disease. Parkinson’s disease is caused by two mechanisms: excessive oxidative stress and abnormal ubiquitin-proteasome system []. The neurotransmitter, dopamine, is a prooxidant by itself and dopaminergic cells are destined to be exposed to high concentrations of radical oxygen species. An abnormal ubiquitin-proteasome system also causes aggregation of insoluble  α-synuclein in the neuronal cell body that leads to neuronal cell death. We made a rat model of hemi-Parkinson’s disease by stereotactically injecting catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in the right striatum []. Ad libitum administration of hydrogen-rich water starting one week before surgery completely abolished the development of hemi-Parkinson’s symptoms. The number of dopaminergic neurons on the toxin-injected side was reduced to 40.2% of that on the control side, whereas hydrogen treatment improved the reduction to 83.0%. We also started giving hydrogen-rich water three days after surgery, and hemi-Parkinson’s symptoms were again suppressed, but not as much as those observed in pretreated rats. The number of dopaminergic neurons on the toxin-injected side was 76.3% of that on the control side. Pretreated rats were also sacrificed 48 hrs after toxin injection, and the tyrosine hydroxylase activity at the striatum, where dopaminergic neurons terminate, was decreased in both hydrogen and control groups. This indicated that hydrogen did not directly detoxicate 6-OHDA but exerted a delayed protective effect for dopaminergic cells. Fujita and colleagues also demonstrated a similar prominent effect of hydrogen-rich water on an MPTP-(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-) induced mouse model of Parkinson’s disease []. MPTP is a neurotoxin that blocks complex I of the mitochondrial electron transport system and causes Parkinson’s disease in mice and humans. It is interesting to note that the concentration of hydrogen that they used for the MPTP mice was only 0.08 ppm (5% saturation), which is the second lowest among all the trials published to date for rodents and humans. The lowest hydrogen concentration ever tested is 0.048 ppm in the dialysis solution for patients receiving hemodialysis [].

Alzheimer’s disease is the most common neurodegenerative disease and is characterized by abnormal aggregation of β-amyloid (Aβ) and tau, the large aggregates of which are recognizable as senile plaques and neurofibrillary tangles, respectively []. Effects of molecular hydrogen on Alzheimer’s disease have been studied in three rodent models. First, Nagata and colleagues made a mouse model of dementia by restricting movement of mice for 10 hrs a day []. They analyzed cognitive functions through passive avoidance learning, object recognition tasks, and the Morris water maze and demonstrated that ad libitum administration of hydrogen-rich water efficiently ameliorated cognitive impairment. They also showed that neural proliferation in the dentate gyrus was restored by hydrogen water . Second, Li and colleagues made a rat model of Alzheimer’s disease by intracerebroventricular injection of Aβ1-42 []. They analyzed cognitive functions by the Morris water maze open field tasks, and electrophysiological measurement of long-term potentiation (LTP) and found that intraperitoneal injection of hydrogen-rich saline for 14 days efficiently ameliorated cognitive decline and preserved LTP. The same team later reported that the protective effects were mediated by suppression of abnormal activation of IL1β, JNK, and NFκB []. Third, Gu and colleagues used a senescence-accelerated mouse strain (SAMP8) that exhibits early aging syndromes including impairment in learning ability and memory []. Ad libitum administration of hydrogen-rich water for 30 days prevented cognitive decline, which was examined by the Morris water maze. Additionally, ad libitum drinking of hydrogen water for 18 weeks showed efficient amelioration of hippocampal neurodegeneration.

Cerebrovascular diseases are the most frequently reported neurological diseases for which hydrogen (water )has prominent effects. As stated in Section 2, current hydrogen (water ) research has broken out after Ohsawa reported a prominent effect of 2–4% hydrogen for a rat model of left cerebral artery occlusion in 2007 [].

In addition to neurodegenerative disorders of Parkinson’s disease and Alzheimer’s disease, effects of molecular hydrogen (water ) have been reported in eight other brain diseases listed under the categories of “brain” and “perinatal disorders” in Table 1. The brain consumes a large amount of oxygen and is predisposed to be exposed to a large amount of radical oxygen species especially under pathological conditions. Molecular hydrogen is thus likely to exert a prominent beneficial effect on brain diseases.

## 4. Molecular Hydrogen Is Effective for Six Human Diseases(known by 2012)

As in other therapeutic modalities, effects of molecular hydrogen have been tested mostly on rodents but have also been studied in six human diseases( by 2012). The reported human diseases include diabetes mellitus type II [], metabolic syndrome [], hemodialysis [], inflammatory and mitochondrial myopathies [], brain stem infarction [], and radiation-induced adverse effects for liver tumor []. These studies are reviewed in detail here. In addition, a therapeutic trial for Parkinson’s disease is currently in progress and exhibits favorable responses as far as we know, but the details are not yet disclosed.

First, Kajiyama and colleagues performed a randomized, double-blind, placebo-controlled, crossover study in 30 patients with diabetes mellitus type II and 6 patients with impaired glucose tolerance []. The patients consumed either 900 mL of hydrogen-rich water or placebo water for 8 weeks, with a 12-week washout period. They measured 13 biomarkers to estimate lipid and glucose metabolisms at baseline and at 8 weeks after hydrogen water treatment. All the biomarkers were favorably changed with hydrogen, but statistical significance was observed only in improvement of electronegative charge-modified low-density lipoprotein-(LDL-) cholesterol, small dense LDL, and urinary 8-isoprostanes. In four of six patients with impaired glucose tolerance, hydrogen normalized the oral glucose tolerance test. Lack of statistical significance in their studies was likely due to the small number of patients and the short observation period. Lack of statistical significance, however, may also suggest a less prominent effect in human diabetes mellitus compared to rodent models [].

Second, Nakao and colleagues performed an open-label trial in 20 subjects with potential metabolic syndrome []. Hydrogen-rich water was produced by placing a metallic magnesium stick in water, which yielded 0.55–0.65 mM hydrogen water (70–80% saturation). The participants consumed 1.5–2.0 liters of hydrogen water per day for 8 weeks and showed a 39% increase in urinary superoxide dismutase (SOD), an enzyme that catalyzes superoxide anion (O2); a 43% decrease in urinary thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxidation; an 8% increase in high-density-lipoprotein-(HDL-) cholesterol; a 13% decrease in total cholesterol/HDL-cholesterol. The aspartate aminotransferase (AST) and alanine transaminase (ALT) levels remained unchanged, whereas the gamma glutamyl transferase (GGT) level was increased by 24% but was still within a normal range. Although the study was not double blinded and placebo controlled, improvements in biomarkers were much more than those in other hydrogen water studies in humans. As this study used a large amount of hydrogen water, the amount of hydrogen might have been a critical determinant. Alternatively, excessive hydration might have prevented the participants from excessive food intake.

Third, Nakayama and colleagues performed an open-label placebo-controlled crossover trial of 12 sessions of hemodialysis in eight patients [] and an open-label trial of 78 sessions of hemodialysis in 21 patients []. In both studies, continuous sessions of hemodialysis with hydrogen-rich dialysis solution decreased systolic blood pressure before and after dialysis. In the short-term study, plasma methylguanidine was significantly decreased. In the long-term study, plasma monocyte chemoattractant protein 1 and myeloperoxidase were significantly decreased.

Fourth, we performed an open-label trial of 1.0 liter of hydrogen water per day for 12 weeks in 14 patients with muscular diseases including muscular dystrophies, polymyositis/dermatomyositis, and mitochondrial myopathies, as well as a randomized, double-blind, placebo-controlled, crossover trial of 0.5 liter of hydrogen water or dehydrogenized water per day for 8 weeks in 22 patients with dermatomyositis and mitochondrial myopathies []. In the open-label trial, significant improvements were observed in lactate-to-pyruvate ratio, fasting blood glucose, serum matrix metalloproteinase-3 (MMP3), and triglycerides. Especially, the lactate-to-pyruvate ratio, which is a sensitive biomarker for the compromised mitochondrial electron transport system, was decreased by 28% in mitochondrial myopathies. In addition, MMP3, which represents the activity of inflammation, was decreased by 27% in dermatomyositis. In the double-blind trial, a statistically significant improvement was observed only in serum lactate in mitochondrial myopathies, but lactate-to-pyruvate ratio in mitochondrial myopathies and MMP3 in dermatomyositis were also decreased. Lack of statistical significance with the double-blind study was likely due to the shorter observation period and the lower amount of hydrogen compared to those of the open-label trial.

Fifth, Kang and colleagues performed a randomized placebo-controlled study of 1.5–2.0 liters of 0.55–0.65 mM hydrogen water per day for 6 weeks in 49 patients receiving radiation therapy for malignant liver tumors. Hydrogen water suppressed the elevation of total hydroperoxide levels, maintained serum antioxidant capacity, and improved the quality of life (QOL) scores. In particular, hydrogen water efficiently prevented loss of appetite. Although the patients were randomly assigned to the hydrogen and placebo groups, the study could not be completely blinded because hydrogen water was produced with a metallic magnesium stick, which generated hydrogen bubbles.

Sixth, Ono and colleagues intravenously administered hydrogen along with Edaravone, a clinically approved radical scavenger, in 8 patients with acute brain stem infarction and compared MRI indices of 26 patients who received Edaravone alone []. The relative diffusion-weighted images (rDWIs), regional apparent diffusion coefficients (rADCs), and pseudonormalization time of rDWI and rADC were all improved with the combined infusion of Edaravone and hydrogen.

No adverse effect of hydrogen has been documented in the six human diseases described above. Among the six diseases, the most prominent effect was observed in subjects with metabolic syndrome, who consumed 1.5–2.0 liters of hydrogen water per day [].

The amount of hydrogen water may be a critical parameter that determines clinical outcome.

It is also interesting to note that lipid and glucose metabolisms were analyzed in three studies and all showed favorable responses to hydrogen [].

Update : since 2012 more clinical trials have been performed.
Acarbose/MOLECULAR HYDROGEN TREATMENT AND THE RISK OF CARDIOVASCULAR DISEASE AND HYPERTENSION IN PATIENTS WITH IMPAIRED GLUCOSE TOLERANCE: THE STOP-NIDDM TRIAL

Molecular  Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome

Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases.

Molecular hydrogen(H2) treatment for acute erythymatous skin diseases. A report of 4 patients with safety data and a non-controlled feasibility study with H2 concentration measurement on two volunteers

MOLECULAR HYDROGEN WATER FOR PATIENTS WITH PRESSURE ULCER – EFFECTS ON NORMAL HUMAN SKIN WOUNDS

MOLECULAR HYDROGEN WATER FOR PATIENTS WITH RHEUMATOID ARTHRITIS: AN OPEN-LABEL PILOT STUDY

EFFECTIVENESS OF ORAL AND TOPICAL MOLECULAR HYDROGEN FOR SPORTS-RELATED SOFT TISSUE INJURIES

MOLECULAR HYDROGEN WATER BENEFITS FOR ATHLETES, EXERCISE, MUSCLE FATIGUE

MOLECULAR HYDROGEN WATER FOR VASCULAR ENDOTELIAL FUNCTION

MOLECULAR HYDROGEN WATER-  PERIODONTITIS TREATMENT
Please see this section:Hydrogen water

## 5. Molecular Bases of Hydrogen Effects

Effects of hydrogen on various diseases have been attributed to four major molecular mechanisms: a specific scavenging activity of  hydroxyl radical, a scavenging activity of peroxynitrite, alterations of gene expressions, and signal-modulating activities. The four mechanisms are not mutually exclusive and some of them may be causally associated with other mechanisms.

The first molecular mechanism identified for hydrogen was its specific scavenging activity of hydroxyl radical []. Indeed, oxidative stress markers like 8-OHdG, 4-hydroxyl-2-nonenal (4-HNE), malondialdehyde (MDA), and thiobarbituric acid reactive substances (TBARSs) are decreased in all the examined patients and rodents. As hydrogen can easily dissipate in exhalation, hydrogen in drinking water is able to stay in human and rodent bodies in less than 10 min (unpublished data). Hydrogen, however, can bind to glycogen, and the dwell time of hydrogen is prolonged in rat liver after food intake []. A question still remains if mice and humans can take a sufficient amount of hydrogen that efficiently scavenges hydroxyl radicals that are continuously generated in normal and disease states.

Another molecular mechanism of hydrogen effect is its peroxynitrite-(ONOO-) scavenging activity []. Although hydrogen cannot eliminate peroxynitrite as efficiently as hydroxyl radical in vitro [], hydrogen can efficiently reduce nitric-oxide-(NO-) induced production of nitrotyrosine in rodents []. NO is a gaseous molecule that also exerts therapeutic effects including relaxation of blood vessels and inhibition of platelet aggregation []. NO, however, is also toxic at higher concentrations because NO leads to ONOO-mediated production of nitrotyrosine, which compromises protein functions. A part of hydrogen effects may thus be attributed to the reduced production of nitrotyrosine.

Expression profiling of rat liver demonstrated that hydrogen has a minimal effect on expression levels of individual genes in normal rats []. Gene ontology analysis, however, revealed that oxidoreduction-related genes were upregulated. In disease models of rodents, expression of individual genes and proteins is analyzed. In many disease models, hydrogen downregulated proinflammatory cytokines including tumor necrosis-factor-(TNF-)  α, interleukin-(IL-) 1β, IL-6, IL-12, interferon-(IFN-)  γ, and high mobility group box 1 (HMGB1) []. Hydrogen also downregulated nuclear factors including nuclear factor kappa B (NFκB), JNK, and proliferation cell nuclear antigen (PCNA) []. Caspases were also downregulated []. Other interesting molecules studied to date include vascular endothelial growth factor (VEGF) []; MMP2 and MMP9 []; brain natriuretic peptide []; intercellular-adhesion-molecule-1 (ICAM-1) and myeloperoxidase []; B-cell lymphoma 2 (Bcl2) and Bcl2-associated X protein (Bax) []; MMP3 and MMP13 []; cyclooxygenase 2 (COX-2), neuronal nitric oxide synthase (nNOS), and connexins 30 and 43 []; ionized calcium binding adaptor molecule 1 (Iba1) []; fibroblast growth factor 21 (FGF21) []. Most molecules, however, are probably passengers that are secondarily changed by hydrogen administration, and some are potentially direct targets of hydrogen effects, which need to be identified in the future.

Using rat RBL-2H3 mast cells, we demonstrated that hydrogen attenuates phosphorylation of FcεRI-associated Lyn and its downstream signaling molecules []. As phosphorylation of Lyn is again regulated by the downstream signaling molecules and makes a loop of signal transduction pathways, we could not identify the exact target of hydrogen. Our study also demonstrated that hydrogen ameliorates an immediate-type allergic reaction not by radical-scavenging activity but by direct modulation of signaling pathway(s). In addition, using murine RAW264 macrophage cells, we demonstrated that hydrogen reduces LPS/IFNγ-induced NO production []. We found that hydrogen inhibits phosphorylation of ASK1 and its downstream signaling molecules, p38 MAP kinase, JNK, and IκBα  without affecting ROS production by NADPH oxidase. Both studies point to a notion that hydrogen is a gaseous signal modulator. More animal and cells models are expected to be explored to confirm that hydrogen exerts its beneficial effect as a signal modulator.

6. Enigmas of Hydrogen Effects

Two enigmas remain to be solved for hydrogen effects. First, no dose-response effect of hydrogen has been observed. Hydrogen has been administered to animals and humans in the forms of hydrogen gas, hydrogen-rich water, hydrogen-rich saline, instillation, and dialysis solution (Table 1). Supposing that a 60-kg person drinks 1000 mL of saturated hydrogen-rich water (1.6 ppm or 0.8 mM) per day, 0.8 mmoles of hydrogen is consumed by the body each day, which is predicted to give rise to a hydrogen concentration of 0.8 mmoles/(60 kg × 60%) = 0.022 mM (2.8% saturation = 0.022 mM/0.8 mM). As hydrogen mostly disappears in 10 min by dissipation in exhalation (unpublished data), an individual is exposed to 2.8% hydrogen only for 10 min. On the other hand, when a person is placed in a 2% hydrogen environment for 24 hrs, body water is predicted to become 2% saturation (0.016 mM). Even if we suppose that the hydrogen concentration after drinking hydrogen water remains the same for 10 min, areas under the curves of hydrogen water and 2% hydrogen gas are 0.022 mM × 1/6 hrs and 0.016 mM × 24 hrs, respectively. Thus, the amount of hydrogen given by 2% hydrogen gas should be 104 or more times higher than that given by drinking hydrogen water. In addition, animals and patients are usually not able to drink 100%-saturated hydrogen water. If the hydrogen concentration is 72% of the saturation level, the peak concentrations achieved by drinking hydrogen water and 2% hydrogen gas should be identical (0.022 mM × 72% = 0.016 mM). Nevertheless, hydrogen water is as effective as, or sometimes more effective than, hydrogen gas.

In addition, orally taken hydrogen can be readily distributed in the stomach, intestine, liver, heart, and lung but is mostly lost in exhalation. Thus, hydrogen concentrations in the arteries are predicted to be very low. Nevertheless, marked hydrogen effects are observed in the brain, spinal cord, kidney, pancreas muscle, and cartilage, where hydrogen is carried via arteries.

The second enigma is intestinal production of hydrogen gas in rodents and humans. Although no mammalian cells can produce hydrogen endogenously, hydrogen is produced by intestinal bacteria carrying hydrogenase in both rodents and humans. We humans are able to make a maximum of 12 liters of hydrogen in our intestines []. Specific-pathogen-free (SPF) animals are different from aseptic animals and carry intestinal bacteria that produce hydrogen. The amount of hydrogen taken by water or gas is much less than that produced by intestinal bacteria, but the exogenously administered hydrogen demonstrates a prominent effect.

In a mouse model of Concanavalin A-induced hepatitis, Kajiya and colleagues killed intestinal bacteria by prescribing a cocktail of antibiotics []. Elimination of intestinal hydrogen worsened hepatitis. Restitution of a hydrogenase-negative strain of E. coli had no effects, whereas that of a hydrogenase-positive strain of E. coli ameliorated hepatitis. This is the only report that addressed a beneficial effect of intestinal bacteria, and no human study has been reported to date. Kajiya and colleagues also demonstrated that drinking hydrogen-rich water was more effective than the restitution of hydrogenase-positive bacteria. If intestinal hydrogen is as effective as the other hydrogen administration methods, we can easily increase hydrogen concentrations in our bodies by an  α-glucosidase inhibitor, acarbose [], an ingredient of curry, turmeric [], or a nonabsorbable synthetic disaccharide, lactulose []. The enigma of intestinal bacteria thus needs to be solved in the future.

## 7. Summary and Conclusions

Effects of hydrogen have been reported in 63 disease models and human diseases (Table 1). Only two diseases of cerebral infarction and metabolic syndrome have been analyzed in both rodents and humans.

Lack of any adverse effects of hydrogen enabled clinical studies even in the absence of animal studies. Some other human studies including Parkinson’s disease are currently in progress, and promising effects of hydrogen are expected to emerge for many other human diseases. We also have to elucidate molecular bases of hydrogen effects in detail.

## 8. Added Note in Proof

We recently reported a line of evidence that molecular hydrogen has no dose-response effect in a rat model of Parkinson’s disease [].

. 2012; 2012: 353152.
Published online 2012 Jun 8. doi:  [10.1155/2012/353152]
PMCID: PMC3377272
PMID: 22720117

# Molecular Hydrogen as an Emerging Therapeutic Medical Gas for Neurodegenerative and Other Diseases

1Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan
2Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi 487-8501, Japan
3Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
Received 2012 Jan 11; Revised 2012 Mar 24; Accepted 2012 Apr 13.

## Acknowledgments

Works performed in the authors’ laboratories were supported by Grants-in-Aid from the MEXT and MHLW of Japan and from the Priority Research Project of Aichi.

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# A Randomized Double-Blind, Placebo-Controlled Pilot Study

## Abstract

### Objectives

The purpose of this study was to investigate whether the ingestion of alkaline-reduced water (ARW) is helpful in improving the symptoms of diarrhea-predominant irritable bowel syndrome (IBS).

### Methods

Twenty-seven patients (male, 25.9%; mean, 41.7 years old) with diarrhea-predominant IBS were randomly allocated to two groups. For eight weeks, the ARW group (n = 13) ingested at least 2 liters/day of ARW, while the control group (n = 14) ingested placebo water. IBS symptom scores (quality-of-life, abdominal pain/discomfort), stool form, and frequency were assessed before and after treatment via questionnaires.

### Results

Eight patients (61.5%) in the ARW group and six patients (42.9%) in the control group indicated that their symptoms had improved in more than four out of the eight weeks of treatment (p = 0.449). The IBS quality-of-life score significantly improved from 57.2 to 30.8 in the ARW group; this improvement was significantly greater than the slight improvement from 48.7 to 42.2 observed in the control group (p = 0.029). The abdominal pain score improved from 1.8 to 0.9 in the ARW group and from 1.8 to 1.1 in the control group, with no significant group difference (p = 0.232).

### Conclusions

Drinking ARW for eight weeks improves the quality of life in patients with diarrhea-predominant IBS.

## 1. Introduction

Irritable bowel syndrome (IBS) is a functional intestinal disorder accompanied by abdominal pain and bowel habit changes, without evidence of an underlying injury. It is a very common disease, occurring in about 11% of people worldwide []. According to the Korean National Health Insurance System database, 5.1% of men and 6.9% of women were diagnosed with IBS []. IBS is one of the most common illnesses in primary care, with a repeated cycle of deterioration and relief over the years. Improving symptoms through appropriate treatment is important; IBS lowers the quality of life and increases medical costs []. Patients with IBS also suffer from anxiety, major depressive disorder, and chronic fatigue syndrome []. However, the cause and mechanisms underlying the various symptoms are not entirely understood. Many hypotheses have been proposed, including small bowel bacterial overgrowth syndrome, genetic factors, food hypersensitivities, gastrointestinal motility disorders, gut-brain axis alterations, hypersensitivity of the intestine, and psychosocial factors []. Recent studies indicate that the intestinal microbiota is one of the important factors affecting the onset of IBS [].

Various drugs have been used to improve symptoms, including antacids, antispasmodics, and drugs that stimulate gastrointestinal motility (prokinetic agents). However, with a lack of convincing evidence for a pathophysiological basis, conventional therapies have not achieved complete symptom improvement. Therefore, several alternative therapeutic methods, including dietary changes, probiotics, and other medications, have been proposed []. Furthermore, mineral water with various electrolyte compositions has been utilized in the treatment of functional gastrointestinal diseases; mineral water supplements have been reported to improve functional dyspepsia associated with IBS by controlling gastric acid output and intestinal transit time []. In addition, carbonated water not only attenuates the hunger but also improves dyspeptic symptoms and heartburn []. Drinking sulfur-rich mineral water for more than three weeks was found to be effective in treating constipation by increasing frequency of bowel movements []. Bicarbonate-containing alkaline-reduced water (ARW) has also been hypothesized to affect various digestive functions. Although animal studies have provided evidence that ARW is effective in treating functional bowel disease, human studies are lacking []. Therefore, the purpose of this randomized double-blind pilot study was to evaluate the effect of ARW ingestion on diarrhea-predominant IBS.

## 2. Methods

### 2.1. Ethical Approval

This study was conducted in accordance with the ethical principles for medical research involving human subjects in the Declaration of Helsinki. This study was approved by the Seoul National University Bundang Hospital Medical Ethics Committee (IRB number: E-1405/250-002) and aspires to protect the lives, health, privacy, and dignity of the research participants. Thus, the purpose and characteristics of the clinical trial were fully explained to the participants. Only patients who voluntarily signed an informed consent were included, and patients were allowed to stop participating at any time during the trial. All results obtained in this clinical study are confidential.

### 2.2. Study Population

Men and women aged 18–75 years who met Rome III criteria [] for diarrhea-predominant IBS, had no underlying disease of the colon on a sigmoidoscopy or colonoscopy performed within 5 years prior to screening, and could understand and respond to the symptom questionnaires were included. Rome III criteria for IBS involve recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months with two or more of the following: improvement with defecation, onset associated with a change in stool frequency, or onset associated with a change in stool form []. Diarrhea-predominant IBS involves loose or watery stools in more than 25% of bowel movements and hard or lumpy stool in less than 25% of bowel movements.

The following were excluded: patients with a psychiatric history; patients with untreated malignant tumors; patients with severe liver or kidney disease (AST, ALT levels 3-fold greater than the normal upper limit, and serum creatinine levels 1.5-fold greater than the normal upper limit); patients with severe heart failure; patients with acute gastrointestinal tract infection within the last 3 months. In addition, patients who were taking medications during the study period that could affect the results were also excluded. This included drugs that might influence IBS symptoms, such as antispasmodics, laxatives, prokinetics, anticholinergics, antianxiety drugs, antidepressants, analgesics, thyroid hormone, antibiotics, and steroids.

It is difficult to predict the therapeutic response rate between the test group and the control group since similar studies related to ARW have not existed before. This is a small-scale preliminary pilot study to investigate feasibility, adverse events, and improvement before a full-scale research project. This study was planned with 30 participants per group, which is the minimum number of participants recommended in a pilot study []. Given an estimated dropout rate of 15%, at least 35 people per group were planned to be enrolled.

### 2.3. Randomization and Allocation

Patients who were diagnosed with diarrhea-predominant IBS by Rome III criteria were equally allocated to experimental and control groups. Randomization was performed using a 1 : 1 computerized block randomization with a predetermined random code. Because both the investigator and the patients were blinded, a research coordinator performed the random assignment. The research coordinator did not provide information on randomization to the patients and researchers until the end of the study. Neither the participants nor the researchers could distinguish group assignments.

### 2.4. Study Design

A flowchart of the study design is provided in Figure 1. Patients completed screening tests (blood, urinalysis, colonoscopy, and a past medical history questionnaire) 1–3 weeks before participating in the study. Laboratory evaluation included assessments of liver function (albumin, total bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels), kidney function (creatinine and blood urea nitrogen levels), electrolytes (sodium, potassium, chloride, calcium, and inorganic phosphorus levels), and the complete blood count (CBC).

Schedule of patients participating in the study.

Baseline questionnaires on the IBS quality of life, abdominal pain/discomfort, stool form, and stool frequency were completed at the start of the study. The IBS quality-of-life questionnaire is an indicator of abdominal discomfort and consists of 34 items (each recorded as 1–5 points: 1: not at all, 2: slightly, 3: moderately, 4: quite a bit, and 5: extremely) []. Symptom scores for abdominal pain/discomfort were rated on a scale of 0–4 (0: asymptomatic, 1: mild, 2: moderate, 3: severe, and 4: very severe) and were based on the worst level of the day. Abdominal discomfort was defined as an uncomfortable sensation not described as pain. Stool form was assessed using the Bristol stool scale, which is a diagnostic tool designed to classify the form of human feces into seven categories. In general, types 1 and 2 (hard or lumpy stool) indicate constipation, and types 5–7 (soft or watery stool) indicate diarrhea []. In addition, the number of bowel movements was recorded daily.

The experimental group ingested ARW from an installed test device, while the control group ingested placebo water from a sham device. Both groups were instructed to ingest more than 2 liters per day for eight weeks. Participants visited the hospital every two weeks and completed self-administered questionnaires on compliance, adverse effects, the amount ingested, symptom scores (abdominal pain/discomfort), stool form, and the number of daily bowel movements. Questionnaires on the IBS quality of life were completed only at the end of the eighth week. If adverse events occurred during the trial period, participants were instructed to stop the medication immediately and visit an outpatient clinic.

The primary outcome was the proportion of participants with adequate symptomatic improvement in more than four weeks of the 8-week treatment period. The secondary outcomes were changes in IBS quality of life, symptom scores (abdominal pain/discomfort), and stool form/frequency.

### 2.5. Research Equipment

ARW with a pH of 8.5–10.0 was produced using an alkali water ionizer (Kim Young Kwi alkali water ionizer, KYK33000). Placebo water was prepared using a sham device (model name: sham KYK33000), which was not able to generate ARW, but had the same appearance as that of the test apparatus. The devices were installed at the patient’s home and patients were allowed to drink water as needed.

### 2.6. Statistical Analyses

Statistical analyses were performed using SPSS for Windows (ver. 22.0, IBM Corporation, Chicago, IL, USA) and STATA software (ver. 14.0, STATA Corporation, College Station, TX, USA). Group differences were evaluated using Student’s t-test for continuous variables and the Chi-square or Fisher’s exact test for categorical variables. Group differences in treatment-related changes in variables related to IBS (abdominal pain/frequency, stool form, and frequency of bowel movements) were evaluated using a linear mixed model with an interaction term between group and time (before and after treatment). Changes in the IBS quality-of-life score were evaluated using the paired t-test. Two-sided p values less than 0.05 were considered statistically significant.

## 3. Results

### 3.1. Baseline Characteristics

Only 29 were enrolled in the study and 2 dropped out during the study; because the patients were burdened with drinking more than 2 liters of water a day for a long time, we failed to enroll the intended 70 patients. Finally, 13 patients in the ARW group and 14 patients in the control group completed the study (Figure 2). There were no significant group differences in baseline characteristics (Table 1). Ten out of thirteen (76.9%) patients in the ARW group and ten out of fourteen (71.4%) patients in the control group were women. The mean age in the ARW group was slightly higher compared to that of the control group, but without statistical significance (43.3 versus 40.1, p = 0.584). At the beginning of the study, IBS symptom scores (quality-of-life, abdominal pain/discomfort), Bristol stool form, and stool frequency were not significantly different between the two groups. In addition, the consumption of water was similar in the two groups (ARW group: 2,124 ± 900 ml/day; control group: 2,052 ± 648 ml/day, p = 0.834).

CONSORT flow diagram of patient recruitment.

### Table 1

Characteristics of baseline demographics of patients.

Alkaline-reduced water group
(n = 13)
Control group
(n = 14)
p value
Female, n (%) 10 (76.9%) 10 (71.4%) 0.745
Mean age ± SD (years) 43.3 ± 14.4 40.1 ± 15.7 0.584
Initial symptom scores
Quality-of-life score 57.2 ± 28.0 48.7 ± 26.4 0.428
Abdominal pain 1.8 ± 0.9 1.8 ± 0.8 0.983
Abdominal discomfort 1.8 ± 0.8 2.1 ± 0.8 0.362
Stool form (BSFS) 5.3 ± 0.5 5.3 ± 1.4 0.939
Stool frequency/day 2.6 ± 1.2 1.9 ± 1.0 0.130
Amount of water (ml/day) 2,124 ± 900 2,052 ± 648 0.834

SD: standard deviation; BSFS: Bristol stool form scale.

### 3.2. Primary Outcome Measure

Table 2 shows the number of responders (a favorable symptom improvement in more than four weeks of the eight-week treatment period) and nonresponders in each group. Although the proportion of patients responding to the treatment was higher in the ARW group (8/13, 61.5%) than in the control group (6/14, 42.9%), the difference was not statistically significant (Fisher’s exact test, p = 0.449).

### Table 2

Proportion of responders who showed symptomatic improvement after treatment (primary outcome measure).

Alkaline-reduced water group (n = 13) Control group (n = 14) p value
Responder, n (%) 8 (61.5%) 6 (42.9%) 0.449
Nonresponder, n (%) 5 (38.5%) 8 (57.1%)

### 3.3. Secondary Outcome Measures

After eight weeks of treatment, the IBS quality-of-life score had improved from 57.2 to 30.8 points in the ARW group and from 48.7 to 42.2 in the control group (Table 3), with a significant group difference (Figure 3(a)p = 0.029). The abdominal pain score improved from 1.8 to 0.9 in the ARW group and from 1.8 to 1.1 in the control group, without a statistically significant group difference (Figure 3(b)p = 0.232). Abdominal discomfort, stool form, and stool frequency were somewhat improved in the ARW group; however, there were no significant group differences (Figures 3(c)3(e)).

Graph of change before and after treatment of IBS. (a) Quality-of-life score. (b) Abdominal pain score. (c) Abdominal discomfort score. (d) Bristol stool form scale. (e) Stool frequency per day.

### Table 3

Symptom scores of patients before and after treatment (secondary outcome measures).

Alkaline-reduced water group (n = 13) Control group
(n = 14)
p value
Quality-of-life score Week 0 57.2 ± 28.0 48.7 ± 26.4 0.428
Week 8 30.8 ± 24.9 42.2 ± 36.3 0.353

Abdominal pain Week 0 1.8 ± 0.9 1.8 ± 0.8 0.983
Week 2 1.6 ± 1.0 1.7 ± 0.8 0.796
Week 4 1.0 ± 0.9 1.4 ± 0.8 0.324
Week 6 0.8 ± 0.8 1.3 ± 0.7 0.123
Week 8 0.9 ± 0.8 1.1 ± 0.6 0.480

Abdominal discomfort Week 0 1.8 ± 0.8 2.1 ± 0.8 0.362
Week 2 1.9 ± 1.1 1.9 ± 0.7 0.964
Week 4 1.4 ± 1.2 1.6 ± 0.8 0.688
Week 6 1.0 ± 0.7 1.5 ± 0.8 0.113
Week 8 1.2 ± 0.9 1.3 ± 0.7 0.777

Stool form (BSFS) Week 0 5.3 ± 0.5 5.3 ± 1.4 0.939
Week 2 4.9 ± 0.8 5.1 ± 0.8 0.546
Week 4 4.5 ± 0.8 4.6 ± 1.0 0.791
Week 6 4.5 ± 0.8 4.4 ± 1.3 0.747
Week 8 4.7 ± 0.9 4.4 ± 1.0 0.313

Stool frequency/day Week 0 2.6 ± 1.2 1.9 ± 1.0 0.130
Week 2 2.5 ± 1.1 1.8 ± 0.7 0.073
Week 4 2.1 ± 0.9 1.7 ± 0.7 0.198
Week 6 2.0 ± 0.8 1.7 ± 0.9 0.349
Week 8 2.1 ± 0.9 1.7 ± 0.7 0.213

Week 0: the time of randomization; BSFS: Bristol stool form scale.

One of the patients in the control group visited the emergency room due to vomiting and abdominal pain during the second week of the study, but improved with conservative treatment. There were no specific adverse effects associated with ARW ingestion during the eight weeks of the trial.

## 4. Discussion

IBS is one of the most common gastrointestinal disorders in the general population []. In addition, because the effects of medications are often temporary, patients may increase the dose of the medication or take several medications, resulting in the occurrence of side effects. Thus, interest in alternative therapies that do not have side effects (even after long-term use) is growing []. Numerous animal studies have investigated the ability of controlling the electrolyte balance or acidity of the drinking water to treat functional gastrointestinal disorders. For example, animal studies have shown ARW to be effective in treating gastritis because it permanently denatures pepsin []. In addition, an animal study demonstrated that ingestion of more than 1.5 liters of bicarbonate-alkaline mineral water for 30 days improves dyspeptic symptoms []. It has also been suggested that a regular course of crenotherapy with bicarbonate-alkaline mineral water can be used to treat functional dyspepsia, improving gastrointestinal motility and secretory function by modulating the secretion of peptide hormones and regulating the movement of digestive organs []. These studies support the hypothesis that ARW can effectively treat IBS; however, prior to the present study, there were no supporting human clinical trials. Given this preclinical basis, we aimed to investigate whether ARW ingestion for eight weeks improved the symptoms of IBS.

This randomized controlled, double-blind, placebo-controlled study was designed to determine whether the ingestion of ARW could improve the quality of life, abdominal pain/discomfort, stool form, and stool frequency in diarrhea-predominant IBS. In terms of the primary endpoint, the proportion of responders (IBS patients who had improved symptoms in more than four weeks of the 8-week treatment period) was higher in the ARW group than in the control group, but the group difference was not statistically significant. This is likely due to the small number of patients who completed the trial; however, it is hard to predict an effect size, as no similar studies exist. We believe that a positive result could be obtained in a larger-scale study. In contrast to the primary outcome, a significant group difference was observed in the secondary outcomes. The IBS-related quality-of-life and abdominal pain scores were decreased to a greater extent with ARW ingestion compared to those with the ingestion of placebo water. This is a meaningful result because it demonstrates that it is possible to reduce IBS symptoms simply by ingesting water with a different pH, without taking any other medication. In addition, ARW has few adverse effects; thus, it shows potential in becoming an important complementary therapy for functional bowel disease. However, there were no significant group differences in the stool form and frequency improvements. At the beginning of the study, the frequency of bowel movements in both groups was 2-3 times a day, which is less than that for the definition of diarrhea (more than three times a day). Thus, the patients in both groups mainly had mild diarrhea, which may explain the lack of a significant change in symptom scores with treatment.

The mechanism by which ARW improves IBS symptoms remains unclear. ARW refers to water with a pH of at least 8.4; in contrast, most tap or bottled water has a pH between 6.7 and 7.4 []. ARW is thought to increase the pH level of the stomach given its large amount of bicarbonate ions. Interestingly, just infusing a small amount (0.1 mol/L) of acid into the stomach can aggravate indigestion in most people []. In addition, acidification of the duodenum exacerbates dyspeptic symptoms by inducing proximal gastric relaxation and inhibiting gastric accommodation to a meal []. In one animal study, duodenal acidification-induced gastric hypersensitivity could be the cause of dyspepsia in patients with IBS and serotonin 5-HT3 receptors play a key role []. Furthermore, in patients with pancreatic insufficiency, such as cystic fibrosis, the small intestine is exposed to an acidic environment, resulting in impaired absorption. Rapid neutralization of gastric acid in the proximal portion of the duodenum and tight regulation of the gastrointestinal pH play important roles in maintaining nutrient absorption and function in the intestines []. In addition, mineral water with a unique electrolyte composition may help improve the symptoms of indigestion []. Carbonated water could regulate gastrointestinal motility diseases by stimulating bile flow and pancreatic exocrine secretion. Furthermore, drinking carbonated water for more than 15 days has been shown to improve gallbladder muscle contractions []. The ingestion of water containing a lot of mineral salts has been shown to improve gastric emptying in patients with indigestion []. It is presumed that the various ions contained in mineral water directly or indirectly (via neuroendocrine secretion of vasointestinal peptides) stimulate the smooth muscle involved in gastrointestinal motility. These actions appear to improve the symptoms of IBS by improving intestinal transit time and excretory capacity. These actions are thought to not only reduce the bowel transit time, but also promote gastrointestinal hormone secretion, thereby improving abdominal bloating. We expect that large-scale studies on ARW with various electrolytic compositions will proceed in the future.

Gut microbiota appear to be one of the important factors contributing to the cause and pathophysiology of IBS []. Postinfectious IBS should be suspected when the patient complains of dyspepsia or abdominal discomfort after acute gastroenteritis []. Postinfectious IBS is thought to be due to persistent low-grade inflammation and alteration of gut flora intestinal microorganisms. The composition of gut microbiota is also associated with the pathophysiology of IBS and the host immune response []. Abundance of Cyanobacteria is associated with bloating, satiety, and increased abdominal discomfort. The amount of Proteobacteria is associated with pain threshold []. Therefore, it was suggested that probiotics, antibiotics, and fecal microbiota transplantation might be effective in the treatment of IBS []. Many gastrointestinal disorders, including IBS, are caused by an imbalance of residential microflora of the intestinal tract. Human intestinal microbiota consist of 96–99% anaerobes and 1–4% aerobes. Microorganisms have their own intrinsic reduction potential (Eh) for each species, and aerobic and anaerobic bacteria grow at different oxidation-reduction potentials. Aerobic bacteria require a positive potential of +400 mV and facultative anaerobic bacteria require negative electric potential between −300 and −400 mV. Electrochemically generated reduced water has a negative potential of 0 to −300 mV, while the tap water has a potential of +300 to +450 mV []. By drinking reduced water, it is possible to improve symptoms of functional bowel disease by accelerating the growth of anaerobic bacteria (Lactobacilli andBifidobacteria) and inhibiting the growth of aerobic pathogens.

The present study has some limitations. First, the statistical power was weak because of the small sample size. Second, patients with IBS tend to be somewhat less adherent due to the distrust of conventional therapies and hospitals. Third, although IBS is a highly prevalent disease, there were some difficulties in recruiting patients. Because the participants expressed difficulty in drinking more than 2 liters of water a day, we could not enroll as many patients as intended. In addition, subjects were already taking several medications before participating in the study, so it was not easy to stop them all and treat them with ARW only for 8 weeks. Patients’ compliance should be taken into account when designing large-scale studies on this topic in the future. Fourth, the lifestyle and diet were not controlled except for the medications. These confounding factors may be somewhat offset in the randomization process. Despite these limitations, the main strength of the present study is its randomized, double-blind, placebo-controlled design. Moreover, ARW is a simple and inexpensive treatment that physicians can easily consider in the treatment of IBS. To our knowledge, this is the first study to show whether ARW can improve IBS in humans, irrespective of the mechanism.

In conclusion, the present study suggests that ingestion of ARW can improve the quality of life and reduce abdominal pain in patients with diarrhea-predominant IBS. We hope that this pilot study provides a cornerstone for future large-scale trials on the effectiveness of ARW in the treatment of IBS.

Published online 2018 Apr 15. doi:  [10.1155/2018/9147914]
PMCID: PMC5925025
PMID: 29849734
###### Effects of Alkaline-Reduced Drinking Water on Irritable Bowel Syndrome with Diarrhea: A Randomized Double-Blind, Placebo-Controlled Pilot Study
1Department of Internal Medicine and Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea
2Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
Dong Ho Lee: rk.oc.oohay@nhojlhd
Received 2017 Nov 3; Revised 2018 Mar 4; Accepted 2018 Mar 6.

## Acknowledgments

Statistical analysis support was provided by the Medical Science Research Institute in Seoul National University Bundang Hospital. This study was funded by a grant from Seongnam Industry Promotion Agency’s 2014 Medibio products clinical trial support program.

## Conflicts of Interest

The authors declare that they have no conflicts of interest.

## Authors’ Contributions

Dong Woo Shin analyzed the data and drafted the manuscript. Hyuk Yoon and Dong Ho Lee designed the study and revised the manuscript. Hyun Soo Kim, Yoon Jin Choi, Cheol Min Shin, Young Soo Park, and Nayoung Kim critically reviewed the manuscript. Dong Woo Shin and Hyuk Yoon have contributed equally to this work.

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Articles from Evidence-based Complementary and Alternative Medicine : eCAM are provided here courtesy of Hindawi Limited

# Hydrogen-rich water for improvements of mood, anxiety, and autonomic nerve function in daily life

## Abstract

Health and a vibrant life are sought by everyone. To improve quality of life (QOL), maintain a healthy state, and prevent various diseases, evaluations of the effects of potentially QOL-increasing factors are important. Chronic oxidative stress and inflammation cause deteriorations in central nervous system function, leading to low QOL. In healthy individuals, aging, job stress, and cognitive load over several hours also induce increases in oxidative stress, suggesting that preventing the accumulation of oxidative stress caused by daily stress and daily work contributes to maintaining QOL and ameliorating the effects of aging. Hydrogen has anti-oxidant activity and can prevent inflammation, and may thus contribute to improve QOL. The present study aimed to investigate the effects of drinking hydrogen-rich water (HRW) on the QOL of adult volunteers using psychophysiological tests, including questionnaires and tests of autonomic nerve function and cognitive function. In this double-blinded, placebo-controlled study with a two-way crossover design, 26 volunteers (13 females, 13 males; mean age, 34.4 ± 9.9 years) were randomized to either a group administered oral HRW (600 mL/d) or placebo water (PLW, 600 mL/d) for 4 weeks. Change ratios (post-treatment/pre-treatment) for K6 score and sympathetic nerve activity during the resting state were significantly lower after HRW administration than after PLW administration. These results suggest that HRW may reinforce QOL through effects that increase central nervous system functions involving mood, anxiety, and autonomic nerve function.

## Introduction

Health and a vibrant life are much craved by everyone. To improve quality of life (QOL), maintain a healthy state, and prevent the onset of various diseases, evaluation of interventional effects for improving QOL is important. The high metabolic rate of the brain results in the generation of disproportionate amounts of reactive oxygen and nitrogen species, leading to increased oxidative stress. Increased oxidative stress and lipid peroxidation initiate a cascade of proinflammatory signals, leading to inflammation. Altered homeostasis of oxidation, inflammation, and protein aggregation has been suggested to contribute to the death of neurons, which is directly related to impairments in various cognitive domains. As such, chronic oxidative stress and inflammation may cause deteriorations in the function of the central nervous system, leading to reductions in QOL. Hydrogen has antioxidant activity and can prevent inflammation.,, The distribution of hydrogen throughout the brain and body indicates actions both in the central and peripheral nervous systems. Previous clinical studies have shown that hydrogen-rich water (HRW) reduces concentrations of markers of oxidative stress in patients with metabolic syndrome,,improves lipid and glucose metabolism in patients with type 2 diabetes, improves mitochondrial dysfunction in patients with mitochondrial myopathies, and reduces inflammatory processes in patients with polymyositis/dermatomyositis. In another study, exercise-induced declines in muscle function among elite athletes were also improved by administering HRW. Although such findings suggest that HRW may help alleviate symptoms of several diseases and increase the physical performance of athletes, the effects of prolonged HRW ingestion on the QOL of individuals in the general population remain unknown.

Some reports have demonstrated that oxidative stress is associated with QOL in patients with chronic obstructive pulmonary disease and cervical cancer., During oncological treatment among patients with cervical cancer, antioxidant supplementation was found to be effective in improving QOL. In addition, Kang et al. reported that treatment with HRW for patients receiving radiotherapy for liver tumors decreased oxidative stress and improved QOL. Although the association between oxidative stress and QOL in healthy individuals is still unclear, aging, job stress, and cognitive load over the course of several hours in healthy individuals have also been found to induce increases in oxidative stress,,,, suggesting that preventing the accumulation of oxidative stress caused by daily stress and daily work may contribute to the maintenance of QOL and amelioration of the effects of aging. Continuous HRW intake might therefore be expected to reduce accumulation of oxidative stress, thus helping to prevent decreases in QOL.

The aim of the present study was to investigate the effects of drinking 600 mL of HRW per day for 4 weeks on the QOL of adult volunteers using questionnaires for sleep, fatigue, mood, anxiety, and depression, an autonomic function test, and a higher cognitive function test.

## Subjects and Methods

### Subjects

Thirty-one adult volunteers between 20 and 49 years old participated in this double-blinded, randomized, placebo-controlled study with a two-way crossover design. Exclusion criteria comprised: history of chronic illness; chronic medication or use of supplemental vitamins; employment in shift work; pregnancy; body mass index ≤ 17 or ≥ 29 kg/m2; food allergy; history of smoking; or history of drinking excessive amounts of alcohol (≥ 60 g/day). Shift workers were excluded because the water was administered at breakfast and dinner, the timings of which are irregular among shift workers. In addition, the mental and physical conditions of shift workers can be greatly affected by the shift schedule for the preceding 2 days, which may impact the results obtained from the questionnaires used in this study. Before each experiment, participants were asked to refrain from drinking alcohol, since drinking excessive amounts of alcohol carries significant risks of fluctuations in physical condition. All experiments were conducted in compliance with national legislation and the Code of Ethical Principles for Medical Research Involving Human Subjects of the World Medical Association (the Declaration of Helsinki) and registered to the UMIN Clinical Trials Registry (No. UMIN000022382). The study protocol was approved by the Ethics Committee of Osaka City University Center for Health Science Innovation (OCU-CHSI-IRB No. 4), and all participants provided written informed consent for participation in the study.

### Study design

Time course of the experiments.

Note: Participants were randomly divided into two study groups. The experiment consisted of 4 weeks of hydrogen-rich water (HRW) administration or placebo water (PLW) administration, a 4-week washout period, and then another 4 weeks of PLW administration or HRW administration. Before (pre) and after (post) each period of HRW or PLW administration, subjective and objective measurements for quality of life were obtained, such as results for sleep, mood, anxiety, feelings of depression, autonomic nerve function, and cognitive function.

### Questionnaire

Severity of fatigue was measured using the Chalder Fatigue Scale (CFS) and a modified version of the Osaka City University Hospital Fatigue Scale. Mood and anxiety were evaluated using the K6 scale.Symptoms of depression were measured using the Center for Epidemiologic Studies Depression Scale.General sleepiness and daytime sleepiness scores were calculated using the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale, respectively. The reliability and validity of the Japanese versions of these questionnaires have been confirmed.,,,,,

### Autonomic function test

Participants underwent simultaneous electrocardiography and photoplethysmography using a Vital Monitor 302 system (Fatigue Science Laboratory, Osaka, Japan) while sitting quietly with their eyes closed for 3 minutes. These data were analyzed using MemCalc software (GMS, Tokyo, Japan). Frequency analyses for R-R interval variation from electrocardiography and a-a interval variation as the second derivative of photoplethysmography (accelerated plethysmography) were performed using the maximum entropy method, which is capable of estimating the power spectrum density from short time series data, and is adequate for examining changes in heart rate variability under different conditions of short duration.,The power spectrum resolution was 600 Hz. For frequency analyses, the low-frequency component power (LF) was calculated as the power within a frequency range of 0.04–0.15 Hz, and the high-frequency component power (HF) was calculated as that within a frequency range of 0.15–0.4 Hz. HF is vagally mediated,,, whereas LF originates from a variety of sympathetic and vagal mechanisms., Some review articles,, mentioned that LF reflects sympathetic nerve activity and is used as a marker of sympathetic nerve activity in original articles. Before autonomic nerve function testing was conducted for 3 minutes, a practice test was conducted for a period of 1 minute, in accordance with previous studies.,, The reliability of these tests has been confirmed.,

### Cognitive function test

Since previous studies have revealed that a switching attention task is useful for evaluating reduced performance under fatigue conditions,,, we used task E of the modified advanced trail making test (mATMT) as a switching attention task for evaluating executive function., Circles with numbers (from 1 to 13) or kana (Japanese phonograms, 12 different letters) were shown in random locations on a screen, and participants were required to use a computer mouse to alternately touch the numbers and kana; this task thus required switching attention. When participants touched a target circle, it remained in the same position, but its color changed from black to yellow. Participants were instructed to perform the task as quickly and correctly as possible, and continuously performed this task for 5 minutes. We evaluated three indices of task performance: the total count of correct responses (number of correctly touched numbers and letters); the total count of errors (number of incorrectly touched numbers and letters); and the motivational response (reaction time from a finished trial to the next trial). Based on our previous study, before participants performed task E of the mATMT on each experimental day, they practiced for a period of 1 minute. The reliability of this test has been confirmed.,

### Blood sample analyses

Blood samples were collected from the brachial vein. The amount of blood sampled was 13 mL per experimental day. We thus collected blood samples on four occasions (once per experimental day) in the study. Blood samples for serum analyses were centrifuged at 1,470 × g for 5 minutes at 4°C. The concentration of high-sensitivity C-reactive protein (hs-CRP) in each serum sample was assessed by particle-enhanced immunonephelometry using a BNII analyzer (BN II ProSpec; Siemens, Munich, Germany). Oxidative activity in each serum sample was assessed with the reactive oxygen metabolites-derived compounds (d-ROMs) test (Diacron International, Grosseto, Italy), while anti-oxidative activity was measured with the biological anti-oxidant potential (BAP) test (Diacron International) using a JCABM1650 automated analyzer (JEOL, Tokyo, Japan). The concentrations of ROMs are expressed in Carratelli units (1 CARR U = 0.08 mg of hydrogen peroxide/dL). The oxidative stress index (OSI) was calculated using the following formula: OSI = C × (d-ROMs/BAP), where C denotes a coefficient for standardization to set the mean OSI in healthy individuals at 1.0 (C = 8.85). All supernatants were stored at -80°C until analyzed. Assays for hs-CRP were performed at LSI Medience Corporation (Tokyo, Japan) and those for serum d-ROMs and BAP were performed at Yamaguchi University Graduate School of Medicine.

### Daily daytime activity and daily journal

Daily daytime activity, representing the expenditure of calories and amount of physical activity (METs × time) was recorded using an Active style Pro HJA-350IT pedometer (OMRON, Kyoto, Japan). A daily journal was kept for 4 weeks, and included information on fatigue (based on a visual analogue scale from 0, representing “no fatigue”, to 100, representing “total exhaustion”) just after waking up and before bedtime, sleeping times, physical condition (1, good; 2, normal; or 3, bad), and special events (if the day was different from a usual day: 1, no; or 2, yes). We carefully checked the daily journal every four weeks, on the 2nd, 3rd, and 4th experimental days.

### Statistical analyses

First, we tested the normality (parametric or non-parametric distributions) of each measured parameter using the Kolmogorov-Smirnov test. Values are presented as the mean ± standard deviation or median and interquartile range based on the results of Kolmogorov-Smirnov test. The Wilcoxon signed-rank test for non-parametric parameters and paired t-test for differences between HRW and PLW administrations after two-way repeated-measurement analysis of variance for parametric parameters were conducted. If significant changes were observed by comparisons within each condition (pre- vs. post-HRW; pre- vs. post-PLW) or between post-treatment values (post-HRW vs. post-PLW), then we compared change ratios between post-HRW/pre-HRW and post-PLW/pre-PLW using the Wilcoxon signed-rank test or paired t-test. All P values were two-tailed, and those less than 0.05 were considered statistically significant. Statistical analyses were performed using IBM SPSS Statistical Package version 20.0 (IBM, Armonk, NY, USA).

## Results

### General results

During the study, we excluded five participants from data analyses due to symptoms of hay fever, prolonged medication use because of a cold, insufficient intake of HRW or PLW intake (≥ 85%), or a frequency of special events ≤ 15% as recorded in the daily diary. We thus analyzed data from a total of 26 participants (13 females, 13 males; mean age, 34.4 ± 9.9 years; mean body mass index, 21.5 ± 2.6 kg/m2). No side, order, and carry-over effects were observed from the oral administrations of HRW and PLW in any participant.

### Questionnaire results

Results from the questionnaires are summarized in Table 1. No questionnaire scores at baseline (pre) showed any significant differences between HRW and PLW administration groups. With HRW administration, scores for K6, CFS, and PSQI were significantly decreased after the 4-week administration period. In addition, the change ratio (post/pre) for K6 score was significantly lower in the HRW administration group than in the PLW administration group (Figure 2). No significant changes were seen in any other questionnaire scores (modified version of the Osaka City University Hospital Fatigue Scale, Center for Epidemiologic Studies Depression Scale or Epworth Sleepiness Scale) after HRW administration and no significant changes in any of the scores were seen after PLW administration. Likewise, these scores did not differ significantly between HRW and PLW after administration.

### Table 1

Changes in parameters related to quality of life due to hydrogen-rich water (HRW) or placebo water (PLW) administration

Comparison of change ratios (post-treatment/pre-treatment) for parameters related to quality of life with administration of hydrogen-rich water (HRW) or placebo water (PLW) for 4 weeks.

Note: Change ratios for K6 score for mood (A) and anxiety and the low-frequency component power (LF) for autonomic nerve function (B). *P < 0.05.

### Autonomic function results

Results for the autonomic nerve function are summarized in Table 1. LF, HF, and LF/HF ratio at baseline (pre) did not differ significantly between HRW and PLW administrations, indicating similar autonomic nerve function in the two groups before water intake. Although the HF and LF/HF ratio were not significantly affected by 4-week administrations of HRW or PLW, LF after HRW administration was significantly lower than that after PLW administration. The change ratio (post/pre) for LF was also significantly lower in the HRW administration group than in the PLW administration group (Figure 2).

### Cognitive function results

Results for the cognitive function test are shown in Table 1. Motivational response and total counts of correct responses and errors at baseline (pre) did not differ significantly between HRW and PLW administrations, indicating similar cognitive function between groups before water intake. Motivational response after HRW administration was significantly faster than that before HRW administration. The change ratio (post/pre) for motivational response was not significantly different in the HRW administration group than in the PLW administration group. No significant differences in motivational response, total counts of correct responses, or errors after water administration were seen between HRW- and PLW-administered conditions.

### Blood sample results

No significant differences were seen in any blood parameters (hs-CRP, d-ROMs, BAP, and OSI) before HRW or PLW administration (Table 1), indicating the comparability of the two groups before water intake. After HRW and PLW administrations, we again found no significant differences in these blood parameters.

### Daily daytime activity and daily journal results

The daily expenditure of calories and amount of physical activity during the 4-week administration periods did not differ significantly between HRW and PLW administration conditions (Table 2). Similarly, visual analogue scale scores for fatigue just after waking and before bedtime, sleeping times, physical condition, and counts of special events were comparable between HRW and PLW administration conditions (Table 2), indicating that living habits were successfully controlled during the experimental period in the two groups.

### Table 2

Daily daytime activity and data recorded in the daily journal during the hydrogen-rich water (HRW) or placebo water (PLW) administration period (4 weeks)

## Discussion

The present findings suggest that HRW administration for 4 weeks may have improved the QOL of adult volunteers in terms of improved mood and anxiety and reduced activity of the sympathetic nervous system at rest.

In terms of associations between hydrogen and the central nervous system, a report by Ohsawa et al. was the first to demonstrate that molecular hydrogen acts, at least in part, as an anti-oxidant as it binds to hydroxyl ions produced in central nervous system injuries. Previous studies have proposed that HRW administration has neuroprotective effects and anti-aging effects on periodontal oxidative damage in healthy aged rats. In a rat model of Alzheimer’s disease, hydrogen-rich saline prevented neuroinflammation and oxidative stress, and improved memory function. In terms of the association between HRW and QOL, only one study reported that HRW administration for 6 weeks improved QOL scores in patients treated with radiotherapy for liver tumors. Although reports on the effects of HRW administration in healthy populations have not been accumulated, job stress, and acute fatigue caused by mental and physical loading for several hours, have been shown to enhance oxidative stress. As for physical fatigue, in order to alleviate acute physical fatigue in healthy volunteers not including athletes, we have previously demonstrated that treatment with antioxidant supplements is effective.,, The present study provided new findings that HRW affects not only physical condition but also mental conditions such as mood, anxiety, and autonomic nerve function. One of the advantages of HRW is the ability to cross the blood-brain barrier, offering high potential to reduce oxidative stress in the brain. A previous study in rats found that levels of malondialdehyde, a marker of oxidative stress, were around 4.8-fold higher in the brain than in the blood (plasma). These results suggest that HRW may be effective for reducing accumulated oxidative stress in the brain in daily life, potentially contributing to the maintenance of central nervous system activity and preventing decreases in QOL.

In the present study, mood and anxiety levels improved after HRW administration. These negative emotions are also known to be involved in conditions related to oxidative stress; social phobia,,depression, anxiety,, and other neuropsychiatric disorders have been shown to be associated with increased oxidative stress. Neuroinflammation is also related to fatigue, mood, anxiety, and sleep.,,, In older mice, HRW administration succeeded in suppressing depression-like behaviors. These findings suggest that administration of HRW for 4 weeks may be effective for controlling such negative emotions by reducing oxidative stress and inflammation of the central nervous system. Increasing evidence suggests that oxidative stress and inflammation in neurons are involved in the pathological manifestations of many neurological and neuropsychiatric disorders, and HRW administration may thus help alleviate the symptoms of these disorders. Previous study revealed that oxidative stress of the brain causes cognitive and motivational deficits in a mouse model of neuropsychiatric disorder (schizophrenia). In the present study, motivational response of cognitive function test was improved by prolonged HRW intake, suggesting that a reduction of oxidative stress in the brain by the intake of HRW may increase motivational performance of cognitive task.

Stressors can enhance sympathetic hyperactivity, promote oxidative stress, and boost pro-inflammatory cytokine production.,, Autonomic nerve function is thus closely associated with oxidative stress and inflammation. Attenuation of sympathetic nervous system activity during the resting state in adult volunteers may therefore be the result of decreases in inflammation and oxidative stress as an effect of prolonged HRW administration. However, the lack of changes in oxidative stress markers noted in the present study after HRW intake for 4 weeks could be due to the low severity of oxidative stress in the participants. Actually, serum d-ROMs (307.1 ± 49.4 CARR U) and BAP (2,549 ± 194 µM) concentrations at the first measurement point in the present study were within normal ranges based on the results of serum d-ROMs (286.9 ± 100.2 CARR U) and BAP (2,541 ± 122 µM) concentrations measured in 312 healthy participants in our previous study. However, levels of oxidative stress fluctuate depending on daily work load and stress. In addition, the rat study by García-Niño et al. that found malondialdehyde levels around 4.8-fold higher in the brain than in plasma indicate that oxidative stress in the brain is more severe. Daily administration of HRW for 4 weeks may thus contribute to attenuation of and prevention from the cumulative oxidative stress in the brain. Mood, anxiety, and autonomic nerve function could thus potentially be improved. Although the range of sympathetic nerve activity in the present study considers to be normal based on our previous studies,, sympathetic nerve activity also fluctuates depending on daily work load and stress. Therefore, lower sympathetic nerve activity of resting state may contribute to suppress an excessive increase in sympathetic nerve activity after the daily work load and stress.

We conducted this study with a limited number of participants. Before our results can be generalized, studies involving larger numbers of participants are essential.

Although we mainly examined the effects of HRW on the central nervous system, we did not directly evaluate the dynamics of inflammation and oxidation in the brain. Neuroimaging studies using positron emission tomography and magnetic resonance imaging are thus underway in our laboratory to identify the mechanisms underlying the effects of HRW intake on the central nervous system that can improve QOL.

In conclusion, HRW administration for 4 weeks in adult volunteers improved mood, anxiety, and autonomic nerve function, suggesting that HRW administration may offer an effective method to reinforce QOL and maintain good health. In a further study, we will try to identify the effects of HRW administration in participants with ongoing stress or chronic fatigue.

. 2017 Oct-Dec; 7(4): 247–255.
Published online 2018 Jan 22. doi:  [10.4103/2045-9912.222448]
PMCID: PMC5806445
PMID: 29497485

## Acknowledgments

We would like to thank Ms. Mika Furusawa for her excellent technical assistances and Forte Science Communications for editorial help with this manuscript.

## Footnotes

Conflicts of interest

This work was presented at Japanese Society of Fatigue Science, Yamaguchi City, Japan on May 16, 2016. Yasuyoshi Watanabe received funding for the present study from Melodian Corporation. The other authors have no conflicts of interest to declare.

Research ethics

All experiments were conducted in compliance with national legislation and the Code of Ethical Principles for Medical Research Involving Human Subjects of the World Medical Association (the Declaration of Helsinki) and registered to the UMIN Clinical Trials Registry (UMIN000022382). The study protocol was approved by the Ethics Committee of Osaka City University Center for Health Science Innovation (OCU-CHSI-IRB No. 4).

Declaration of participant consent

The authors certify that they have obtained all appropriate participant consent forms. In the form the participants have given their consent for their images and other clinical information to be reported in the journal. The participants understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Data sharing statement

Datasets analyzed during the current study are available from the corresponding author on reasonable request.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Open peer reviewers

Lei Huang, Loma Linda University, USA; Qin Hu, Shanghai Jiao Tong University, China.

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Articles from Medical Gas Research are provided here courtesy of Wolters Kluwer — Medknow Publications

# Modulation of the oxidative plasmatic state in gastroesophageal reflux disease with the addition of molecular hydrogen rich water : A new biological vision

## Abstract

Gastroesophageal reflux disease (GERD), a clinical condition characterized by reflux of gastroduodenal contents in the oesophagus, has proved to demonstrate a strong link between oxidative stress and the development of GERD. Proton pump inhibitors (PPIs) have been universally accepted as first‐line therapy for management of GERD. The potential benefits of electrolysed reduced water (ERW), rich in molecular hydrogen, in improving symptoms and systemic oxidative stress associated with GERD was assessed. The study was performed on 84 GERD patients undergoing control treatment (PPI + tap water) or experimental treatment (PPI + ERW) for 3 months. These patients were subjected to the GERD‐Health Related Quality of Life Questionnaire as well as derivatives reactive oxigen metabolites (d‐ROMs) test, biological antioxidant potential (BAP) test, superoxide anion, nitric oxide and malondialdehyde assays, which were all performed as a proxy for the oxidative/nitrosative stress and the antioxidant potential status. Spearman’s correlation coefficient was used to evaluate the correlation between scores and laboratory parameters. Overall results demonstrated that an optimal oxidative balance can be restored and GERD symptoms can be reduced rapidly via the integration of ERW in GERD patients. The relative variation of heartburn and regurgitation score was significantly correlated with laboratory parameters. Thus, in the selected patients, combination treatment with PPI and ERW improves the cellular redox state leading to the improvement of the quality of life as demonstrated by the correlation analysis between laboratory parameters and GERDsymptoms.

## 1. INTRODUCTION

Generally, oxidative stress can be easily defined as the condition arising from the imbalance between toxic reactive oxygen species (ROS) and the antioxidant systems.1 As the first step in generating persistent ROS, the majority of superoxide anion radicals (·O2) are generated in mitochondria by electron leakage from the electron transport chain. Superoxide dismutase converts the superoxide anion to hydrogen peroxide (H2O2), which is metabolized by glutathione peroxidase and catalase to generate water. Highly reactive hydroxyl radicals (·OH) are generated from H2O2 via the Fenton or Weiss reaction in the presence of catalytically active metals, such as Fe2+ and Cu2+.2 In the last few years, molecular hydrogen (H2) has been pointed out to be a preventive and therapeutic antioxidant. Several research articles have confirmed the efficacy of H2 both in vitro than in various animal models.3 H2, because of its physicochemical properties of solubility, neutrality and small size, has some high distribution properties allowing it to quickly penetrate bio‐membranes and get to intracellular compartments, where it can carry out its biological effects. Ohsawa et al4 first reported that pre‐treatment with H2 inhalation ameliorates brain lesions after cerebral infarction in rats. Emerging data have shown that H2‐rich water has beneficial effects on oxidative stress‐related diseases such as cancer, arteriosclerosis, diabetes, neurodegenerative diseases and the side effects of haemodialysis.5 Moreover, it was reported that H2 treatment resulted in significantly improved gastrointestinal (GI) transit, protected organs from tissue damage induced by ischaemia reperfusion and effectively ameliorated stress‐associated gastric mucosal damage via its anti‐inflammatory, antioxidant and anti‐apoptotic effects.678 A new technology based on electrolysis of water has been suggested for clinical amelioration of several pathologies. Electrolysed reduced water (ERW), rich in H2, generated at the cathode during water electrolysis, has a high pH, low dissolved oxygen and an extremely negative redox potential (ORP).9 Moreover, in our recent study, we have demonstrated that human histiocytic lymphoma cells line U937 cultured in an ERW‐medium could alleviate H2O2‐induced cytotoxicity of cells through the modulation of cellular redox state.10 Gastroesophageal reflux disease (GERD) is a clinical condition in which the reflux of gastric contents into the oesophagus induces complications and complex symptoms, impairing quality of life.1112 Even if the gastric mucosal acts as a protective barrier, pathogens and ingested materials can induce an unbalance of the redox cell state and GI inflammatory responses.13 In fact, several studies have highlighted that oxidative stress is involved in the development and progression of several GI disorders such as GERD, enteritis, gastritis, peptic ulcer, GI cancers and colitis.1415 ROS are produced within the GI tract, but their involvement in pathophysiology of GERD have not been well investigated.1316 The production of ROS in cell systems is attributable to the activity of many enzymes such as peroxidases, xanthine oxidase, NADPH oxidase, NADPH oxidase isoforms, glucose oxidase, lipoxygenases, myeloperoxidase and cyclooxygenases.1317 Proton pump inhibitors (PPIs) have been universally accepted as a first‐line therapy for management of GERD and are among the most commonly prescribed medicines for gastroesophageal reflux and peptic ulcer disease.18PPIs block acid production irreversibly inhibiting H+/K+ adenosine triphosphatase in gastric parietal cell.19 Omeprazole, the first drug in this class, was introduced in 1989 and was followed by lansoprazole (1995), pantoprazole (2000), esomeprazole (2001) and dexlansoprazole (2009). Current guidelines recommend empiric therapy with PPIs for patients suspected of having GERD.11 Despite their efficacy, several studies have shown that a significant proportion of GERD patients are either partial or non‐responders to PPI therapy. In a recent article in JAMA Internal Medicine, some researchers report data on the negative effects of the often overuse of PPIs, widely used in the United States (as well as in Italy, as pointed out by OsMed data).20 A series of systematic reviews have brought further evidence to support the thesis that PPIs are overprescribed and are associated with a number of adverse effects. Numerous observational studies have documented probable causal links with the use of PPIs and adverse reactions, including acute and chronic kidney disease, fractures, hypomagnesaemia, bacterial infections and cardiovascular risk.2122232425 Thus, GERD reduces the quality of life and significantly affects the health care system.26 For these reasons, the aim of this study was to assess the efficacy of H2‐rich water, called ERW, in modulating the symptoms and systemic oxidative stress associated with GERD. We hypothesize that the ERW could be considered as supplementary treatment for GERD, because it could reduce the heartburn and regurgitation in turn enhancing the well‐being of the patients. Thus, the goal of our study was to investigate whether ERW reduces the plasmatic level of oxidative stress in ex vivo peripheral blood mononuclear cells (PBMCs) of GERD patients, relating to scores GERD, as total score (TS), heartburn score (HS) and regurgitation score (RS). Altogether 84 patients reporting moderate to severe heartburn and regurgitation symptoms underwent control treatment (PPI + tap water) or experimental treatment (PPI + ERW) for 3 months. Our findings demonstrated that experimental treatment improves the oxidative balance through a reduction in typical GERD symptoms such as heartburn and regurgitation compared to control treatment.

## 2. MATERIALS AND METHODS

### 2.1. Electrolysed reduced water

Electrolysed reduced water was prepared as described previously using the medical device Alka vitha.10The apparatus for the electrolysis of water consists of an active carbon filter (0.2 μm) for water purification and a Pt‐coated Ti electrode for water electrolysis. Furthermore, the apparatus has a pH control system (pH 8.10‐11.60) and Eh values from −200 to −800 mV. The Eh represents the redox potential of an aqueous solution, and it is a measure of the reductive power ability of dissolved molecular hydrogen (H2).

### 2.2. Patients

We enrolled a group of drug‐naïve patients with a diagnosis of GERD. The diagnosis was carried out in accordance with the guidelines for GERD.27 The study was conducted in compliance with the “ethical principles for medical research involving human subjects” of the Helsinki Declaration. The local ethics committee has revised and finally approved this study (trial registration: number CE; 992 of 2015/07/07). The individuals were patients of the “Sant.ma Annunziata” Hospital of Chieti between September 2015 and March 2016. The study follow‐up ended on June 2016. The study included adults (age ≥ 18 years) who had a diagnosis of GERD, with a history of frequent episodes of GERD‐related symptoms (regurgitation, heartburn, retrosternal pain) for more than a month prior to the study screening. Patients were excluded from the study if they had experienced one of the following conditions within the previous 3 months: acute infections, vascular access thrombosis, acute myocardial infarction, stroke, diabetes, clinically relevant bleedings, major surgical procedures, blood transfusions, systemic inflammatory of metabolic diseases, active malignancies, smoking habit and participation in other experimental clinical studies. Moreover, patients were also excluded if they suffered from any type of GI disorders, gastroduodenal ulcers, Barrett’s oesophagus, use of concomitant therapy, as well as alcohol or drug abuse. Patients with a BMI of <20 and >33 kg/m2, as well as unusual dietary habits (eg vegetarians), were also excluded. The participants of study were subjected to a blood sample and submitted to GERD‐Health Related Quality of Life Questionnaire (GERD‐HRQL), to define successful response both clinically and systemically to the 3‐month dose of PPI or ERW + PPI. C‐reactive protein (CRP) was measured as a non‐specific marker for inflammation. All the patients underwent 2 monitoring visits, at baseline (t 0) and after 3 months (t 1).

### 2.3. GERD‐Health Related Quality of Life Questionnaire (GERD‐HRQL)

The Gastroesophageal Reflux Disease‐Health Related Quality of Life (GERD‐HRQL) instrument is a self‐administered questionnaire introduced to provide a quantitative method of measuring frequency and severity of GI symptoms in gastroesophageal reflux disease (GERD). The purpose of GERD‐HRQL was to measure symptomatic change as a result of medical or surgical treatment of GERD. The GERD‐HRQL instrument is practical and generally administered by simply handing it to the patient during a screening visit.28 The questionnaire measuring 16 items (6 related to heartburn, 2 to dysphagia, 6 to regurgitation, 1 to the impact of medication on daily life and 1 on the satisfaction level) on the VAS scale from 0 (no symptoms) to 5 (worst symptoms). The results are expressed as TS, heartburn score (HS) and RS. TS was calculated by summing the individual scores to questions 1‐15 with scores ranging from 0 (no symptoms) to 75 (worst symptoms). HS was calculated by summing the individual scores to questions 1‐6 with scores ranging from 0 (no heartburn symptoms) to 30 (worst heartburn symptoms). RS was calculated by summing the individual scores to questions 10‐15 with scores ranging from 0 (no regurgitation symptoms) to 30 (worst regurgitation symptoms). Satisfaction level‐related quality of life was measured considering the responses at treatment experience assessing in satisfied, neutral and not satisfied.

### 2.4. Isolation of human peripheral blood mononuclear cells

Blood samples for laboratory screening were collected at t0 (before administration of ERW or tap water + PPI) and t1 (at study end‐point) in 4‐mL endotoxin‐free Heparin tubes (Vacutainer; Becton Dickinson, NJ, USA). Venipuncture was performed in the morning (08.00‐10.00 am.) after an overnight fast and before breakfast. Tubes were kept at room temperature and transported to the laboratory for processing within 1 hour of collection. PBMCs were isolated by density‐gradient centrifugation through Ficoll‐Hypaque (Pharmacia) as described previously.29 Cell viability in each culture was assessed by Trypan blue die exclusion. All solutions were prepared using pyrogen‐free water and sterile polypropylene plastic‐ware and were free of detectable LPS (<0.1 EU/mL), as determined by the Limulus amoebocyte lysate assay (sensitivity limit 12 pg/mL; Associates of Cape Cod, MA, USA). All reagents used were tested before use for mycoplasma contamination (minimum detection level 0.1 μg/mL) (Whittaker Bioproducts, Walkersville, MD, USA) and found negative. The same batches of serum and medium were used in all experiments. After 24 hours incubation, samples were centrifuged at 400 g for 10 minutes at room temperature and supernatants were collected and stored at −80°C until assay. The PBMCs yield per ml of blood was approximately 1 × 106 cells. The plasma was obtained by blood centrifugation as described previously and was kept frozen at −20°C.30

### 2.5. Assessment of oxidative stress

Plasma was tested for total oxidant capacity and antioxidant potential using a derivatives reactive oxygen metabolites (d‐ROMs) and a biological antioxidant potential (BAP) test kit (Diacron International s.r.l., Grosseto, Italy), respectively.

#### 2.5.1. d‐ROMs test

The test is based on the concept that the amount of organic hydroperoxides present in serum is related to the free radicals from which they are formed. Serum sample is dissolved in an acidic buffer (pH 4.8). The d‐ROMs test is based on the ability of a plasma sample to oxidize the chromogen substrate (N‐N‐diethylparaphenilendiamine) to its radical cation; the reaction is monitored photometrically at 37°C at 505 nm, and the results are expressed as Carratelli Units (CARR U, ΔAbs5050 nm/min), where 1 U‐CARR. corresponds to 0.8 mg/L H2O2. The normal values of the test are between 250 and 300 U‐CARR. (Carratelli Units Values) outside this range are considered indicative of an alteration in the equilibrium between pro‐oxidant and antioxidant capability of patients. Values >300 U‐CARR. indicate a condition of oxidative stress.

#### 2.5.2. BAP assay

Through this test, the components of the antioxidant plasma barrier were measured directly by the active scavengers. The BAP test was performed according to the manufacturer’s instructions (Diacron). A chromogen reagent containing trivalent iron was added to a plasma sample. BAP assay is based on the ability of a plasma sample to reduce Fe3+ to its colourless ferrous derivative (Fe 2). The reaction is monitored by photometric reading at 37°C at 505 nm, and the results are expressed in μEq/L of reduced iron using vitamin C as a standard. The optimal value of a BAP test is >2200 μEq/L. Values lower than 2.200 μEq/L indicate a reduced “biological potential” and hence a decreased effectiveness of the antioxidant plasma barrier, according to an arbitrary scale of severity.

#### 2.5.3. Nitro blue tetrazolium (NBT) assay

The production of intracellular superoxide anion was performed using nitro blue tetrazolium (NBT) (Sigma‐Aldrich SRL, Milano, Italy, Catalog No: N6639) as described previously.31 After PBMC extraction, cells were incubated with NBT (0.1 mg/mL) in culture medium for 3 hours at 37°C; and were further washed 3 times with methanol. The amount of NBT‐formazan produced is an index of O2  intracellular level. After the solubilization of crystals in 200 mL of KOH 2M/DMSO solution, the quantization was determined spectrophotometrically (Spec‐traMaxH 190; Molecular Devices) at 630 nm. The results were expressed as nmol/mL of O2  released.

#### 2.5.4. Griess assay

The assay was carried out as described previously.32 Two ×106 cells were seeded in 6 wells/plates, and nitrite was measured in culture supernatants as an indicator of the nitric oxide production. Aliquots of the culture supernatant were mixed with an equal volume of the Griess reagent (Sigma‐Aldrich, USA; Catalog No: G4410) and absorbance was determined at 540 nm using a microplate reader. Sodium nitrite, at concentrations of 0 to 100 μM, was used as a standard to assess nitrite concentrations.

### 2.6. Measurement of CRP

The amount of circulating CRP levels was assayed using specific ELISA development systems (Diagnostics Biochem Canada Inc, Neptune Crescent, London, ON, Canada, Catalog No: CAN‐CRP‐4360). The experiments were performed in triplicate according to the manufacturer’s instructions. CRP values are expressed as mg/L. The CRP assay sensitivity was <10 ng/mL. The intra‐ and inter‐assay reproducibility was >90%. Triplicate values that differed from the mean by more than 10% were considered suspect and were repeated.

### 2.7. Measurement of malondialdehyde (MDA)

MDA levels were assayed using specific ELISA development systems (Elabscience; Catalog No: E‐EL‐0060). Plates were scanned using a specialized charge coupled device cooled tool. The integrated density values of the spots of known standards were used to generate a standard curve. Density values for unknown samples were determined using the standard curve for each patient to calculate the real values in pg/mL. All steps were performed in triplicate and at room temperature. The MDA assay sensitivity was <18.75 ng/mL. The intra‐ and inter‐assay reproducibility was >90%. Triplicate values that differed from the mean by more than 10% were considered suspect and were repeated.

### 2.8. Statistical analysis

The quantitative variables were summarized as mean and standard deviation (SD) or median and interquartile range (IQR), according to their distribution. Qualitative variables were summarized as frequency and percentage. A Shapiro‐Wilk’s test was performed to evaluate the departures from normality distribution for each variable. An analysis of variance (ANOVA) for repeated measures was performed to evaluate the effect of time (baseline vs post‐therapy), group (PPI vs PPI + ERW) and their interaction on laboratory parameters. Chi‐square test was performed to evaluate differences in distribution of d‐ROMs test and BAP test between groups when analysed as categorical data. A Friedman’s test was performed to evaluate the differences in GERD total scores, heartburn score and regurgitation score from baseline to post‐therapy. Mann‐Whitney U‐test was performed to evaluate differences in score relative variation between groups. Spearman’s correlation coefficient (Ρ) was performed to evaluate the correlation among laboratory parameters and scores. The false discovery rate correction (FDR) was used to control the family‐wise type I error rate and an FDR‐adjusted P‐value < .05 was determined to be statistically significant. Statistical analysis was performed using IBM® SPSS Statistics v 20.0 software (SPSS Inc, Chicago, IL, USA).

## 3. RESULTS

### 3.1. Patients

As reported in Figure Figure1,1, 139 patients took part in the study, 7 of these withdrew while 38 were excluded after the screening interview. In the end, 84 consecutive individuals were included in the study. After giving their written informed consent, the patients were assigned to the control treatment (PPI + tap water) or to the experimental treatment (PPI + ERW) for 3 months. According to the protocol, on a daily basis, the participants drank 1.500 mL of ERW containing dissolved H2 or tap water. All patients included into the experimental treatment received the medical device for the time set for the study. Firstly, all patients received a shock treatment of pantoprazole, 40 mg⁄d, orally for 4 weeks and then 20 mg⁄d for 8 weeks. Pantoprazole was taken 30 minutes before breakfast for a period of 3 months. Of the 84 patients with GERD who were enrolled in this survey, 44 patients were female and 40 patients were male. The mean age of the patients was 51.95 ± 10.90 years, ranging from 23 to 71 years of age. The patients were randomized into PPI (control group‐CG‐) and PPI + ERW (experimental group‐EG‐) groups. Of the 40 patients included in the control group (CG), the mean age as 52.3 ± 10.7 years, 18 patients were male (45%) and 22 patients were female (55%). Of the 44 individuals included in the EG, with mean age of 51.6 ± 11.1 years, 22 patients were male (50%) and 22 patients were female (50%). Statistical analysis showed no statistical differences between the 2 groups regarding age, gender and BMI.

Flow diagram of patient selection

### 3.2. Quality of life outcome

The typical symptoms of GERD include heartburn and regurgitation, occurring both during the night, frequently waking the patient up from sleep, and during the day, frequently associated with meals which have a great impact on a patients’ quality of life.33 Table 1 shows the difference of the frequency of GERD presentations, before and after treatment among all the patients. As the table shows, the frequency of presentations decreased in both CG and EG groups after treatment. Baseline GERD total scores were 63.0 (53.8‐71.0) and 56.5 (47.3‐64.8) in the CG and EG groups, respectively (P < .05). Post‐treatment results were 38.0 (30.0‐46.0) and 27.5 (19.5‐37.8) in the CG and EG groups, respectively (P < .001), with a relative variation of 0.4 and 0.5, respectively (P = .013). Baseline HS and RS were, respectively, 25.0 (20.3‐27.0) and 25.0 (21.3‐27.0) for the CG and 23.5(20.0‐26.0) and 25.0 (21.3‐28.0) for the EG groups. Post‐treatment results were, respectively, 15.0 (12.0‐19.0) and 15.5 (12.0‐18.0) for the CG and 7.0 (4.0‐12.0) and 7.5 (4.0‐11.0) for the EG. The effect of time was significant for all considered scales (P < .001). Relative variation of HS and RS were, respectively, −0.4 for the CG, −0.7 for the EG group (both P < .001). At 3 months’ follow‐up, the median GERD‐HRQL scores improved significantly after treatment both in CG and in EG groups (38.0 CG vs 27.5 EG), but the statistical analysis revealed that in the patients that associate with the intake of PPI also ERW there is a better significance in relation to HS and RS parameters (P < .001). In summary, treatment with ERW + PPI, for 3 months, gave significantly better symptom control than PPI treatment. Finally, in our study, 75% of the patients studied report a good satisfaction level after ERW treatment. Taken together the results showed that there was significant increase in quality of life at 3 months after supplementation with ERW when compared to baseline (P < .005).

### Table 1

Differences in scores variation expressed as median and interquartile range

Baseline Post‐treatment Relative variation P‐valuea P‐valueb
TS Item GERD
CG 63.0 (53.8; 71.0) 38.0 (30.0; 46.0) −0.4 (−0.5; −0.2) <.001 .013
EG 56.5 (47.3; 64.8) 27.5 (19.5; 37.8) −0.5 (−0.7; −0.4)
HS
CG 25.0 (20.3; 27.0) 15.0 (12.0; 19.0) −0.4 (−0.5; −0.2) <.001 <.001
EG 23.5 (20.0; 26.0) 7.0 (4.0; 12.0) −0.7 (−0.9; −0.5)
RS
CG 25.0 (21.3; 27.0) 15.5 (12.0; 18.0) −0.4 (−0.5; −0.3) <.001 <.001
EG 25.0 (21.3; 28.0) 7.5 (4.0; 11.0) −0.7 (−0.8; −0.5)

CG, control group (PPI + TAP water); EG, experimental group (PPI + ERW); TS, total score; HS, heartburn score; RS, regurgitation score; ERW, electrolysed reduced water; PPI, proton pump inhibitors.

aEffect of time assessed by Friedman’s test.
bDifferences between PPI and PPI + ERW therapy group assessed by Mann‐Whitney U‐test.

Bolded P‐values are significant after FDR correction.

### 3.3. Effect of ERW on oxidative stress in GERD patients

Laboratory parameters trends in the CG and EG groups during follow‐up are reported in Table 2. Several studies have been highlighted that inflammatory cytokines and oxidative stress are involved in the development and progression of GERD.34 Our results confirmed that patients affected by GERD presented higher levels of systemic nitrosative and oxidative stress at baseline. On recruitment, the mean values of nitric oxide, MDA and O2  were 61.75 ± 24.90 nmol/mL/106 cells, 193.45 ± 121.20 pg/mL and 89.66 ± 24.60 nmol/mL, respectively. Moreover, the analysis of the balance between ROS and antioxidant barrier demonstrated that the values of d‐ROMs and BAP test in GERD patients at baseline were 394.05 ± 110.65 U‐CARR and 847.15 ± 443.05 μEq/L, respectively. Our data are consistent with Wetscher et al35, who observed that free radicals/active oxygen species are involved in the pathogenesis of reflux oesophagitis. After treatment, the balance between ROS and antioxidant barrier were generally found to have progressively returned to normal range. Indeed, the follow‐up visit at 3 months after treatment (t1) revealed an average reduction in the value of the d‐ROMs test and an average increase in the value of the BAP test. ANOVA test for repeated measures indicated a significant difference for nitric oxide level (P = .025) and BAP test (P < .001) between 2 groups. Nitric oxide levels were significantly decreased in EG vs. CG (57.2 ± 12.29 vs 41.1 ± 14.9; P‐value < .001). These data are supported by the remarkable increase in the antioxidant barrier in EG patients compared to controls (798.1 ± 339.3 vs 1796.7 ± 467.2; P‐value < .001). Significant effect of period (P < .001) was found for all laboratory parameters. Interaction group × period was significant for all parameters (P < .001) except for CRP. These values indicated a positive modulation of the pro‐oxidant/antioxidant balance with a reduction in oxidative damage in GERD patients. In addition, we analysed the severity of oxidative stress and of antioxidant barrier impairment (Table 3). On recruitment, about the same percentage of the patients belonging to CG and EG exhibited highly oxidative stress (>500 U‐CARR). Moreover, at the t0, 92.5% of patients belonging to CG and 88.6% of patients in EG had a very strong reduction in the antioxidant barrier (BAP test value < 1400). After 3 months of treatment (t1), no changes in antioxidant barrier were observed in the CG. Notably, in the EG, 23.3% of patients fall within the optimum range of antioxidant barrier and the 53.5% have an optimal value of plasmatic oxidative stress.

### Table 2

ANOVA for repeated measures performed to evaluate pre‐ and post‐therapy parameters between PPI + TAP water (CG) and PPI + ERW (EG) therapy group

Baseline Post‐treatment P‐value* P‐value** P‐value***
CRP (mg/L)
CG 2.3 ± 2.2 1.6 ± 1.6 <.001 .839 .455
EG 2.2 ± 1.6 1.4 ± 1.1
NO (nmol/mL/106 cells)
CG 59.3 ± 13.6 57.2 ± 12.9 <.001 .025 <.001
EG 64.2 ± 11.3 41.1 ± 14.9
MDA(pg/mL)
CG 190.3 ± 106.8 203.0 ± 112.0 .001 .084 <.001
EG 196.6 ± 135.4 117.9 ± 91.6
d‐ROMs test (U‐CARR)
CG 385.1 ± 86.4 380.9 ± 71.6 <.001 .062 <.001
EG 403.0 ± 134.9 292.2 ± 89.2
Biological antioxidant potential test (μEq/L)
CG 839.2 ± 441.2 798.1 ± 339.3 <.001 <.001 <.001
EG 855.1 ± 444.9 1796.7 ± 467.2
O2  (nmol/mL)
CG 83.53 ± 21.00 78.1 ± 14.3 <.001 .218 <.001
EG 95.8 ± 28.2 57.1 ± 21.2

CG, control group; EG, experimental group; CRP, C‐reactive protein; NO, nitric oxide; MDA, malondialdehyde; O2, superoxide anion; d‐ROMs, derivatives reactive oxygen metabolites; ERW, electrolysed reduced water; PPI, proton pump inhibitors.

Bolded P‐values are significant after FDR correction.

Probability that effect on the addressed variable is influenced by: *period. For each variable, the differences have been tested between the means of each period of the 2 groups (CG and EG); **groups. For each variable, the differences have been tested between the means of PPI group in 2 time (Baseline and post‐treatment) and the means of the EG group in 2 time; ***probability that the effects of period is greater in one distinct group (interaction period × group).

### Table 3

Difference in d‐ROMs and biological antioxidant potential (BAP) test measurements between CG (PPI + Tap Water) and EG (PPI + ERW) group

Baseline Post‐treatment
CG n (%) EG n (%) χ2 P‐value CG n (%) EG n (%) χ2 P‐value
d‐ROMs test (U‐CARR)
<300 8 (20.0) 9 (20.5) .290 4 (10.0) 23 (53.5) <.001
300‐320 3 (7.5) 3 (6.8) 3 (7.5) 3 (7.0)
321‐340 2 (5.0) 5 (11.4) 5 (12.59 5 (11.6)
341‐400 12 (30.0) 6 (13.6) 13 (32.5) 9 (20.9)
401‐500 12 (3.0) 12 (27.3) 14 (35.5) 1 (2.3)
>500 3 (7.5) 9 (20.5) 1 (2.5) 2 (4.7)
BAP test (μEq/L)
≥2200 0 0 .393 0 10 (23.3) <.001
2200‐2001 0 0 0 4 (9.3)
2000‐1801 3 (7.5) 3 (6.8) 0 9 (20.9)
1800‐1601 0 0 1 (2.5) 8 (18.6)
1600‐1401 0 2 (4.5) 2 (5.0) 3 (7.0)
≤1400 37 (92.5) 39 (88.6) 37 (92.5) 9 (20.9)

CG, control group; EG, experimental group; d‐ROMs, derivatives reactive oxygen metabolites; ERW, electrolysed reduced water; PPI, proton pump inhibitors.

χ2 P‐value = Chi‐squared test. p value < 0,05 are considerated statistically significant.

### 3.4. Correlation between laboratory parameters and GERD

Spearman’s correlation coefficient was used to evaluate the link among scores and laboratory parameters. TS relative variations correlated with laboratory parameters relative variations, except for BAP test, as shown in Table 4. HS and RS relative variations were significantly correlated with laboratory parameters variation, except for PCR. BAP was significantly associated with HS and RS reduction (ρ = −.439 and −.505, respectively).

### Table 4

Spearman’s correlation coefficient assessed to evaluate correlation among scores relatives variation and laboratory parameters relative variation

TS HS RS
CRP (mg/L)
ρ .245 .092 .088
P‐value .025 .407 .424
NO (μmol/L/106 cells)
ρ .341 .384 .423
P‐value .001 <.001 <.001
MDA(pg/mL)
ρ .469 .363 .344
P‐value <.001 .001 .001
d‐ROMs test (U‐CARR)
ρ .414 .371 .310
P‐value <.001 .001 .004
BAP test (μEq/L)
ρ −.170 −.439 −.505
P‐value .123 <.001 <.001
O2  (nmol/mL)
ρ .398 .350 .294
P‐value <.001 .001 .007

CRP, C‐reactive protein; NO, nitric oxide; MDA, malondialdehyde; O2 , superoxide anion; TS, total score; HS, heartburn score; RS, regurgitation score; BAP, biological antioxidant potential.

Bolded P‐values are significant after FDR correction.

## 4. DISCUSSION

. 2018 May; 22(5): 2750–2759.
Published online 2018 Mar 7. doi:  [10.1111/jcmm.13569]
PMCID: PMC5908129
PMID: 29512923

## CONFLICTS OF INTEREST

We state that there is no conflict of interest and declare that we have no financial and personal relationship with other people or organizations that could influence this work.

## ACKNOWLEDGEMENTS

This work is supported by the Italian Ministry for the University and Research. We thank Marco Reato for providing the medical device Alka vitha.

## Notes

Franceschelli S, Gatta DMP, Pesce M, et al. Modulation of the oxidative plasmatic state in gastroesophageal reflux disease with the addition of rich water molecular hydrogen: A new biological visionJ Cell Mol Med. 2018;22:2750–2759. https://doi.org/10.1111/jcmm.13569

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# Positive effects of molecular hydrogen-water bathing in patients of psoriasis and parapsoriasis en plaques

## Abstract

Psoriasis and parapsoriasis en plaques are chronic inflammatory skin diseases, both representing therapeutic challenge in daily practice and adversely affecting the quality of life. Reactive oxygen species (ROS) has been evidenced to be involved in the pathogenesis of the chronic inflammatory diseases. We now report that molecular hydrogen water, an effective ROS scavenger, has significant and rapid improvement in disease severity and quality of life for patients with psoriasis and parapsoriasis en plaques. At week 8, our parallel-controlled trial revealed 24.4% of patients (10/41) receiving molecular hydrogen-water bathing achieved at least 75% improvement in Psoriasis Area Severity Index (PASI) score compared with 2.9% of patients (1/34) of the control group (Pc = 0.022, OR = 0.094, 95%CI = [0.011, 0.777]). Of patients, 56.1% (23/41) who received bathing achieved at least 50% improvement in PASI score compared with only 17.7%(6/34) of the control group (P = 0.001, OR = 0.168, 95%CI = [0.057, 0.492]). The significant improvement of pruritus was also observed (P = 3.94 × 10−4). Besides, complete response was observed in 33.3% of patients (2/6) of parapsoriasis en plaques and partial response in 66.7% (4/6) at week 8. Our findings suggested that molecular hydrogen-water bathing therapy could fulfill the unmet need for these chronic inflammatory skin diseases.

Introduction

Psoriasis and parapsoriasis en plaques are both chronic inflammatory skin diseases characterized by persistently scaling and inflammatory eruptions,. They represent therapeutic challenge in daily practice and adversely affect the quality of life of patients. Psoriasis is so common that has been recognized since ancient times, affecting about 1% to 3% of the general population. It is associated with a high degree of morbidity. Indeed, disability and impact on quality of life secondary to psoriasis parallels that of heart disease and arthritis,. Parapsoriasis en plaques is a relatively rare group of disorders which has been classified into small plaque parapsoriasis (SPP) and large plaque parapsoriasis (LPP) according to the size of the lesions. Although the relation of SPP with mycosis fungoides (MF) is still a matter of discussion, there are about 10–30% of cases of LPP result in MF finally. The interactive network of the immune system and skin cells is thought to play a vital role in the pathogenesis of both diseases. To be more accurate, psoriasis is considered a Th1⁄Th17-driven disease, while parapsoriasis en plaques is a model of cutaneous T cell lympho-proliferative disorders and has been proved to be a monoclonal disorder in many cases. For a long period, conventional treatment to both diseases has not fully met the needs of patients while having well-known side-effects. The improved understanding of the autoimmune inflammatory pathways and associated changing concepts in pathogenesis have led to the development of biological drugs, which especially revolutionized the treatment of psoriasis,. However, slow onset of action, high cost, efficacy lost over time and the long-term safety profile of these biologics still remain unsolved.

Recently, it has been evidenced that oxidative stress such as increased reactive oxygen species (ROS) production may be involved in the pathogenesis of chronic inflammatory diseases,. The possibility of using this information to develop novel strategies for treatment is of considerable interest. Hydrogen molecule (H2) has been used in medical applications as a safe and effective antioxidant and immunomodulator with minimal side effects. Unlike other antioxidants, which are unable to target organelles, H2 can penetrate biomembranes and diffuse into the cytosol, mitochondria and nucleus. Moreover, it has also been reported to selectively scavenge ROS and show positive influence in Th1, Th2, and pro-inflammatory cytokine imbalance. Up to date, molecular hydrogen water (solubilized H2) as a treatment strategy for psoriasis-associated skin lesions has been tried by few case reports, and neither has molecular hydrogen water for patients with parapsoriasis en plaques. Apart from drinking molecular hydrogen water, inhalation of molecular hydrogen gas and injecting H2-dissolved saline, molecular hydrogen-water bathing is a new approach highlights by its skin-directed, safe and painless administration. Thus, our study conducted a parallel-controlled trial in patients with psoriasis and a self-controlled trial in patients with parapsoriasis en plaques to evaluate the efficacy of molecular hydrogen-water bathing to these chronic inflammatory skin diseases.

Results

### Improvement of psoriasis

In all, 41 psoriasis patients were assigned to treatment with molecular hydrogen-water bathing therapy and 34 patients were assigned to the control group. The treatment groups were well balanced with respect to demographics and baseline characteristics (Table 1). Only one patient of the control group withdrew during the course of the study at week 2 due to a lack of improvement and she was counted as a non-responder in the control group. Response was evident after 8-week bathing therapy. The mean Psoriasis Area Severity Index (PASI) score and median visual analog scale (VAS) score of the molecular hydrogen-water bathing group at week 8 was 5.8 and 0 respectively, significantly lower than the baseline scores (P = 7.08 × 10−6P = 2.42 × 10−5).

### Table 1

Characteristics of the psoriasis patients.

The molecular Hydrogen-water bathing group The control group
Baseline Week 8 Baseline Week 8
No 41 41 34 33
Sex(male/female) 24/17 24/17 18/16 18/15
Age 40 ± 15 (18–78) 40 ± 15 (18–78) 39 ± 12 (18–72) 39 ± 13 (18–72)
BMI 23.8 ± 3.8 (17.5–35.5) 23.7 ± 3.9 (17.2–35.6) 23.1 ± 4.2 (15.5–31.4) 23.0 ± 4.6 (15.3–31.4)
Waistline (cm) 82.7 ± 10.3 (63.3–103.3) 82.8 ± 9.8 (63.3–103.3) 76.8 ± 8.7 (58.2–95.4) 76.8 ± 8.9 (58.2–95.4)
PASI score 9.8 ± 5.9 (1.4–25.2) 5.8 ± 5.5 (0.2–25.2) 8.5 ± 4.1 (2.8–23.8) 7.9 ± 6.8 (0.8–34.5)
VAS score (median, range) 2 (0–8) 0 (0–4) 0 (0–7) 0 (0–9)

PASI: Psoriasis Area Severity Index; VAS: the visual analog scale; BMI: Body Mass Index.

After 8 weeks of therapy, patients treated with molecular hydrogen-water bathing showed significantly greater improvement than those who were of the control group as evaluated by both PASI and VAS (Table 2 and Fig. 1). Of patients, 24.4% receiving molecular hydrogen-water bathing achieved the end point of at least 75% improvement in PASI score compared with 2.9% of patients of the control group (Pc = 0.022, OR = 0.094, 95%CI = [0.011, 0.777]). Of patients, 56.1% who received bathing achieved at least 50% improvement in PASI compared with only 17.7% of the control group (P = 0.001, OR = 0.168, 95%CI = [0.057, 0.492]). Molecular Hydrogen-water bathing treatment also resulted in substantial improvement in pruritus as measured by VAS. The median change from baseline to week 8 in the bathing group was −2, compared with a median change of 0 in the control group (P = 3.94 × 10−4).

### Table 2

Summary of the improvement of Psoriasis Area and Severity Index (PASI) and visual analog scale (VAS) at week 8.

The Hydrogen-water bathing group The control group Pvalue
Baseline PASI score Baseline PASI score
Mild Moderate Severe Total Mild Moderate Severe Total
(N = 26) (N = 11) (N = 4) (N = 41) (N = 24) (N = 9) (N = 1) (N = 34)
PASI (%) >PASI90 1 (2.4) 1 (2.4) 0 2 (4.8) 0 0 0 0 >0.05
>PASI75 5 (12.2) 3 (7.3) 2 (4.9) 10 (24.4) 1 (2.9) 0 0 1 (2.9) 0.022*
>PASI50 13 (31.7) 8 (19.5) 2 (4.9) 23 (56.1) 4 (11.8) 2 (5.9) 0 6 (17.6) 0.001
VAS improvement (%) ≤−5 3 (7.3) 0 (0) 0.31*
≤−3 9 (22.0) 1 (2.9) 0.04*
<0 21 (51.2) 7 (20.6) 0.006
≥0 20 (48.8) 27 (79.4) 0.006

*The corrected P (Pc) values were adjusted by using Yate’s correction for continuity.

Clinical improvement of psoriasis of an 8-week course of molecular hydrogen-water bathing therapy. Case 1: A 64-year-old psoriasis patient at baseline (PASI 16.4, a,b) and after the bathing therapy (PASI 1.8, c,d). Although he had been treated with acitretin capsules 30 mg daily for more than 4 months, the psoriatic lesions had not improved except for the partially reduced scale on the plaque. He refused to increase the drug dose due to intolerable dryness and chapping of the mucous membranes. Case 2: A 40-year-old psoriasis patient at baseline (PASI 21.1, a,b) and after the last bathing therapy (PASI 4.1, c,d). He complained of severely itching and treatment-resistant lesions (acitretin capsules 40 mg daily for more than 6 months), and after bathing therapy he was able to reduce the dose. Case 3: A 43-year-old psoriasis patient at baseline (PASI 20.2, a,b) and after the last bathing therapy (PASI 4.8, c,d). This man had been continuously treated with methotrexate 5 mg weekly for more than 10 months and was able to reduce the dose successfully after bathing therapy. Note that patients experienced similar responses in the areas not shown.

### Improvement of parapsoriasis en plaques

Six patients were included: 1 man and 5 women, with mean age of 32.8 ± 4.9 (range: 25–40) years and mean course duration of 34.4 ± 31.1 (range: 12–96) months. Four patients were categorized as LPP and two as SPP. Features of the patients were presented in Table 3. In all patients, an improvement in the morphology or distribution of lesions had occurred (Fig. 2). Complete response was observed in 33.3% of patients (2/6), partial response in 66.7% (4/6).

### Table 3

Characteristics and the clinical outcomes of patients with parapsoriasis en plaques.

Patients Sex/Age Type of parasporiasis Distribution at initial presentation Morphology at initial presentation Duration of disease (month) Clinical response at week 8
1 F/40 LPP trunk and extremities patch, plaque 25 PR
2 F/31 LPP trunk papule, patch 12 PR
3 F/33 SPP trunk and extremities papule, patch, plaque 28 PR
4 F/33 SPP trunk papule, patch 15 PR
5 M/35 LPP trunk and extremities patch, plaque 30 CR
6 F/25 LPP trunk and extremities patch, plaque 96 CR

SPP: small plaque parapsoriasis; LPP: large plaque parapsoriasis; PR: partial response; CR: complete response.

Clinical evaluation of a patient of parapsoriasis en plaques who achieved complete response rapidly 4 weeks after molecular hydrogen-water bathing. A 35-year-old man with large plaque parapsoriasis had been followed up for 30 months and during that time two biopsies were taken showing no progression. He had suffered flare-up after 10-month narrow-band UVB therapy and failed to have evident improvement in the later 6-month phototherapy despite of increasing the power. Even if only 4 weeks, his lesions rapidly achieved significant improvements without concomitant therapy (a). The Hematoxylin-eosin stain shows mildly hyperkeratotic and focally parakeratotic epidermis with moderately dense superficial perivascular infiltrate. Lymphoid cells are mostly small, cytologically normal lymphocytes, and there is focal single-cell epidermotropism (b).

Two psoriasis patients complained of the temperature of the molecular hydrogen water. The discomfort was relieved once the actual temperature was adjusted according to the satisfaction of patients. No other adverse reactions were found during the study.

## Discussion

The results of the parallel-controlled trial demonstrated that molecular hydrogen-water bathing therapy led to significant improvements in psoriasis for the majority of patients. The response rate observed was obviously higher than those seen with Alefacept and fumaric acid esters; and was similar to those seen with Efalizumab, low dose of oral methotrexate (MTX) (5–15 mg/week) and cyclosporine A (1.25 mg/kg/day). Furthermore, patients receiving molecular hydrogen-water bathing showed rapid onset of improvement from baseline. Approximately one forth of patients showed at least 75% improvement in PASI score 8 weeks after their initial bath, a level of response that has only been observed after 12 or more weeks of therapy in patients receiving some biologic agents,,. Patients treated with molecular hydrogen-water bathing also showed substantial improvement in pruritus as assessed by VAS. This is beneficial to the quality of life of psoriasis, which is considered to be similar to, if not worse than, that of other major chronic diseases. Although concomitant treatment was used for the skin lesions, it should be noted that the dosage of MTX, UVB phototherapy and systemic retinoids concomitantly used were not effective for at least 4 months prior to participation in the present study. Surprisingly, 6 patients were able to reduce or even stop the drug dosage (4 patients: acitretin; 2 patients: MTX) after the bathing course. Although the possibility that the improvements were caused by concomitant treatment cannot be fully excluded, it is indicated that the quick relief of symptom was in great part owing to the bathing therapy.

To parapsoriasis en plaques, our result suggested that molecular hydrogen-water bathing was rapidly effective and safe for the control of the disease with 66.7% partial response and 33.3% complete response. Currently, PUVA and narrow-band UVB are used as main treatment options for parapsoriasis en plaques with up to 80% complete remission rates and a median time to clearance of 2–6 months,,. In general, UVB is preferred in patients with patches and thin plaques and PUVA photochemotherapy should be used for patients with thick plaques, with phototypes ≥III and unresponsive to UVB. However, in addition to requirement of long time to induce the response and the maintenance, all these therapies are associated with potential risk of photocarcinogenesis and photoaging limits their long-term use.

Psoriasis and parapsoriasis en plaques are known as representative diseases that show the orchestrated mechanisms of chronic inflammation. The clinical effectiveness of molecular hydrogen-water may partially be explained by H2 selectively scavenger ability against highly active oxidants, such as hydroxyl radical and peroxynitrite, and cytoprotective effects against oxidative stress. Hydroxyl radical is known as a major trigger of the chain reaction of free radicals, and the absence of the specific scavenger of this species spontaneously causes oxidative states in chronic inflammation,. Thus, H2 may have an advantage to suppress the chain reaction, which produces lipid peroxide and leads to the generation of oxidative stress markers, such as malondialdehyde (MDA) which has been proved to be in association with the exacerbation of psoriasis. Another target of H2, peroxynitrite, which is generated from the reaction of nitric oxide with superoxide, activates p38 MAPK pathways which are related to production of inflammatory cytokines, such as TNF-α,IL-6, IL-8 and many others, resulting in the development of plaque of psoriasis. Subsequent studies indicate that the effect of H2 is mediated by Nrf2-Keap1 system,, a transcriptional factor known to be an activator of intrinsic protective mechanisms against oxidative stress, but the mechanisms remain to be solved. However, radical scavenging effects of H2cannot fully explain the anti-inflammatory and anti-apoptotic effects, which should involve a number of fine-tuned signaling pathways. Studies also have shown that H2 suppresses signaling pathways in allergies and inflammation without directly scavenging reactive oxygen/nitrogen species.

In fact, anti-oxidant therapies to psoriasis have already been tested, e.g. using fumaric acid esters particularly in Germany. However, most of them exhibited limited therapeutic success. Furthermore, recent studies suggested that some ROS act as signaling messengers to regulate a wide variety of physiological process,. In view of this background, an ideal antioxidant is expected to mitigate excess oxidative stress, but not disturb redox homeostasis. H2 has the capability to scavenge specifically potent ROS but does not react with those that have important physiological roles. The safety of H2 is also established by its intrinsic production in the human body and inertness against biogenic components. It has been already used for the prevention of decompression sickness in deep divers. The clinical practice of H2 in the treatment of chronic inflammatory disease was recently attempted in patients of rheumatoid arthritis (RA). Moreover, a latest case report suggested H2 could relieve psoriasis-associated skin lesions and arthritis. Apart from other methods of application,molecular hydrogen-water bathing is a new approach highlights by its skin-directed, safe and painless administration and can be carried out in daily life.

Regarding the present study, our results showed a decreased trend of BMI in psoriasis patients treated with bathing therapy without any lipid-lowering interventions. This result matches those of previous studies, which have demonstrated the clinical improvement in patients with psoriasis was associated with a reduction in the levels of lipid peroxidation and an increased serum antioxidant capacity. In addition, it should be noted that the itching sensation was markedly reduced in most cases. The influence of molecular hydrogen water on itching sensation suggests the presence of neurogenic inflammation associated with ROS in the psoriatic lesion and the possibility of a therapeutic approach similar to that for neurological inflammatory disorders. Some limitations of this study need to be pointed out. As an open trial of limited sample size, this study may include selection bias although the baseline characteristics of the psoriasis groups including primary PASI and VAS scores showed well balanced. Attention should be paid that the patients receiving molecular hydrogen-bathing therapy are those who have failed to conventional treatment for more than 4 months. This at least implied the disease activities of these “refractory” patients were in less stable condition. Secondly, this study did not involve a placebo control group owing to the ethics concern. However, all the ones of the control group had received tap-water bathing more than twice a week during this study. Thus, the control group of psoriasis was administered with the combination therapy of the conventional therapy and the placebo (tap-water) bathing.

In summary, patients with psoriasis and parapsoriasis en plaques who were treated with molecular hydrogen-water bathing therapy achieved significant and rapid improvement in disease severity and quality of life. We suggested that molecular hydrogen-water bathing therapy could fulfill the unmet need for an alternative therapeutic option for these patients. Further large randomized placebo-controlled trials are required to verify and extend these results. The mechanism and long-term efficacy of molecular hydrogen-water in these diseases are also warranted.

Methods

### Patients

Forty-one patients of psoriasis and six patients of parapsoriasis en plaques were enrolled from February 2016 to April 2017 from Huashan Hospital affiliated to Fudan University and Huadong Hospital affiliated to Fudan University. The control group of psoriasis included thirty-four patients recruited from the dermatology clinics of Huashan Hospital. The study was registered and approved by China Ethics Committee of Registering Clinical Trials (ChiCTR-ONC-17013055, 2017/10/20). All patients signed an informed consent form and agreed to publish identifying information or images. All methods were performed in accordance with the relevant guidelines and regulation.

Patients of psoriasis had a history of plaque psoriasis for a minimum of 12 months. Among them, 21 patients were resistant to topical corticosteroid and calcipotriol ointments; the rest of patients suffered conventional treatment failure or failed to reduce the existing dosage of drugs beyond topical corticosteroid and calcipotriol ointments for more than 4 months. The failed therapeutic options include UVB phototherapy (10/41), MTX (3/41), and systemic retinoids (7/41). All the patients declined treatment of other drugs (include biologics) due to financial issues and safety concern. Patients of parapsoriasis en plaques were diagnosed based on clinical, histopathological and immunohistochemical findings (SPP: 2/6, LPP: 4/6). They had been followed up for more than 8 months. Among them, 4 patients had received UVA or narrow-band UVB therapy for more than 6 months without evident improvements. Two patients suffered flare-ups during phototherapy. All biopsies reported dense lymphocytic infiltrates, occasionally with lymphocyte exocytosis. None of the patients had axillary or inguinal lymphadenopathy. The laboratory results of all patients were unremarkable. Patients with serious cardiovascular diseases or infectious diseases, and those who were unable to receive treatment regularly were excluded.

During the duration of molecular hydrogen-water bathing therapy, the present treatments of psoriasis patients were continued the same as before (except for drug tapering), including systemic and topical therapy. The patients of the psoriasis-controlled group were administered the same traditional Chinese patent medicine called “Qu-Yin oral solution”, topical treatment of corticosteroid and calcipotriol ointments. One major ingredient of this widely-used solution is glycyrrhizin, which has been evidenced to enhance the clinical response of psoriasis with its anti-inflammatory and immune-modulating effect. All the ones of the control group had received tap-water bathing more than twice a week during this study. Patients of parapsoriasis en plaques did not use any concomitant therapy, except for topical corticosteroid and emollients.

### Molecular Hydrogen water bathing

Molecular Hydrogen-water bathing was administrated through skin by immersing whole body in the molecular hydrogen-water twice a week (interval of 3 days). Each bathing took 10 to 15 minutes. molecular Hydrogen water bathing paused one week in case of menstruation in female subjects. The molecular hydrogen-water bathing machine (provided by Shanghai Yiquan Investment Limited Partnership) freshly prepared molecular hydrogen water using nanobubble technology to dissolve hydrogen gas into pure deionized water. In briefly it contained the following process:

(1) Tap-water passed through a filtration system (composed of quartz sand, activated carbon, ultrafiltration and reverse osmosis membrane) and an ultraviolet disinfection unit to be deionized and disinfected.

(2) molecular Hydrogen generator electrolyzed treated tap-water into oxygen and molecular hydrogen and then collected pure molecular hydrogen gas.

(3) molecular Hydrogen gas was forced into micro-nano-level bubbles and the bubbles were then dissolved directly and evenly into deionized water. The freshly prepared molecular hydrogen water had the following physical and chemical characteristics: (1) pH 6.8–7.3.

(2) Temperature ranged from 38 to 42 °C (the actual temperature based on the satisfaction of patients).

(3) High content of dissolved molecular hydrogen with a concentration of 1.0 ppm (for reference, the dissolved molecular hydrogen of tap-water is less than 0.001 ppm).

(4) With an extremely negative oxidation reduction potential (ORP) of −580 mV~ −650 mV (for reference, tap water: +250 mV~ +350 mV). Each time before therapy the same equipment was used to test pH, temperature, ORP (RM-30P, DKK-TOA Corp., Japan) and molecular hydrogen concentration (ENH-1000, Trustlex Corp., Japan) to make sure molecular hydrogen water having the same properties.

### Efficacy evaluation

#### Psoriasis

Clinical assessments including physical examinations, vital signs, concomitant medications, adverse events and measures of psoriasis activity (PASI scores and photos) were estimated at baseline and following each bathing treatment. For the PASI, patients are rated on the basis of erythema, scaling, and thickness divided in four anatomical parts (head, trunk, upper extremities, and lower extremities). The area of each anatomical part is factored into the overall value. The score was divided into mild (1–10), moderate (10–20) and severe (>20) PASI. The PASI score at week 8 was the predefined efficacy endpoint, where a favorable response was an improvement of at least 50% from the baseline PASI. The pruritus of the skin lesions was measured by the VAS for itching   .

### Parapsoriasis en plaques

Clinical responses were evaluated at week 8, classified as complete response, >90% clearance of lesions; partial response, 50–90% clearance; no response, <50% clearance with persistent skin lesions despite continuing treatment. The pruritus of the skin lesions was measured by VAS as well.

### Statistical analysis

Analyses of effectiveness endpoints were based on the intent-to-treat (ITT) population. The last-observation-carried-forward (LOCF) analysis was used to estimate the missing data for effectiveness variables. Descriptive variables were summarized by number (percentages), median or mean ± standard deviation. Measurement data were compared using paried t-test. Comparison of the count data or level data was performed using χ2 tests, Fisher’s exact tests or Mann-Whitney U tests. Odds ratio (OR) were calculated with Haldane’s modification, which adds 0.5 to all cells to accommodate possible zero countsP values were two-tailed. Differences were considered significant at P < 0.05. The corrected P (Pc) values were adjusted by using Yate’s correction for continuity. Data were analyzed by SPSS17.0 (SPSS Inc., Chicago, IL, USA) software.

### Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

. 2018; 8: 8051.
Published online 2018 May 23. doi:  [10.1038/s41598-018-26388-3]
PMCID: PMC5966409
PMID: 29795283
1Department of Dermatology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Rd., Jing’an District, Shanghai, China
2Department of Dermatology, Huadong Hospital, Fudan University, 221 West Yan-an Rd., Jing’an District, Shanghai, China
3Department of Dermatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Xuhui District, Shanghai, China
4Department of Dermatology, Shanghai Dermatology Hospital, 200 Wuyi Road, Chang-ning District, Shanghai, China
5Department of Dermatology, Changhai Hospital, The Second Military Medical University, 168 Changhai Rd., Shanghai, China
6Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Shanghai, China
Xiaoqun Luo, moc.621@319nuqoaixoul.
Corresponding author.
#Contributed equally.

## Acknowledgements

We would like to thank Shanghai Yiquan Investment Limited Partnership for the technical support. This study was supported by the HOPE Program launched by the Branch Association of Hydrogen Biomedicine, China-Japan Medical Science and Technology Exchanges Association.

## Author Contributions

Qinyuan Zhu wrote the main manuscript text, analyzed the data and prepared figures. Xiaoqun Luo, Yueshen Wu, Yongmei Li, Erhong Dai, Jianhua Wu and Bin Fan provided follow-up visits to the patients and collected the clinical data. Zihua Chen, Lanting Wang, Hao Xiong and Li Ping contributed to the supervision of regular molecular hydrogen-water bathing therapy. Xiaoqun Luo was in charge of the design and execution of this study. All authors reviewed the manuscript.

## Competing Interests

The authors declare no competing interests.

## Footnotes

Qinyuan Zhu and Yueshen Wu contributed equally to this work.

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Articles from Scientific Reports are provided here courtesy of Nature Publishing Group

# How Water Quality Impacts water Ionizer Performance

Water quality will play a significant role in how your water ionizer – in fact any water ionizer – performs and its longevity. A water ionizer requires mineral content to create those valued ionizations/ alterations in pH, ORP and to also produce molecular hydrogen H2 in water. Minerals are not only required, they are good. Calcium, potassium and magnesium all naturally occur in water and are called the “essential alkalizing minerals” because they are essential to our health.

The minerals in water are conductive. Conductivity allows for the electrical charge that produces the alterations we are seeking in alkaline, ionized water. Minerals provide a certain “vitality” to water.

Water that lacks mineral content, such as water from reverse osmosis or distillation, as no conductivity and is considered by many to be “dead” or denatured water. It is important to note that all water found in nature has some level of dissolved mineral content, so these types of “pure” waters are literally a man-made phenomenon. Our bodies are designed to drink water with minerals, to use calcium for bones and magnesium for the heart etc. and mankind has been doing so since the dawn of time. It is only in the last few decades, that we have been exposed to pure and mineral free water – often in bottles.

The more mineral content your water has, the more easily your water ionizer will alter/ionize the water and the better water ionization performance(pH,OR, H2) it will achieve and conversely. Water with a high level of mineral content is called hard water, while water with a low mineral content is called soft water.

That stated, all AlkaViva water ionizers will produce an ideal range of healthy drinking water, in both hard and soft water areas, unless used in extreme water quality situations. Please contact AlkaViva Technical Support if your water is unusually hard or soft as you will probably need pretreatment (more details below).

# Hard Water Explained

## What is Hard Water?

If you live in a hard water area, perhaps you have noticed mineral deposits on your dishes and hot water kettle, or rings of insoluble soap scum in your bathtub. These are signs of hard water. Hard water is water that contains high levels of scaling calcium, iron or magnesium mineral ions. These minerals do not pose any health threat, unless in very high amounts, but they can engage in reactions that leave deposits or scale that may damage surfaces or appliances.

Hard water mineral deposits or “scaling”, is the precipitation of minerals which form lime scale. Scale can clog pipes and can decrease the life of virtually all appliances in the home, especially those that use hot water. Scale can do the same thing to your water ionizer, decreasing water flow, water ionization performance and longevity of the water ionizer .

## Signs of Hard Water

* Difficult to form lather with soap
* White mineral deposits on your glassware
* Soap scum in your bath tub
* White mineral deposits in your tea pot, iron, or other electrical appliance that uses water

## Water Hardness and Water Ionizer Performance

A water ionizer requires mineral content to operate because minerals conduct electrical charge that produces the alterations found in ionized water. Water that has little or no minerals has no pathway for the electrolysis or “ionization” to occur. water Ionizers are designed to perform optimally within a specific range of mineral content in the source water; too many minerals may damage any water ionizer, too few you may experience decreased water ionization performance. With the right range of conductive minerals your water ionizer will easily alter the water and produce expected water ionization performance measurements in H2, pH and ORP.

## Hard Water Treatment Solutions

To protect your investment properly, you must first determine the level of hardness in your water. You can use the Hard Water Test Kit that is supplied with every AlkaViva water ionizer, have your water tested, or get test data from your supplier. The following are AlkaViva’s recommended treatment solutions:

## Extreme Water Quality Tolerances

AlkaViva does not recommend using a water ionizer without pretreatment of water that has one or more of the following measurements :

• Hardness (or Calcium Carbonate) over 150 ppm (8.5 grains).
• Iron over .3ppm.
• TDS below 40ppm or over 600ppm.
• Calcium above 50ppm.

Note: some reports will show “ppm” some will show “mg/l” – they are the same. Knowingly operating your water ionizer above these levels may void your warranty and/or decrease your water ionizer’s performance.
In no event shall AlkaViva or its dealers be liable for any direct, indirect, incidental or special consequential damages to property whatsoever, arising from use of its products with improperly treated or untreated hard water.

# AlkaViva’s AquaSafe Water Quality Assurance Program

Many water  ionizer companies will sell you an expensive water ionizer and never mention hard water. If you live in an area that has hard water, that is like throwing money down the drain! To properly protect the investment you’ve made in your ionizer, and ensure you get the right pre-treatment at a great price, we are proud to offer our AquaSafe Water Quality Assurance Program.

AquaSafe Water Quality Assurance Program offers you two important water quality “insurance” benefits:

• Hard Water Test Kit. Each AlkaViva water ionizer / H2 Generator includes a highly effective Hard Water Test Kit. The kit includes a simple-to-use hard water test strip which in less than a minute will determine how hard your water is (if at all). The test results fall in ranges of hardness. We include our recommended pre-treatment solution for each range.
• The Most Complete Range Of Hard Water Solutions. The AquaSafe Water Quality Assurance Program allows you to purchase the appropriate pre-treatment solution within 30 days of purchasing your water ionizer ]

# Other Considerations

## water Softeners

AlkaViva does not recommend using a water ionizer downstream (or after) a sodium or potassium based ion-exchange water softener. If you have a sodium or potassium ion-exchange water softener, you will need to do one of the following:

• Bypass the system (if the source water meets the above Water Quality criteria).
• Change the plumbing connectors and install the water softener on the hot water only.
• Install a Reverse Osmosis water prefiltration unit and water ionizer Remineralization Cartridge. The Reverse Osmosis will take out the sodium or potassium while the remineralizing cartridge will add healthy minerals back into the water.

## Reverse Osmosis (RO) and water Distillers

water ionizers will not work well downstream (or after) a ReverseOsmosys or water distiller. Many homes with an ion-exchange water softening system will have an RO system. These systems remove virtually all the mineral content and leave the water with no conductivity. If you have an RO or distiller, you will need to do one of the following:

• Bypass the reverse osmosys prefiltration system (if the source water meets the below Water Quality Tolerances).
• Install an AlkaViva Remineralization Cartridge after the ReverseOsmosys system (an easy solution).

## Soft Water Treatment Solution

Soft water is very low in mineral and dissolved solid content which gives water its conductivity. Such water would have a TDS below 40 ppm.

In areas with extremely soft water (or if using a rainwater catchment system), it may not be possible to achieve optimal water ionization performance of your AlkaViva water ionizer. In this situation, an AlkaViva Remineralization Cartridge is recommended. AlkaViva has incorporated a proprietary blend of 70+ organic and inorganic minerals into its Remineralizing Cartridge.

## Well Water

The quality of well water can vary greatly and pose some health risks if not tested and mitigated. Well water needs to be tested before using with a water ionizer. Most wells are perfectly suitable for water ionizer operation; you just don’t want to be on the wrong side of that equation unwittingly.

The use of well water poses a number of questions when considering use of a water ionizer. In addition to measurements of water quality for water ionization performance and durability /longevity, health safety related issues are also important considerations when using well water.

Recommendation: Many states require a well water test report in the closing documents of a home sale. Many local governmental Health Agencies offer free testing of well water. We recommend contacting them first. AlkaViva offers at a discounted price a Professional Water Test done in a certified laboratory. More details here.

### Important Notes:

• If you are uncertain of the water quality in your area, please contact your local water supplier and request the specific Water Quality information above. The appropriate phone number will be on your water bill. If using well water, contact your county or state health department to inquire about water testing services.

# We don’t just say we are the #1 water ionizer company. We prove it!

We have sold many top brands water ionizers(Kangen Enagic, Toyo, AlkaBlue, Nexus, KYK, Tyent, Life Ionizer EmcoTEch, BionTech) and think all the top water ionizer models(no matter the brand) make good alteration to water. The similarity ends there. The differences are in water filtration power, technology , sophistication & design(i.e.:SMART electrodes & DARC II electrode cleaning systems,AutoAdjust optimal performance with low power ), manufacturing quality and durability. Our unique focus is on the importance of clean water. AlkaViva’s UltraWater filter performance (and testing ) is unique .

We are the only company who represents two top manufacturers offering water ionizer models that fill different niches. We offer you the best of the best – in water filtration, water ionizer performance, electrodeselectrode cleaning system & durability and customer experience. That is choice. That is smart.

# EMCOTECH -1st AlkaViva manufacturer

### https://royalwater.en.ec21.com/company_info.html

• – established in  1970
• – Total employees  501 – 1000
• – annual income of over  100 million USD

http://www.royalwater.com/

EmcoTech is sold in over 60 countries, the most popular and best-selling brand water ionizers in the world.

## BionTech – 2nd  AlkaViva manufacturer

#### https://biontech.en.ec21.com/company_info.html

 FOUNDED 1986 EMPLOYEES 101-500 ANNUAL INCOME USD 10.000.000-50.000.000

EXPORTS in over 25 countries, shares 50% of Korean market

please search and compare AlkaViva’s manufacturers with other manufacturers, for example Tyent

https://tyent.en.ec21.com/

• – established in  1995
• – Total employees  51-100
• – Annual revenue  USD 5.000.000-10.000.000

OR CHANSON (TAIWAN) https://cswater.en.ec21.com/company_info.html…

Try searching data about KANGEN or others … I think the numbers speak for themselves

A water  ionizer is a serious investment, so who you buy from is important. AlkaViva is the oldest direct importer in the USA. Between our two founding partners you get over 30 years of USA-specific water ionizer industry expertise. Virtually all our USA competitors started with us as dealers including Life IonizersTM, Tyent, Echo and Chanson.We have helped develop and launch major new water ionization technology that have been emulated by many others, such as MESH electrodes/plates and MARC/DARC improved electrode cleaning systems. We have been instrumental in launching and supplying water ionization components for commercial applications. Most notably, we supply Tennant Company, water cells for their Ec-H2O floor cleaning product line. Ec-H2O was the first commercially successful application of water ionization technology and has won numerous international awards.

Together, our OEM partners offer 69 years of water ionizer manufacturing. They both hold ISO 9001 and 14001 certifications, own patents too numerous to list, and have won many awards for their business practices and products. Both are firmly rooted in ongoing research and development and in quality management practices.

You can trust that our history, experience, knowledge and partnerships allow us to source top performing products from the best manufacturers in the world. Manufacturers that carry the best certifications and the latest cutting edge technology in water ionizers- ensuring you will make the best purchase.

Here is a sampling of industry-first innovations AlkaViva has brought to market:

• AlkaViva was the first company to launch MESH electrodes.
• Robotically sprayed platinum coating technique that results in precise and highly uniform electrode surface.
• Introduced the new Smart Electrodes which deliver the highest efficiency and performance in producing ORP and H2 alteration.
• The only company to offer proprietary membrane technology.
• introduced next Gen SMPS & AutoAdjust to optimally power the electrodes according to (changes in ) your input water

## Other reasons to choose AlkaViva:

• The first to offer a dedicated under sink water ionizer model with remote tower.
• The first to offer color LCD screens to identify the selected water type.
• The company with the longest history as an exclusive importer (since 2004 with Emco Tech).

# Water Ionizer Performance

What you need to know about water ionizers performance…

water ionizer performance is NOT absolute. It depends on three important variables: water quality, the power applied at each setting and water flow rate. In addition to these three variables, performance year-in and year-out is important and depends on how well a water ionizer’s electrode cleaning system works to keep the electrodes and membranes clean. Beware of any company or sales person who tells you “our water ionizer will do “X”. It is simply not true. What is true is that when you understand the variables, and water ionizer cleaning systems, you can make an informed choice. Learn how our AutoAdjust technology helps overcome the three variables and why DARC II cleaning keeps water ionization performance optimal over time. Be smart.

Truth: over the years, the alkaline water ionizer industry has run rife with undocumented water ionization performance claims around pH and ORP and now molecular hydrogen (H2).

Truth: many people who sell alkaline water ionizers state performance absolutes, as in our water ionizer will do “X”.

Truth: you can cut through all this. Below are four things you need to know about water ionizer’s performance metrics in ANY electric water ionizer.

This first point cannot be emphasized enough. water ionization performance levels are significantly impacted by source water – whether you are talking about H2, pH and/or ORP. Any water ionizer running on hard water, or water with elevated levels of minerals or high Total Dissolved Solids (TDS), will always perform better. The harder or more mineralized the water, the better the top-end water ionization performance. Conversely, the exact same water ionizer on soft water with low mineral content will always perform lower than it can in hard water.

Comparisons are only legitimate if done using the exact same source water. Beware of importers in hard water areas who over-state performance. For example, Life Ionizers™ is located in Carlsbad, California. They have extreme TDS – over 600ppm1. To contrast, our TDS in Reno is 10% of that at between 60 – 70 ppm. Any credible water ionizer company will state a range of water ionization performance. Not absolutes.

## Your water Ionizer’s Flow Rate Matters.

The second important point is that a water ionizer’s flow rate will affect water ionization performance. All things being equal, slower water flow rate will produce more water ionization performance as water will stay longer in contact with the electrodes. Some manufacturers intentionally produce water ionizers with slower flow rates to compensate for less efficient electrodes. Slowing the flow will also typically raise pH, and high pH water doesn’t taste good to most people. The vast majority of alkaline ionized water drinkers settle on lower pH ranges for regular drinking.

## Electrode Power Matters.

water Ionizers offer selectable alkaline levels – typically four – that you choose with a push of a button. Each time you choose a higher level, more power is sent to the electrodes and incrementally more water ionization performance is achieved. water Ionizers that advertise high power (some go as high as 800 watts!) are ironically only advertising that they have inefficient electrodes and membrane systems. An incredibly important and often overlooked point is that water ionizers that utilize higher power will experience higher electrode heat. When electrodes get hot, the platinum plating deteriorates. Compromised plating delivers less water ionization performance over time. Many water ionizers tout higher power as the solution to water ionization performance. In the long run, it isn’t.

AutoAdjust in AlkaViva water ionizers detects the hardness of filtered water and dynamically adjusts/sets power applied on electrodes to what is required.

## Electrode Cleaning is King.

The effectiveness of a water ionizer’s electrode cleaning system affects water ionization performance over time. This is also an overlooked point. You can have the perfectly mineralized water, the greatest electrodes, proper water flow rate and power, but if your water ionizer can’t eliminate scale, its water ionization performance will drop. Quickly, if you have very hard water. We have tested scaled up water ionizers that do not produce any alteration in the water. To achieve optimal water ionization performance the electrodes must be kept clean – over time. How effectively an water ionizer’s electrode cleaning system works is critical. Don’t be misled by gimmicky marketing names for electrode cleaning systems – it all boils down to the acid to alkaline cleaning ratio. When shopping, ask what the cleaning ratio is and how the system achieves that. If you do not get a lucid answer, run. Fast.

## The Ultimate Solution.

While we can’t control source water, we do offer you the most advanced and effective solutions to all the other variables.

Convenience. You want a water flow rate that is fast enough, but not too fast. Super-fast flow rates will not only lower water ionization performance but they will significantly compromise water filtration. Water filters work on contact time. The faster water flow, the less contact time, especially in GAC and vitamin C water filters. The AlkaViva  H2 water ionizer Series runs at 3 lpm which is the ideal balance between great water ionization performance and great water  filtration.

Superior water Filtration. USA made UltraWater filters are the only water ionizer filters that have been independently tested against 172 contaminants and shown to reduce virtually all of them to 99.9%. Even the toughest. There is no better water filter available – because AlkaViva believes that healthy water should start by being clean.

molecular hydrogen H2 Infusion Technology. We employ the highly advanced Smart Electrode design and manufacturing. Next, we match the Smart Electrodes with our own proprietary membrane technology that is optimized to produce optimal molecular hydrogen H2 and ORP -water ionization performance.

Superior electrode cleaning means lasting water ionization & durable performance. AlkaViva H2 Series water ionizers employ our newly improved DARC II Cleaning System which previously (as DARC) was for 9 years the best cleaning system in the industry. DARC II offers the most effective 1:1 cleaning ratio using a constantly reversing polarity system controlled by a non-scaling ceramic valve.

Efficiency. AlkaViva H2 water ionizers employs the most sophisticated and advanced power delivery system. The correct current density ensures the longest electrode life and is only possible using more advanced (smaller sized) plates. You get power  efficiency and water ionization performance. While other less advanced water ionizers are required to use maxed out power of up to 800 watts to achieve water ionization performance, AlkaViva H2 water ionizers run 150 watts of peak power ensuring fantastic power density, unmatched water ionization performance and long durable  plate/electrode life. Our power supply also includes Auto Adjust which automatically adjust the background power using pulse width modification technology – optimizing water ionization performance. You get great water ionization/alteration – even at the better tasting and lower pH levels that most people drink.

Independent testing. AlkaViva is the only water ionizer company to have commissioned an EPA-certified, third party, independent laboratory to document the water performance results of different brands and prove our point about efficiency and performance. Bigger just isn’t better. When it comes to technology – including water ionizers – smaller is.

Note on molecular hydrogen H2 Performance: while we understand the basic science of how molecular H2 is produced during electrolysis, it is a new focus in our industry. No one fully understands all the unique nuances of this delicate electro-chemical process. We don’t fully know how certain properties, in addition to hardness and TDS, affect molecular  H2 performance. Apart from TDS and hardness, it is entirely possible that certain water chemistries lend to better performance, and others to less.

That is a lot of information. However, we feel these are all important points for properly informed customers to consider before simply reading – and believing – a company’s declaration that “our water ionizer does X”.

To get optimal benefits, we offer AlkaViva’s DARC II electrode cleaning and our Smart Electrodes that are perfectly powered for maximum efficiency and water ionization performance that lasts. Exactly what you want.

# water ionizer electrodes in the water cell

We drink alkaline ionized water for the healthy properties. The electrodes create the water electrolysis /ionization which deliver those benefits. When it comes to water ionizers, understanding electrodes in the water cell is like understanding the importance of your cardiac system to your overall health.

The water cell is the heart of a water ionizer. It consists of a series of electrodes (plates), each separated by a membrane. This page will explain how water ionizers electrode technologies differ and what that means to water ionizer performance and ultimately your health.

There is so much hype and misinformation about water ionizer electrodes or plates. Some say bigger plates are better. Others make you think that more plates are better. Some advertise more power applied on electrodes– like 800 watts – as if we were powering 20-inch sub-woofers. We are ionizing water. The reality is that bigger or more plates or more power means inefficient engineering and lower quality materials and manufacturing. More or bigger DOES NOT mean better water ionization performance. An often overlooked yet incredibly important point is that more power also means more heat, which means the platinum plating breaks down faster on the surface of the water ionizer electrode. This equals poor water ionization performance over time.

There is hype too around water ionizers electrode/plate type. water ionization performance is not about the electrode/ plate type, but rather the sophistication of the engineering and the quality of the materials and manufacturing.
Educate yourself on some basics and you will easily see why our Smart Electrodes offer you the most advanced engineering, along with the best materials and manufacturing. This means more efficient water ionization performance and lasting durability for electrodes/water cell/water ionizer. That is powerful. That is smart.

All things that smart shoppers look for.

## Smart Electrodes

Smart Electrodes start with the highest quality materials. We use certified 99.9% pure titanium from Japan and the highest quality platinum.

The electrodes are engineered employing an advanced flat design that offers more effective surface area than slotted or mesh plates of the same size.

Then the electrodes are robotically electro-plated using a proprietary technique. A computer controlled robotic arm is used to apply the platinum, under pressure, multiple times and from different angles that allows the most precise plating application. The resulting plate surface can direct a uniform electron flow and provide the most efficient power saturation.

AlkaViva’s proprietary electroplating process and the resulting Smart Electrodes feature technological advances and enhanced water ionization performance characteristics which allow superior water ionizer performance in the following ways:

• Superior conductivity which allows for lower power and higher water ionization efficiency
• Increased surface area; up to 3x the number of vertices as smooth dipped plates
• Optimized water flow dynamics over the plate surface due to vertices (increased water ionization performance proven in independent US EPA certified testing)

## Material Composition

Titanium is the base material in every water ionizer electrode/plate, because it has proven safe and effective. It is corrosion resistant, has the highest strength-to-weight ratio of any metal, is very durable, and demonstrates the ability to easily change polarity, which is critically important in the water ionization process. The best water ionizer plates are coated with platinum because it was determined in a 1992 study by the Japanese Ministry of Health, Labor and Welfare, that platinum is the only entirely safe material to use in water ionizer plating/coating.

## Electrode Types

There are three basic types of plates:

• Flat Plate/electrode: The most common, basic and simple plate design.
• Mesh Plate/electrode: The most technically advanced configuration; also the most expensive to manufacture.
• Slotted or “Hybrid” Plate/electrode: A less expensive and less effective version of mesh plate technology.

Regardless of what you read, the most critical part of an water ionizer electrode is not the type but rather how the electrodes are engineered, what materials are used and how they are applied or manufactured.

# Mesh or Solid electrodes/Plates?

There are three, distinctly different, types of electrodes / plate designs offered in the market today and each has its own advantages or disadvantages. These are solid plates, slotted or “hybrid” electrodes / plates and mesh electrodes / plates.

These differences have a dramatic effect on power delivery inside of the cell. All three types of plates can deliver the electrical current to the water, but why are AlkaViva electrodes / plates the most efficient? Easy … our highly advanced Smart Electrode Technology!

A low quality flat plate has no way to organize or channel the current being delivered, meaning it has an inconsistent saturation of electrons. They move across the electrodes / plate finding the path of least resistance, often channeling together and are not effectively or evenly dispersed. This is like watering a garden and having the water run to the low spots and pool there. This results in an inconsistent delivery of power and less efficient / effective water ionization results.

## Slotted electrodes /Plates

In contrast to a flat electrodes /plate, with slotted electrodes, there is a clear path for the electrons to travel in more predictable directions – effectively distributing the power in a consistent pattern. When we till our garden into rows and irrigate we are channeling the water to be delivered to the roots where it is needed most. The slotted electrodes /plate is more effective than the traditional flat electrode/ plate. Often has a less effective surface area, depending on the size of the slot.

## Mesh electrodes /Plates

A mesh electrode /plate uses the same principle as the slotted plate, but improves upon it by providing cross-channeling to more evenly direct electron flow. The applied current more evenly saturates the plate, increasing the effective delivery of electrical current to create better alteration /ionization in your water. Can have a less effective surface area depending on the design of the mesh electrodes .

Long term research and development findings derived from a 1992 study by the Japanese Ministry of Health, Labor and Welfare indicate platinum to be the only entirely safe material for use in water ionizer plating/coating.

Two distinct methods – Plating (dipping) and Coating; are employed to apply the platinum surface to the titanium electrode/ plate:

Plating: Also known as Cladding or Dipping, plating is the process by which a titanium plate is submerged in a platinum solution. This is the most commonly used manufacturing process due to its cost efficiency.

Coating: Also known as Electroplating, coating is a technically advanced process designed to achieve a higher degree of consistency and uniformity.

The two biggest differences between plating and coating are:

• The amount of titanium crystals produced
• The surface coverage characteristics

The following examples visually illustrate two distinct platinum application techniques, Plating (dipping) and Coating (Electroplating).

## Plating or Dipping

Both dust and voids are clearly visible

##### Plate surface from above:

Black spot represent voids

D company
Dipping method

##### X 6000 (Cross section):

X 6000 (Cross section)

D/H company
Dipping method

## AlkaViva Coating (Electroplating)

Note the distinct vertices (peaks and valleys) and a 3-dimensional crystalline surface, as compared to the inconsistent surface of the dipped electrodes.

##### Plate surface from above:

No voids, thin spots or inconsistencies

AlkaViva plate
(coated platinum)

##### X 6000 (Cross section):

No voids, thin spots or inconsistencies

AlkaViva plate
(coated platinum)

## Prevention of Titanium Leaching

AlkaViva is able to totally prevent titanium leaching on the electrodes by two methods:

• Complete and uniform coverage. Our coating process surpasses all other processes in the water ionization industry to more completely and evenly cover the titanium plates with pure platinum, including all edges and all surfaces.
• More efficient use of power. This means we can apply less power more efficiently which creates far less heat and stress on the water ionizer electrode/plate during the electrical load phases.

View a certified analytical test result from the United States Environmental Protection Agency Primacy Laboratory for the State of Nevada showing that there is no plate leaching.

## Optimal water ionization Results Without Additives

AlkaViva employs proprietary technologies which are able to achieve optimal water ionization-alkalizing and acidifying results without the use of (potentially harmful) solutions such as salt enhancers.

## It isn’t ALL about Electrodes: Membranes

All water ionizers employ ion-selective membranes to separate the electrodes and enable the water to “ionically separate” the water into an alkaline and acidic stream. The membrane is absolutely critical in how a waterionizer performs. You can have a well-designed electrode/plate, powered optimally but if you have poor membranes, then you have poor water ionization performance.

AlkaViva’s Infusion Membranes are made in-house and are ultrasonically pressed, rather than chemically bonded. This provides you with a distinctly superior electrode membrane, designed to work specifically with our Smart Electrodes, giving you unmatched water ionization performance-pH, -ORP, H2.

usage of more watts and amps , spreading the same input voltage over a larger surface area results in less efficiency. This does not deliver the power evenly or efficiently and must do so with greater resistance.

More power means more heat, which means the platinum plating breaks down faster on the surface of the water ionizer electrode. This equals poor water ionization  performance over time.

So now you can see that in truth, bigger electrode is not better. This is why the electronics industry (and others) has shown that when technology advances, it typically results in smaller, more powerful and devices. Why would water ionizers be any different? The truth is they are not.

# Water Ionizer Cleaning Systems: Why DARC II auto cleanse is the best electrode cleanse.

## Water Ionizer Cleaning Systems: Why DARC II auto cleanse is the best electrode cleanse.

We drink alkaline ionized water to enjoy the profound benefits created from the transformation of water through created through electrolysis – or more loosely “water ionization”.

Here is the situation: Water has minerals/electrolits. Minerals build up on the electrodes and membranes and these are the two components in your water ionizer that transform the water. Scale essentially “coats” these components, compromising their ability to transform/ionize the water. This mean a decrease in pH, ORP and H2 -water ionization performance, which in turn, reduces any benefit you receive from the water – precisely what you bought your water ionizer for in the first place.

All water ionizers have cleaning systems for electrodes, but all plate cleaning systems are not created equal. Most water ionizers employ outdated plate cleaning systems that have been around for years without any advancement or technological improvement.

Smart Shopper’s Shortcut
What you need to know about water ionizer cleaning systems…Before you buy a water ionizer, it is crucial that you understand what type of electrode/plate cleaning cycle it employs. This is one of the most important considerations because it determines how well your water ionizer will perform over the long haul. If you are shopping around, ask about the type of electrode / plate cleaning system and how it works. If all the salesperson can do is quote a gimmicky cleaning system name, but can’t tell you the specific acidic to alkaline ratio in their system, or tell you specifically how it works…run. Fast! Then call us. We’ll tell you precisely how DARC II works and why it is the best  water ionizer cleaning system available.

AlkaViva set a new industry standard in 2006 when it launched the patented Dual Automatic Reverse Cleaning system (USA Patent No. 6,951,225). DARC was, and still is – thanks to the patent protection – revolutionary because it cleans the electrodes in the water cell with every use, eliminating damaging scale buildup. It accomplishes this by reversing polarity each time you use the water ionizer.

The revolutionary DARC cleaning system eliminates mineral scaling on the electrodes – protecting your investment and ensuring years of healthy water from your water ionizer. DARC is highly effective because it works in the background to clean your electrode, each time you use your water ionizer and while you are actually using it. The result is a vastly improved acidic to alkaline cleaning ratio, which is critical to keeping the electrodes cleaner than other systems that offer a 15:1 ratio or a 30:1 ratio. The Kangen Enagic™ SD501 which retails at almost \$4000, only cleans using a 30:1 ratio1. The importance of this breakthrough cannot be understated.

Additionally, with the dual solenoid system that directs water flow (actually what is patented and what DARC refers to), you never have to wait while your water ionizer cleans to get your alkaline water – an industry first! AlkaViva’s Jupiter  Athena JS 205 Classic and UltraDelphi IO  400 U water ionizers  employ DARC cleaning for electrodes.

## The Best just got Better: the New and Improved DARC II electrodes autoclean system .

AlkaViva once again sets a new industry standard by launching DARC II in its new H2 water ionizer series. Over the 11 years since we released DARC we have learned a few things and consequently saw how it could be substantially improved. DARC II offers you the same highly effective cleaning as the original DARC, and convenience of never waiting, but now gives you increased DURABILITY.

Because the original patented DARC solenoid system is outside the water cell, the solenoids DO NOT benefit from the acidic cleaning. The electronic solenoids in DARC contain a metal actuator that operates on a very tight tolerance. Once it gets even a hint of scale, it becomes susceptible to failure. Over 11 years since we launched DARC this was not an uncommon issue in hard water areas.

We improved DARC II by eliminating the electronic solenoid containing the metal actuators. We eliminated the potential failure of the electronic solenoid and also now employ a mechanical ceramic valve (replacing actuator) that is 100% resistant to any scaling. We did not stop there. Reversing the polarity each time you used the water ionizer did not in reality create the best possible acidic to alkaline ratio – which would be 1:1. Imagine you fill an 8 oz glass, then one liter, then a 16 oz glass, then a gallon and on and on. You don’t come close to a 1:1 ratio – even over the life of the water  ionizer. We now reverse the polarity every 5 liters – which creates a ratio much closer to 1:1, thus improving the effectiveness.

DARC II is the new standard in on-board water ionizer cleaning systems borne of experience and research and development. Another AlkaViva first.

## Reverse Polarity Cleaning.

Each electrode in your water ionizer has either a positive or negative polarity. Reverse polarity cleaning is simply when your water ionizer reverses the polarity; positive electrodes become negative and conversely. When an electrode is “bathed” in alkaline water containing scaling minerals, it becomes susceptible to scaling. When the polarity is reversed, the same electrode is now exposed to acidic water which removes the scale.

All water ionizers clean using reverse polarity. However, the cleaning systems differ radically in how they trigger it, the interval at which they perform the electrode cleaning cycle, and most importantly, how effective they are.

## Understanding other Cleaning Systems.

Since it is the acidic water which eats away the scale, for optimal efficacy the cleaning cycle must feature a good “acid to alkaline cleaning ratio”. The more acidic water that is run to bath the electrodes the cleaner they remain and the greater their water ionization performance and longevity.

The way a water ionizer is “programmed” to clean the electrodes is crucial in determining the electrode cleaning ratio. The most common systems have been in use many years without improvement:

• Manual system: you must remember to reverse the polarity and initiate the electrode cleaning cycle yourself.
• Timer system: cleans at a set-interval, such as every 15 minutes of use. After 15 minutes of run time, the next time you turn the water  ionizer on, the unit starts the cleaning cycle. Most often you must wait while it completes the electrode cleaning cycle.
• Volume system: Similar to the timer system, but cleans based on a set volume of water (Say for example 10 gallons) passing through the water ionizer. You must also wait.
• Post cleaning systems: while they clean after each use, the clean cycle is extremely short resulting in a poor acidic to alkaline ratio. They also use a finite amount of water to clean – only the water that is in the water cell (since the cleaning is triggered after the water ionizer is shut down). The better post-use systems drain the cell when the cycle is complete, so you do not have contaminated water in the cell that will expel into the drinking water when the water ionizer is turned on. These draining systems are prone to failure at both the PCB and drain valve level.. Not as robust, effective or durable as DARC.

Each has its draw backs: you can forget to trigger a manual cycle, the timer and volume systems have poor acidic to alkaline electride cleaning ratios. The worst drawback is that with each of the above systems you have to wait for the cycle to complete before you can receive alkaline ionized water.

In summary, we love that you have read this far! Because now you can see – emphatically – why cleaning is so important and why and how AlkaViva’s H2 water ionizer Series with its new and improved DARC II autocleanse system for electrodes is your best choice. Consider your searching over!

*1) The Kangen Enagic  SD501 water ionizer cleans for 20 seconds for each 10 gallons of use. It would take the Kangen Enagic water ionizer approximately 10 minutes of run time at 1 gpm water flow rate to produce 10 gallons. Therefore, 10 mins X 60 seconds = 600. The water ionizer plate cleaning ratio is then 600:20 or reduced is 30:1.

# AlkaViva UltraWater filtration technology

Simply put, AlkaViva UltraWater filtration is the best alkaline water ionizer filter you can buy. In fact, it is the best water filter — of any type — that is currently available. Our unmatched Independent EPA / NELAP certified lab tests prove it. We often get asked how we can achieve such stunning water filtration/contaminant removal results.
Smart Shopper’s Shortcut
What you need to know about UltraWater filtration…What good is healthy water if it isn’t also clean water? Better than 0.01 micron UltraFiltration or a series of external water filters, UltraWater incorporates  Sediment shield, BioStone Booster, BioStone Carbon Block with Impregnation Plus(zeolite and silver), Bioceramic Tourmaline with Scale Guard, UltraWater Disc Technology to offer ultraclean alkaline ionized and molecular hydrogen water and most important has been tested and certified by a governmental laboratory for efficient removal of 172 water contaminants  – UltraWater filtration technology – the most thoroughly tested and safest water filtration option available.

## Here’s How We Do It

Let’s start with an analogy: turbocharged gas engines. When they first came out, they combined new and existing technologies in a novel way. The result was a powerful new combination and unprecedented performance. Similarly, UltraWater filtration technology starts with the water industry’s proven top-performing media, adds in cutting edge medias in a new application, and then creates a new twist on existing manufacturing techniques. The result isn’t just a water filter. It’s a proprietary water filtration technology. This unique combination effectively “turbocharges” the media and water filtration processes, allowing better water filtration performance and better results.

## What’s Inside:

### Sediment Shield

Standard GAC water filters do not offer this component. It is an electrostatic wrap comprised of polypropylene spun fiber. It is designed to provide a mechanical barrier to sediment – meaning it traps the sediments.

### Biostone Booster

Comprised of NSF certified CaSO3 slow-eluting bio-ceramic balls. They target chlorine, chloramine certain heavy metals. CaSO3 is more effective than granulated active carbon or KDF. One hundred grams (100g) of CaSO3 will outperform carbon and KDF by a factor of x2.

### BioStone Carbon with Impregnation Plus

Our NSF certified carbon is catalyzed with an oxidizer and has the highest oxidation and adsorption pore concentration available. The carbon is impregnated with natural zeolite(vulcanic rock) and silver(antimicrobial).

The zeolite provides increased heavy metal reduction and a slight ion-exchange effect.

The silver prevents bacteria growth between uses.

We use both carbon block and loose bed applications.

Our carbon blocks are sintered and compressed under high temperature and heat (not extruded) resulting in a superior carbon block. Either way, our proprietary process greatly increases the surface area, contact time and the resulting capability.

### UltraWater Disc Technology

This leading-edge technology is the real turbocharger in UltraWater filter. It combines a high-tech NSF certified reticulated foam which is impregnated with three different medias. All are NSF certified. All offer unmatched heavy metal and organics reduction allowing us to target contaminants that other alkaline water ionizer filters can’t – such as arsenic.

### Bioceramic Tourmaline with Scale Guard

The tourmaline is in a very hard, slow-eluting biocermic ball from. It releases FAR infrared energy lowering surface tension. Scale Guard is a sequestering agent that is a highly effective anti-scale media. It is in a slow-eluting crystal bead form and is there to protect the water ionizer from hard water damage.

## What it Does

UltraWater is the ONLY alkaline water ionizer filter tested for 172 contaminants. Independent EPA / NELAP certified lab testing shows UltraWater is the ONLY water filter that can reduce virtually all contaminants up to 99.9% — even the toughest including arsenic, chromium VI, lead, VOCs and pharmaceuticals

UltraWater filtration technology selectively reduces the bad contaminants while allowing the good, naturally occurring minerals to pass through. This alkaline water ionizer filter design is used in AlkaViva’s UltraWater electric water ionizer range to produce electric ionization.

UltraWater filtration  can also be formulated to create natural water ionization without electricity. Some of the world’s renowned sources of healing water are passively ionized by contact with certain earth alkali minerals, silicate and crystalline complexes. We have formulated an exclusive “passive water ionization” technology inside our non-electric Elita Series which contains the same type of mineral complexes. As water passes over the passive water ionization media we create increased pH, –ORP and molecular hydrogen (H2 water). While multiple beneficial minerals are dissolved, it chiefly infuses magnesium, which is shown to be absorbed best by the body when dissolved in water.

So regardless of which AlkaViva water product you choose, ultraclean and effective UltraWater is the best answer!

# UltraWater Water Ionizer Filters – Tested for 172 Contaminants

## Better water filtration Performance. Safer Water. Better Health.

Healthy water has to be clean water. Other ionizer filters simply cannot handle well known water contaminants such as lead, arsenic, chromium VI – and a host of others. Independent EPA / NELAP certified lab testing shows UltraWater reduces virtually all contaminants up to 99.9% — even the toughest including arsenic, chromium VI, lead, VOCs and pharmaceuticals.

# AlkaViva testing is:

• Certified & credible: All tests performed in Independent, EPA / NELAP Certified Labs
• Thorough: we omit nothing and we show results for everything tested.
• Real world: we tested contaminant levels in parts per million and that were as close the EPA Maximum Contaminant Level as we could get .
• Nothing hidden or left out: we reported everything – even the toughest to remove contaminants such as arsenic, chromium VI etc.
• Comprehensive: We tested 21 heavy metals, 65 pharmaceuticals, 3 OTC drugs, 7 Hormones, 15 pesticides and herbicides, preservatives and wastewater indicators, 45 VOCs, and 5 other anions & disinfectants – a total of 172 contaminants!
• 16 Supercharged Medias
>See Test Results

# AlkaViva UltraWater Filter Removes

Arsenic
Prescription Drugs
Industrial Chemicals
Hormones
Chloramine
Trihalomethane
Preservatives
Herbicides
Volatile Organic Compounds
Chromium VI
Chlorine
OTC Drugs
Pesticides
Heavy Metals

# Peer Reviewed Articles on Alkaline Diet Benefits from Increasing Alkalinity in the Body

“Alkaline water produced by a water ionizer has become the most important advancement in health care since Sir Alexander Fleming’s discovery of penicillin.”
— Dr. William Kelly, author, Cancer Cure.

Over the past decade, there has been a growing interest in alkaline diets and living an alkaline lifestyle. Part of this interest may involve drinking alkaline, ionized water from a water ionizer as a way to improve wellness, enhance performance, and prolong vitality. Alkaline, ionized water is water that has been selectively altered in a water ionizer to raise pH from neutral to pH 9 or more and also to display negative change (-ORP). Water above a pH 7 is alkaline and water below pH 7 is acidic. pH can be easily measured by using pH reagent or a meter, and ORP is measured using an ORP meter.

Life on earth depends on appropriate pH levels in and around living organisms and cells. Human life requires a tightly controlled pH level in the serum of about 7.4 (a slightly alkaline range of 7.35 to 7.45) to survive. The ability of the body to maintain this level of pH can be compromised by poor diet, lack of or excessive exercise, pollutants, dehydration, and stress. From available evidence, it would be prudent to consider the effects of alkaline water on the body and an alkaline diet to reduce morbidity and mortality from the chronic diseases that are plaguing our aging population. (www.ncbi.nlm.nih.gov/pmc/articles/PMC3195546/)

Along with this interest in all things alkaline, there have also been some unsubstantiated health claims made. Such claims give rise to pseudo-sciences that undermine the significant body of peer-reviewed, published research into how altering alkaline (pH) levels can bring about health changes. Part of the issue in studying the beneficial effects of an alkaline diet is the lack of funding available for such research coupled with the complexity in trying to isolate what factors are creating change. Indeed, a few studies failed to find health changes from altering diet, although other studies acknowledge distinct benefits. Everyone agrees that more research is needed to further investigate alkaline health benefits.

Not only do AlkaViva water ionizers produce clean, alkaline water, but they can also create a significant amount of diatomic hydrogen (H2) in the water. The peer-reviewed benefits from drinking H2 water are NOT covered in this article.

Below are excerpts from peer-reviewed, ALKALINE diet/water studies along with references as to where the full articles can be found if you wish to study further. We welcome feedback.

## Alkaline water Hydration for Athleets

It is the position of the American College of Sports Medicine that adequate fluid replacement helps maintain hydration and, therefore, promotes the health, safety, and optimal physical performance of individuals participating in regular physical activity.
Convertino VA, Armstrong LE, Coyle EF, Mack GW, Sawka MN, Senay LC Jr, Sherman WM., American College of Sports Medicine position stand. Exercise and fluid replacement. Med Sci Sports Exerc. 1996 Jan;28(1):i-vii.

A significant difference in whole blood viscosity was detected in this study when assessing a high-pH, water versus an acceptable standard purified water during the recovery phase following strenuous exercise-induced dehydration.
Joseph Weidman, Ralph E. HolsworthJr., Bradley Brossman, Daniel J. Cho, John St.Cyr, Gregory Fridman, ffect of electrolyzed high-pH alkaline water on blood viscosity in healthy adults, Journal of the International Society of Sports Nutrition.

After using an alkalizing supplement trained Nordic skiers experienced significant changes in cardiorespiratory, blood lactate, and upper body power output measures. Studies also indicate that drinking alkaline water can enhance the body’s buffering capacity and temper the acidity, thus improving performance.
Daniel P Heil, Erik A Jacobson, and Stephanie M Howe, Influence of an alkalizing supplement on markers of endurance performance using a double-blind placebo-controlled design, J Int Soc Sports Nutr. 2012; 9: 8. Published online 2012 Mar 20. doi: 10.1186/1550-2783-9-8.

Supplementing with alkalizing minerals (calcium, magnesium, potassium) decreases cardio-respiratory stress and blood lactate responses, while improving power output in endurance athletes. Alkaline water may work similarly.
Y. Kilkian, F. Engel. P. What, J. Master, Markers of Biological Stress, https://www.researchgate.net/publication/308012779.

Consumption of alkaline water was associated with improved acid-base balance (i.e., an alkalization of the blood and urine) and hydration status when consumed under free-living conditions. In contrast, subjects who consumed the placebo bottled water showed no changes over the same period of time. These results indicate that the habitual consumption of alkaline water may be a valuable nutritional vector for influencing both acid-base balance and hydration status in healthy adults. Also, over time, the mineral content of alkalized water could help active people retain more fluid in the cardiovascular system. This might improve overall hydration status and fluid reserves.
D,. Heil, Acid-base balance and hydration status following consumption of mineral-based alkaline bottled water. Movement Science/Human Performance Laboratory, Montana State University.

The physiology of intense exercise that produces acidosis is far more complex than originally thought. In the transition to higher exercise intensity, proton release is even greater than lactate production which indicates acidosis is only partially related to production of “lactic acid.”
Robergs, R. Exercise-induced metabolic acidosis: where do the protons come from? Sport Science 5(2) sportsci.org/jour/0102/rar.thm, 2001.

## The Evolution of Diet

Estimates of the net systemic load of acid in ancestral pre-agricultural diets as compared to contemporary diets reflect a mismatch between the nutrient compositions of the diet and genetically determined nutritional requirements. The result is that contemporary diets generate diet-induced metabolic acidosis in contemporary Homo Sapiens.
Sebastian A, Frassetto LA, Sellmeyer DE, Merriam RL, Morris RC Jr., Estimation of the net acid load of the diet of ancestral pre-agricultural Homo sapiens, www.ncbi.nlm.nih.gov/pubmed/12450898.

Report compiled by the World Health Organization from studies in different regions of the world on the importance of minerals in drinking water.
Ong, Choon. Minerals from drinking-water: Bioavailability for various world populations and health implications. WHO | Water Sanitation Health. World Health Organization, 17 Aug 2004.

Because of the increased incidence of obesity in our population, electrolyzed water at 2 liters/day for 2 months was given to four obese subjects. Statistical evaluation of the results of the present study suggests that electrolyzed water as used resulted in near significant weight loss and a significant loss of body fat in obese subjects.
Abraham, Guy, and Jorge Flebas. The effect of daily consumption of 2 liters of electrolyzed water for 2 months on body composition and several physiological parameters in four obese subjects: a preliminary report. Highbeam Research. Original Internist, 01 Sep 2011. Web. 2 Jul 2013. http://www.highbeam.com/doc/1G1-269433201.html.

## Alkalinity/alkaline water and Muscles

As we age, there is a loss of muscle mass, which may predispose to falls and fractures. A three-year study looking at a diet rich in potassium, such as fruits and vegetables, as well as a reduced acid load, resulted in preservation of muscle mass in older men and women.
Dawson-Hughes B, Harris SS, Ceglia L. Alkaline diets favor lean tissue mass in older adults. American Journal of Clinical Nutrition. 2008;87(3):662–665.

Correction of acidosis may preserve muscle mass in conditions where muscle wasting is common such as diabetic ketosis, trauma, sepsis, chronic obstructive lung disease, and renal failure.
Gerry K. Schwalfenberg, University of Alberta, The Alkaline Diet: Is There Evidence That an Alkaline pH Diet Benefits Health? Journal of Environmental and Public Health, Volume 2012 (2012), Article ID 727630.

Chronic metabolic acidosis increases net muscle protein degradation in rat muscle tissue. Metabolic acidosis stimulates protein degradation in rat muscle by glucocorticoid-dependent mechanism.
Mitch WE, Medina R, Grieber S, May RC, England BK, Price SR, Bailey JL, Goldberg AL., University School of Medicine, Georgia,Metabolic acidosis stimulates muscle protein degradation, https://www.ncbi.nlm.nih.gov/pubmed/8182144.

## Bone Loss prevention with alkaline water

The bone minerals that are wasted in the urine may not have complete compensation through intestinal absorption, which is thought to result in osteoporosis. An alkaline diet typically does improve the K/Na ratio and may benefit bone health, reduce muscle wasting, as well as mitigate other chronic diseases such as hypertension and strokes. It has been found increases in the alkali content of a diet, may attenuate bone loss in healthy older adults.
G. K. Schwalfenberg, University of Alberta, Oct 2011. www.ncbi.nlm.nih.gov/pmc/articles/PMC3195546/-.

Dietary acid charge enhances bone loss. Bicarbonate or alkaline diet decreases bone resorption in humans. We compared the effect of an alkaline mineral water, rich in bicarbonate, with that of an acid one, on bone markers, in young women with a normal calcium intake.
Wynn, E, MA Krieg, JM Aeschlimann, and P Burckhardt. Alkaline mineral water lowers bone resorption even in calcium sufficiency: alkaline mineral water and bone metabolism. Bone. Elsevier, 27 Oct 2008. Web. 1 Jul 2013. http://www.thebonejournal.com/article/S8756-3282(08)00781-3/abstract.

Excess dietary protein with high acid renal load may decrease bone density if not buffered by ingestion of supplements or foods (water) that are alkali rich.
G. K. Schwalfenberg, 2012 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195546/.

This work shows that bone depletion is absolutely dependent on extracellular acidification; these cells are inactive at pH levels above about 7.3 and show maximum stimulation at a pH of about 6.9. Bone resorption is most sensitive to changes in H+ concentration at a pH of about 7.1 (which may be close to the interstitial pH in bone). In vivo, severe systemic acidosis (pH change of about -0.05 to -0.20) often results from renal disease; milder chronic acidosis (pH change of about -0.02 to -0.05) can be caused by excessive protein intake, acid feeding, prolonged exercise, ageing, airway diseases or menopause. Acidosis can also occur locally as a result of inflammation, infection, wounds, tumors or diabetic ischemia. Cell function, including that of osteoblasts, is normally impaired by acid; the unusual stimulatory effect of acid on osteoclasts may represent a primitive ‘fail-safe’ that evolved with terrestrial vertebrates to correct systemic acidosis by ensuring release of alkaline bone mineral when the lungs and kidneys are unable to remove sufficient H+ equivalent. The present results suggest that even subtle chronic acidosis could be sufficient to cause appreciable bone loss over time.
Arnett T., Department of Anatomy and Developmental Biology, University College London, https://www.ncbi.nlm.nih.gov/pubmed/14506899.

Humans generally consume a diet that generates metabolic acids leading to a reduction in the systemic bicarbonate and a fall of pH. Chronic metabolic acidosis alters bone cell function; there is an increase in osteoclastic bone resorption and a decrease in osteoblastic bone formation. As we age, we are less able to excrete metabolic acids due to the normal decline in renal function.
Bushinski DA., Nephrology Unit, Strong Memorial Hospital, New York, https://www.ncbi.nlm.nih.gov/pubmed/11842949.

Chronic metabolic acidosis is a process whereby an excess acid load is placed on the body due to excess acid generation or diminished acid removal by normal homeostatic mechanisms. Excessive meat ingestion and aging are two clinical conditions often associated with chronic metabolic acidosis. The body’s homeostatic response to this pathology is very efficient. Therefore, the blood pH is frequently maintained within the “normal” range. However, these homeostatic responses engender pathologic consequences such as nephrolithiasis, bone demineralization, muscle protein breakdown and renal growth.
Alpern RJ1, Sakhaee K., Department of Internal Medicine, University of Texas, https://www.ncbi.nlm.nih.gov/pubmed/9016905.

Excessive dietary intake of protein with consequent increase in metabolic acid production result in compensatory mechanisms that lead to progression of kidney stones, bone disease, renal disease and a catabolic state.
Alpern, R. Trade-offs in the adaptation to acidosis, Kidney International 47: 1205-1215, 1995.

The acid load inherent in the Western diet results in mild chronic metabolic acidosis in association with a state of cortisol excess. An alkali balanced diet modulates bone resorption and the associated alterations in calcium and phosphate homeostasis.
Maurer, M.; Riesen, W.; Muser, J.; Hulter, H. and Krapf, R. Neutralization of Western diet inhibits bone resportion independently of K intake and reduces cortisol secretion in humans, American Journal of Physiology and Renal Physiology 284: F32-40, 2003.

Osteoclast activity is modulated by small pH changes and is a key determinant of bone resorption in mouse calvarial cultures.
Sajeda Meghji, Matthew S. Morrison, Brian Henderson, Timothy R. Arnett, pH Dependence of Bone Resorption American Journal of Physiology – Endocrinology and Metabolism Vol. 280 no. 1, E112-E119.

## Alkaline Diet and Growth Hormones

It has long been known that severe forms of metabolic acidosis in children, such as renal tubular acidosis, are associated with low levels of growth hormone with resultant short stature. Correction of the acidosis increases growth hormone significantly and improved growth. Improving growth hormone levels may improve quality of life, reduce cardiovascular risk factors, improve body composition, and even improve memory and cognition.
Wass JAH, Reddy R. Growth hormone and memory. Journal of Endocrinology. 2010;207(2):125–126.

## Alkaline Minerals (in water) and Back Pain

There is some evidence that chronic low back pain improves with the supplementation of alkaline minerals. With supplementation there was a slight but significant increase in blood pH and intracellular magnesium. Ensuring that there is enough intracellular magnesium allows for the proper function of enzyme systems that improves back pain and also allows for activation of vitamin D.
Gerry K. Schwalfenberg, The Alkaline Diet: Is There Evidence That an Alkaline pH Diet Benefits Health? J Environ Public Health. 2012; 2012: 727630.

## Alkalinity/alkaline water and Chemotherapy

The effectiveness of chemotherapeutic agents is markedly influenced by pH. Numerous agents such as epirubicin and adriamycin require an alkaline media to be more effective. Cell death correlates with acidosis and intracellular pH shifts higher (more alkaline) after chemotherapy may reflect response to chemotherapy. It has been suggested that inducing metabolic alkalosis may be useful in enhancing some treatment regimes.
Gerry K. Schwalfenberg, The Alkaline Diet: Is There Evidence That an Alkaline pH Diet Benefits Health? J Environ Public Health. 2012; 2012: 727630.

## Alkalinity/alkaline water and Cancer

Diet-induced acidosis is a potential upstream and indirect trigger in a multifactorial cascade of molecular events associated with carcinogenesis. The American Institute for Cancer Research (AICR) comprehensive global report has compiled numerous studies demonstrating associations between dietary habits and cancer risk. The findings recommend increased or regular consumption of vegetables, fruits, whole grains, and legumes, while discouraging excess consumption of sugary and energy-dense foods and drinks, red and processed meats, and salty processed foods.
Ian Forrest Robey, University of Arizona, Examining the relationship between diet-induced acidosis and cancer, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3571898/.

Oral administration of pH buffers can reduce the development of spontaneous and experimental metastases in mice, and has been proposed in clinical trials. It is notable that cancer cells maintain a high level of glucose metabolism even in the presence of oxygen, which was first documented by Warburg more than 80 years ago. This is a consistent finding across a variety of cancers, and has been recognized as a “hallmark” of cancer.
Maria de Lourdes C Ribeiro, Ariosto S. Silva, Kate M. Bailey, Nagi B. Kumar, Thomas A. Sellers, Robert A. Gatenby, Arig Ibrahim-Hashim, and Robert J. Gillies, Buffer Therapy for Cancer, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872072/.

A significant consequence of increased glucose metabolism is the production of acids, such as lactic acid, which can be an independent negative prognostic factor for cancer outcome. Prior mathematical models and empirical studies have shown that solid tumors export acid into the surrounding parenchyma. This is consistent with measurements of tumor pH in mouse models, which have shown that the extracellular pH of solid tumors is acidic. Combined, these observations have led to the generation of the “Acid Mediated Tumor Invasion” hypothesis, which proposes that fast-growing tumors export acid to surrounding stroma, and that reduced pH contributes to the tissue remodeling required for tumor invasion.
Ian F. Robey, Brenda K. Baggett, Nathaniel D. Kirkpatrick, Denise J. Roe, Julie Dosescu, Bonnie F. Sloane, Arig Ibrahim Hashim, David L. Morse, Natarajan Raghunand, Robert A. Gatenby, and Robert J. Gillies, Bicarbonate Increases Tumor pH and Inhibits Spontaneous Metastases, Cancer Res. 2009 Mar 15; 69(6): 2260–2268.

## Alkalinity/alkaline water and Effects on Aging

Changes in renal physiology and function with aging put the elderly patient at risk for adverse effect of drug therapies due to the incidence of common problems like metabolic acidosis.
Lonergan, E. Aging and the kidney: adjusting treatment to physiologic change, Geriatrics 43: 27-30, 32-33, 1998.

Authors examined peer-reviewed literature to determine whether systemic acid-base equilibrium changes with aging in normal adults humans. Using linear regression analysis, they found that with increasing age, there is a significant increase in the steady-state blood H+ indicating a progressively worsening low-level metabolic acidosis in what may reflect, in part, the normal decline of renal function with increasing age.
Frassetto, L. and Sebastian, A. Age and systemic acid-base equilibrium: analysis of published data, Journal of Gerontology, Advanced Biological Science and Medical Science, 51: B91-99, 1996.

Dietary changes over the last two centuries have resulted in a mismatch between genetically-determined nutritional requirements in humans. Excess sodium chloride, a deficiency of potassium and excess dietary acids that are not mediated by dietary bicarbonates lead to chronic low-grade metabolic acidosis that amplifies the age-related pathophysiological consequences in humans (such as loss of bone substance, increase in urinary calcium, disturbance in nitrogen metabolism, and low levels of growth hormone).
Frassetto, L.; Morris, R.; Sellmeyer, D.; Todd, K. and Sebastian, A. Diet, evolution and aging: the pathophysiologic effects of the post-agricultural inversion of the potassium-to-sodium and base-to-chloride ratios in the human diet, European Journal of Nutrition 40:5 200-213, 2001.

Otherwise healthy adults manifest a low-grade, diet-dependent metabolic acidosis, the severity of which increases with age at constant rate described by an index of endogenous acid production, apparently due in part, to the normal age-related decline of renal function.
Frassetto, L.; Morris, R. and Sebastian, A. Effect of age on blood acid-base composition in adult humans: role of age-related renal functional decline, American Journal of Physiology, 271: 1114-22, 1996.

Age-induced decline in renal functions explains, at least in part, clinically important age-related conditions including metabolic acidosis.
Krapt, R. and Jehle, A. Renal function and renal disease in the elderly, Schweizerische Medizinische Wochenschrift, 130:11 398-408 2000.

Acid-base homeostasis exerts a major influence on protein function, thereby critically affecting tissue and organ performance. Deviations in body acidity can have adverse consequences and when severe, can be life-threatening.
Adrogue, H. and Madias, N. Management of life-threatening acid-base disorders, New England Journal of Medicine 338: 26-34, 1998.

Decline in the ability to adjust acid-base balance is a feature of aging. Regulation of pH ultimately depends on the kidneys and lungs, however, the ability of these organs is decreased with physiological aging. Renal insufficiency and/or chronic obstructive pulmonary disease and various drugs, such as diuretics, often affect the acid-base balance in the elderly.
Nabata, T.; Morimoto, S. and Ogihara, T. Abnormalities in acid-base balance in the elderly, Nippon Rinsho 50: 2249-53, 1992.

## Alkaline ionized Water and Free Radicals

Active oxygen species or free radicals are considered to cause extensive oxidative damage to biological macromolecules. The ideal scavenger for active oxygen should be “active hydrogen”. “Active diatomic hydrogen” can be produced in reduced (alkaline) water near the cathode during electrolysis of water. Reduced (alkaline) water exhibits high pH, low dissolved oxygen (DO), extremely high dissolved molecular hydrogen (H2), and extremely negative redox potential (-ORP) values. Reduced water suppresses single-strand breakage of DNA b active oxygen species suggesting that reduced water can scavenge different types of free radicals.
Shirahata S, Kabayama S, Nakano M, Miura T, Kusumoto K, Gotoh M, Hayashi H, Otsubo K, Morisawa S, Katakura Y., EmoryElectrolyzed-reduced water scavenges active oxygen species and protects DNA from oxidative damage, Biochem Biophys Res Commun. 1997 May 8;234(1):269-74.

## ionized water Benefits backed by research.

Over 600 PEER-REVIEWED STUDIES show that molecular hydrogen – or H2 -water / alkaline ionized water has a therapeutic benefit in every organ of the human body and positively affects over 150 disease models and health conditions.

Free radical damage causes oxidative stress and is one of the primary causes of aging. Oxidation causes iron or apples to “rust”. Antioxidants prevent or slow that damage. Unfortunately, anti-oxidants are non-selective neutralizing both beneficial and harmful radicals. The molecular hydrogen Hin UltraWater selectively targets only the damaging radicals – making it the “ULTIMATE” ANTIOXIDANT.

## Drink more. Improve your health.

When molecular hydrogen  H2 neutralizes damaging oxygen radicals, it creates water (H2O) – increasing your CELLULAR HYDRATION.Great tasting, silky-smooth, alkaline UltraWater is also easier to drink. When you drink more, you enjoy optimal hydration and better health.

## Ease your aches and pains.

Oxidative stress damages your cells, causing pain and inflammation. As we age, inflammation increases. Studies show that H₂ neutralizes the damaging radicals. Drinking UltraWater can ease chronic and acute aches and pain.

## Go longer. Go stronger.

ATP powers your cells. It is the source of your energy. Research shows molecular hydrogen(water) H₂ helps INCREASE ATP PRODUCTION giving you more energy while decreasing lactic acid levels. Athlete? Exerciser? Just want more pep? UltraWater helps improve performance and recovery.

# AlkaViva H2 water ionizers Certificates

## AlkaViva H2 water ionizers Certificates

### Company Registration

Permission for medical device manufacturing item
The manufacturer of the medical device shall be examined according to the medical device technique (Article 6) for the approval of the product and the facility and quality system for the product to be manufactured.
Since receiving the manufacturing approval of No. 889 in 2000, AlkaViva’s manufacturer has obtained 28 licenses of alkaline water ionizer items as of 2017.
US food pharmacy medical device manufacturing site and device registration
The US Department of Health and Human Services (FDA) is responsible for the distribution and management of medical devices in the United States under the Ministry of Health and Welfare. Manufacturers, distributors, and importers of medical devices must be approved and certified by the FDA. AlkaViva’s manufacturer was approved in 2005 and registered all items of water ionizer equipment.
The KIPO is a government agency that manages industrial property rights such as patents, utility models, designs and trademarks. When the inventors filed industrial property rights, the Korean Intellectual Property Office obtained the rights by examining them.

### Management System

Medical device manufacturing and quality control certification
Good Manufacturing Practice (GMP) is a system for manufacturing and selling quality medical devices that are guaranteed by the organization, from the design of the product, the purchase of raw materials, to the manufacture, It is a standard that defines the things to be managed and maintained. AlkaViva’s manufacturer has been certified for the first time in 2005 and has maintained its effectiveness since its regular review.
Quality system
It is an international standard for quality management system enacted by the International Organization for Standardization (ISO) to evaluate and certify the quality assurance system throughout the entire production process, from products and services.
Environmental system
ISO 14001 This system evaluates the environmentally friendly management of the environment by introducing an environmental management system throughout the company’s activities. We identify the environmental hazards that occur during the production process and apply them as a method to manage the management system. AlkaViva’s manufacturer was certified in 2008.
Certificate of Origin Certification
The customs authorities shall issue a certificate of origin to the exporter who certifies that the exporter has the capability to prove that he satisfies the criteria for determining the origin of the exported goods in accordance with the Enforcement Rule of the Act on the Exemption of Customs Act for the Implementation of the FTA As a system to simplify the submission of attached documents, AlkaViva’s manufacturer has obtained certification for each item in 2013.

### Electric Safety

European Community Integration Certification
It is a mandatory certification mark indicating that the product has been tested and is in conformity with the applicable EU standards for requirements relating to safety, health, environment and consumer protection in accordance with national certification schemes and technical regulations in the European Union. AlkaViva’s manufacturer was certified by product in 1998.
North American Electrical and Electronic Products Safety Certification
The NRTL program is part of the Occupational Safety and Health Administration (OSHA) guidelines to ensure that the product is safe for use in North America. Normally, when you want to export to North America, you have to obtain UL-marks for the US market, CSA-marks for the Canadian market, and NOM-marks for the Mexico region. One NRTL-marks after NAFTA (North American Free Trade Agreement) I can solve it easily. Since its acquisition of UL certification in 1998, AlkaViva’s manufacturer has obtained the 1201sus NRTL factory certification.
International electric appliance certification
It is an international electrical certification system operated by IECEE. It is a system that tests the safety of electrical and electronic products in accordance with the IEC international standard and mutually recognizes the test results internationally among the member countries. Currently, many countries, mainly in Europe, adopt the IEC standard as their own standards. AlkaViva’s manufacturer has been certified by product in 2010.
National Integrated Certification Mark KC
You can safely use it as a proven product that keeps safety standards. KC certification is made from materials that are harmless to human body, it is given after verifying that it is safe enough to maintain buoyancy and durability, so it is a product that you can trust and buy more.
Japan electric appliance type certification
It is the certification system according to the Electrical Appliance and Material Safety Law applicable to electrical and electronic products in Japan. It is compulsory certification that the customs clearance and sale in Japan are prohibited before obtaining the certification. In 2006, AlkaViva’s manufacturer certified DIAMOND PSE Certified Electrical Appliances.
Germany certified
It is an international electrical certification system operated by IECEE. It is a system that tests the safety of electrical and electronic products in accordance with IEC international standards and mutually recognizes the test settlement internationally among the member countries. Currently, many countries, mainly in Europe, adopt the IEC standard as their own standards. AlkaViva’s manufacturer has been certified by product in 2010.

# Alkaline ionized water, obliterating arteritis and diabetes

Alkaline ionized water, obliterating arteritis and diabetes – ionized alkaline water saves from amputation one leg of the patient with obliterated arteritis and diabetes

“I write these lines both for my facebook friends and for the multitude of patients suffering from diabetes and implicitly by obliterant arteritis and who sooner or later reach stents mounted in coronary, iliac, subclavicular arteries, or worse -amputation of the lower limbs.
I retired in 2002 following a myocardial infarction and since then the troubles (medical problems) have kept coming.
Due to the insulin-induced diabetes diagnosed in the 1990s, between 2002-2005, three (2-foot) surgeries were done to replace the arteries (due to massive atheroma deposits) with femoral-popliteal vascular prostheses (by-passes) at the right foot twice.
In 2011, the right foot bypass began to close (by deposition of the atheroma), which made the stenosis of the arteries under the knee (tibial and peronian) almost reach 100%. Having had major coronary problems, the doctors refused to change my right foot bypass (it would have been the third time and recommended me to make a daily infusion of “vasaprosta”(  expensive and which was distributed by CNAS with special approval) for 30 days, the procedure being considered (then) as a means of rescuing the foot from amputation.
In my case this procedure (vasaphase infusions) proved to have the effect of rubbing with “Galenica” on an acacia wood leg. As the number of infusions increased, the pain of the foot soles was increasing and the leg was all the time cold.
I informed him several times of the doctor under whose supervision these perfusions were being made, of the evolution of the disease (unbearable pain and cold leg) but not only did he not count me but he did not even take a strain on my leg. For peace reasons I do not give  the name of the doc!
After 20 days of infusions, one morning after I woke up, I noticed that my toes were black and soaked. We had the gangrene.
I turned to emergency and the surgeon at the vascular surgery department (as a day of rest) refused to interfere because they did not cut off fingers and advised emergency staff to call the surgery department for leg amputation.
I went to Bucharest and admitted to the Emergency University Hospital at the Vascular Surgery Clinic.
On December 6, 2011 I my right leg fingers were amputated . Because the gangrene continued, on December 9 I underwent a new metatarsal amputation and replaced my vascular prosthesis with a saphenous vein harvested from the amputee foot
On December 12, I had a heart attack and I was admitted to intensive care. On December 15 we made a cardiac arrest and I was intubated …
I stayed intubated for several days in incapacity, while my lungs were sucked several times a day.
After I was discharged from intensive care, I was admitted to cardiology and after a while I began to cough more and more. I was treated with bronchitis until discharge from the hospital
The cough continued after discharge and eventually I went to emergency in Constanta at the Otolaryngology section, where it was ascertained that due to intensive care suction maneuvers, after the cardiac arrest, my trachea was injured, which led to the appearance of an excrescence that finally almost obstructed my trachea.
I had surgery (post-tubal tracheostomy) and through surgery I was mounted a plastic cannula under the apple of Adam through which we breathe.
The operation of the foot has never healed.
In June 2013, I was implanted (I do not know if the term is correct) 5 stents in the coronary hearts at Fundeni Hospital.
In September 2013 (year with bad luck) the foot pain again began to amputate, having to accept a new amputation this time above the knee.
Finally, in September, three successive amputations were made at my right foot by a “great” doctor professor, but more about the professionalism and competence of the individual maybe another time.
After the third amputation, I went home with half the stools from the bumps and with my leg in the amputation area. After another month of home treatment, a nurse in surgery managed to heal my dent.
Since spring last year, my left foot, which has a femur-popliteal prosthesis since 2004 (they are guaranteed for 5-6 years) has started to hurt and the situation worsens in the beginning of 2017, with all medications, ointments and massages (including lymphatic) that have been given and done all along.
In February 2017, I did a vascular / arterial doppler exam that revealed that the bypass has a 70% stenosis, the anterior tibial is oval, the posterior tibial has 98% occlusion, and the peroneal artery has a 98% occlusion. Finally, the cardiologist who did my doppler exam, probably to encourage me,  said that in 2-3 weeks I will get to left foot amputation and showed me where they were going to amputate ….

I have a good friend and colleague from high school class, the energetic engineer GIDEA- SANDUTU VERGICA from Filiasi whom I told of my misfortune and that soon I will lose my left leg through amputation

Very relaxed and with great confidence he told me that I do not have to worry -they will not amputate my leg as he’ll help solve my problem. I replied that it was not good a joke … not to say anything else. He explained that there was no joke, that he would not allow himself to make jokes with me in the given situation and asked me if I heard anything about ALKALINE IONIZED WATER. NO, I said. I said that I do not know what it is, and that I do not think there is any drug in the world (which we also know, foolishness) that can dissolve the arteries deposits … much less a water,she would call it she-chiara, holy water or ionized alkaline water. Having realized he had no palpable arguments to convince me, he told me that this water produces absolutely nothing wrong with the body when drinking it and that he will send me water starting from the next day, having previously bought a water ionizer for producing this ionized alkaline water;he also told me that in my situation, I have two possibilities, namely:

– first, to expect the blood circulation to the leg to close definitively and reach to the gangrene and amputation,

-second  to drink at least 5 liters of ionized alkaline water daily, the water that will melt the atheroma from the arteries, the circulation of the blood going back to normal and save my foot.

I chose the second variant, knowing it was terrible it’s hard to live without a foot and get you I do not think it’s worth the pain anyway, I think it would not be worth the trouble for those around you, I would have become a calvary (I do not know if I’m wrong about that) I began to drink ionized alkaline water, sent by my friend, in the first few days 3 liters after which, I easily drank 5-6 liters a day. By then, the foot was from the kneel down, cold and white, and pains and burns, especially at night, were unbearable; I got 3-4 ketone pills per night. After 2 weeks of drinking ionized alkaline water the pains and burns diminished and in a few days they finally disappeared. 3 weeks ago his leg warmed and so remained. On March 17 we went to a private clinic in Constanta and I did (against the sum of 800 lei, CNAS funds not yet allocated) an angio CT scan of the arteries of in the pelvis and lower limbs that revealed:

– thigh amputation its right;

– 50% bypass stenosis

– 70% tibio-peronian occlusion trunk

– posterior tibial artery

– occlusion

In the meantime I was scheduled to be admitted to the Emergency University Hospital of Bucharest and on May 12, 2017, I made an arteriography revealed that the aorta and the iliac shaft are permeable, the femoropoplite bypass is permeable and permeable gambling trunk. Arteriography is an invasive artery investigation and remains the most significant in analyzing blood circulation, measurements and images being made from within the arteries.

I will express in words what I felt when the doctor who made the investigation recorded her voice with the result of viewing the monitor on which the arteriography was displayed. Never before, in my life, a word so common as  “PERMEABLE” had such GREAT significance and value.

I think the sun has appeared on my street, which is what I want. If you want to document and see that ionized alkaline water seems to be the universal medicine, you can find hundreds of sites about it and its benefits. In the meantime I bought a  ALKAVIVA water ionizer  !

I wish only good things!

.PS I WILL TALK AND ABOUT THE DIABETES SPPN …A FEW MONTHS AGO I HAD 40 MIXTARD UNITS IN THE MORNING AND 20 AT NIGHT

NOW- 20 UNITS IN THE MORNING AND 10 IN THE EVENING …

TODAY THE GLICEMIC INDEX IN THE MORNING WAS 124 AND I DID NOT HAVE ANY MIXTARD .NOW I HAVE GLYCEMIA 70 AND I HAVE NO NEED FOR MIXTARD ”

DESPRE APA ALCALINA IONIZATA Scriu aceste randuri atat pentru prietenii mei de pe…

Posted by Alexandru Bîzdîc on 18 Iunie 2017