Tag Archives: Molekularer Wasserstoff

dissolved hydrogen for PERITONEAL DIALYSIS patients to suppress oxidative stress in the peritoneal cavity

Abstract

Background

Oxidative stress (OS) related to glucose degradation products such as methylglyoxal is reportedly associated with peritoneal deterioration in patients treated with peritoneal dialysis (PD). However, the use of general antioxidant agents is limited due to their harmful effects. This study aimed to clarify the influence of the novel antioxidant molecular hydrogen (H2) on peritoneal OS using albumin redox state as a marker.

Methods

Effluent and blood samples of 6 regular PD patients were obtained during the peritoneal equilibrium test using standard dialysate and hydrogen-enriched dialysate. The redox state of albumin in effluent and blood was determined using high-performance liquid chromatography.

Results

Mean proportion of reduced albumin (ƒ(HMA)) in effluent was significantly higher in H2-enriched dialysate (62.31 ± 11.10%) than in standard dialysate (54.70 ± 13.08%). Likewise, serum ƒ(HMA) after administration of hydrogen-enriched dialysate (65.75 ± 7.52%) was significantly higher than that after standard dialysate (62.44 ± 7.66%).

Conclusions

Trans-peritoneal administration of H2 reduces peritoneal and systemic OS.

Background

Peritoneal deterioration is one of the most serious complications of peritoneal dialysis (PD) therapy, leading to ultrafiltration failure and the more severe complication of encapsulating peritoneal sclerosis (EPS). As the duration of PD increases, so does the risk of peritoneal deterioration []. More than 40% of patients in Japan who were on PD treatment for longer than 8 years stopped it due to the progression of peritoneal damage []. The pathological mechanisms of peritoneal damage are multi-factorial, but accumulated data have revealed the critical role of glucose degradation end-products (GDPs), i.e., chemically reactive carbonyl compounds. Methylglyoxal (MG) is one of the representative toxic GDPs, causing detrimental effects due to its rapid and indiscriminate oxidative nature [], and its production of toxic reactive oxygen species (ROS) such as hydroxyl radical, methyl radical, and undetermined carbon-centered radicals []. These used to be present in conventional dialysate, and also enter into the dialysate from uremic plasma []. Bio-compatible low-GDP dialysate is currently available, but a Japanese multicenter nationwide study, the NEXT-PD study [], revealed the occurrence of EPS even with the use of low-GDP solutions [under submission]. This indicates the need for novel therapeutic approaches to suppress possible insults from enhanced oxidative stress (OS) due to uremic oxidants in the peritoneal cavity.

Recently, the novel role of molecular hydrogen (H2) as an antioxidant has been revealed. H2 eliminates the hydroxyl radical in cultured cells and living organisms []. Interestingly, H2 does not influence other ROS, including superoxide, peroxide, and nitric oxide; these ROS play important physiological roles in body []. In humans, the safety of H2 has been tested, particularly in the field of deep diving. In contrast to general drugs, which usually have some harmful effects, no toxicity was found even at high concentrations of H2[]. H2 thus has therapeutic potential for pathological states related to ROS [].

The present study tested the effects of peritoneal dialysate containing a high concentration of molecular hydrogen (H2-enriched dialysate) as a novel anti-oxidant among patients treated with PD. As a result, we demonstrated that the use of hydrogen-enriched dialysate could reduce not only peritoneal, but also systemic OS in clinical settings.

Methods

Preparation of hydrogen-enriched dialysate

Hydrogen-enriched dialysate was prepared using MiZ nondestructive hydrogen dissolver (MiZ, Kanagawa, Japan), as reported elsewhere []. When commercial peritoneal dialysate is immersed in H2-enriched water, hydrogen permeates through the container, resulting in the H2 concentration of dialysate gradually increasing in a time-dependent manner (Figure 1). We prepared H2-enriched dialysate using this apparatus by immersing commercial peritoneal dialysate bags for more than 2 hr. Hydrogen-enriched dialysate was then applied as a test solution for peritoneal equilibrium testing.

An external file that holds a picture, illustration, etc. Object name is 2045-9912-3-14-1.jpg

MiZ nondestructive hydrogen dissolver (A) and the hydrogen concentration of peritoneal dialysate in hydrogen-saturated water (B). Hydrogen concentration of dialysate and hydrogen-saturated water around dialysate was measured using a dissolved H2 measurement apparatus DH-35A (DKK-TOA, Tokyo, Japan).

Patients

Six male PD patients were studied (mean age, 55 years; range, 44–71 years; length of PD, 39 ± 17 months; weight, 68.1 ± 16.1 kg; height, 166.2 ± 5.6 cm). The pathology underlying end-stage renal disease was as follows: chronic glomerulonephritis, n = 3; diabetic nephropathy, n = 2; and hypertensive nephropathy, n = 1. Patients with active infection, bleeding, liver dysfunction, collagen disease, systemic vasculitis, cardiovascular accident within 6 months, or malignancy were excluded from this study. Performance status of all patients was class 1 according to American Heart Association criteria []. All patients had been receiving daily continuous ambulatory PD (3–4 bags/day) using neutral low-GDP dextrose solution. The ethics committee of Fukushima Medical University approved this study protocol (Acceptance No. 1362) and written informed consent was obtained from all patients prior to enrollment.

Protocol

Patients underwent a simplified peritoneal equilibration test (fast PET) using standard dialysate, then underwent fast PET using hydrogen-enriched dialysate 2 weeks later. Fast PET was conducted in accordance with the method of Twardowski []. In brief, peritoneal dialysate (2 L of 2.5% dextrose-dialysate) was intraperitoneally infused with a Tenckhoff catheter, and the entire volume of dialysate was drained from the body after 240 min. The drained effluent was mixed well and 2 mL was collected as an effluent sample. Blood samples were obtained before and after fast PET, then 2 mL of serum was drawn after centrifugation and stored at −80°C for 1–4 weeks until analysis. Samples of serum and effluent collected to measure albumin redox were stored at −80°C for 1–4 weeks until analysis. During fast PET, blood pressure, cardiac pulse, and hydrogen concentration in the breath were measured repeatedly every 60 min. Breath hydrogen concentration was also measured in three cases just after, 15 min after, and 30 min after infusion of H2-enriched dialysate. Breath hydrogen concentration was measured using a biological gas (gas in the oral cavity) H2 measurement apparatus BGA-1000D (Aptec, Kyoto, Japan).

Measurement of albumin redox state

Human serum albumin (HSA) is a protein composed of 585 amino acids. The amino residue at position 34 from the N-terminus is a cysteine, containing a mercapto group (SH group). This mercapto group deoxidizes other substances according to the degree of surrounding OS and is itself oxidized. From the perspective of cysteine residues, HSA is a mixture of human mercaptoalbumin (HMA) in which the mercapto group is not oxidized, human non-mercaptoalbumin-1 in which disulfide bond formation is reversibly oxidized mainly by cysteine (HNA-1), and human non-mercaptoalbumin-2 which is strongly oxidized and forms a sulfinic (−SO2H) or sulfonic (−SO3H) group.

The redox state of HSA was determined using high-performance liquid chromatography (HPLC), as previously reported []. The HPLC system consisted of an autosampler (AS-8010; Tosoh, Tokyo, Japan; injection volume, 2 μL) and double-plunger pump (CCPM; Tosoh) in conjunction with a system controller (CO-8011; Tosoh). Chromatographs were obtained using a UV6000LP photodiode alley detector (detection area, 200–600 nm with 1-nm step; Thermo Electron, Waltham, MA, USA). A Shodex-Asahipak ES-502N 7C column (10 × 0.76 cm I.D., DEAE-form for ion-exchange HPLC; Showa Denko, Tokyo, Japan; column temperature, 35 ± 0.5°C) was used in this study. Elusion was performed as linear gradient elusion with graded ethanol concentrations (0 to 1 min, 0%; 1 to 50 min, 0 → 10%; 50 to 55 min, 10 → 0%; 55 to 60 min, 0%) for serum in 0.05 M sodium acetate and 0.40 M sodium sulfate mixture (pH 4.85) at a flow rate of 1.0 mL/min. De-aeration of the buffer solution was performed by bubbling helium.

HPLC profiles obtained from these procedures were subjected to numerical curve fitting with PeakFit version 4.05 simulation software (SPSS Science, Chicago, IL, USA), and each peak shape was approximated by a Gaussian function. Values for fractions of HMA, HNA-1, and HNA-2 to total HSA were then calculated (ƒ(HMA), ƒ(HNA-1), and ƒ(HNA-2), respectively).

Statistical analysis

Values are expressed as mean ± standard deviation unless otherwise stated. StatView version 5.0 statistical software (SAS Institute, Cary, NC, USA) was used for statistical analysis. The significance of collected data was evaluated using a paired t-test or 1-factor repeated-measures analysis of variance (ANOVA) followed by Scheffe’s test as a post-hoc test, as appropriate. For magnitude of correlation, Pearson’s correlation coefficient (R) was used. Differences or correlations were considered significant for values of P < 0.05.

Results

Table 1 shows changes in blood pressure, heart rate, and breath hydrogen concentration during fast PET. Regarding blood pressure and heart rate, no significant difference was seen between standard and H2-enriched dialysate (paired t-test). No significant changes were observed during fast PET in either standard or H2-enriched dialysate (1-factor repeated-measures ANOVA).

Table 1

The changes of blood pressure, cardiac pulse, and breath H2 concentration during fast PET

Standard dialysate H2-enriched dialysate
Blood pressure mmHg




   0 min


130 ± 12 / 79 ± 10


135 ± 13 / 81 ± 10


   60 min


130 ± 11 / 79 ± 5


131 ± 14 / 82 ± 12


   120 min


125 ± 9 / 79 ± 7


134 ± 8 / 80 ± 14


   180 min


123 ± 12 / 75 ± 12


136 ± 5 / 78 ± 12


   240 min


128 ± 9 / 78 ± 7


132 ± 9 / 81 ± 13


Pulse /min




   0 min


81 ± 7


82 ± 12


   60 min


76 ± 6


79 ± 12


   120 min


74 ± 6


78 ± 14


   180 min


77 ± 4


78 ± 17


   240 min


78 ± 7


81 ± 15


Breath H2 ppm




   0 min


4.7 ± 6.6


3.2 ± 2.0


   60 min


1.8 ± 1.3


8.3 ± 7.5*


   120 min


3.0 ± 1.7


8.5 ± 11.0


   180 min


4.2 ± 2.8


5.8 ± 4.8


   240 min 5.5 ± 6.7 7.2 ± 4.6

*; p < 0.05 vs. standard dialysate.

Changes in breath hydrogen concentration in all cases are shown in Table 1 and Figure 2 (A, B). Although no significant changes were observed during fast PET in both standard and H2-enriched dialysate, the hydrogen concentration at 60 min was significantly higher in H2-enriched dialysate than in standard dialysate.

An external file that holds a picture, illustration, etc. Object name is 2045-9912-3-14-2.jpg

Change in breath hydrogen concentration during fast PET. A) Hourly change in PET using standard dialysate. No significant changes were observed. B) Hourly change during PET using H2-enriched dialysate. The hydrogen concentration at 60 min was significantly higher in H2-enriched dialysate than in standard dialysate. C) Breath hydrogen concentrations before, just after, 15 min after, and 30 min after administration of H2-enriched dialysate in three cases. Hydrogen concentrations just after and 15 min after administration were significantly higher than that before administration.

Breath hydrogen concentrations before, just after, 15 min after, and 30 min after administration of H2-enriched dialysate in three cases are shown in Figure 2C. Hydrogen concentrations were significantly higher just after and 15 min after administration (22.7 ± 5.7 and 15.3 ± 3.5 ppm, respectively) than before administration (4.0 ± 1.7 ppm).

Figure 3 shows the redox state of albumin in effluent fluid. The mean proportion of HMA (ƒ(HMA)) was significantly higher in H2-enriched dialysate (62.31 ± 11.10%) than in standard dialysate (54.70 ± 13.08%). In contrast, ƒ(HNA-1) was significantly lower in H2-enriched dialysate (34.26 ± 10.24%) than in standard dialysate (41.36 ± 12.04%). Like ƒ(HNA-1), ƒ(HNA-2) was significantly lower in H2-enriched dialysate (3.43 ± 0.92%) than in standard dialysate (3.94 ± 1.13%). These results suggest that the use of H2-enriched dialysate reduced peritoneal OS. Regarding the result of fast PET (D/P-Cre, drained volume) and effluent creatinine, albumin, interleukin 6 and carbohydrate antigen 125 levels, no differences were evident between standard and H2-enriched dialysate (Table 2).

An external file that holds a picture, illustration, etc. Object name is 2045-9912-3-14-3.jpg

Redox state of albumin in effluent fluid. Mean proportion of reduced albumin (ƒ(HMA)) was significantly higher (A), and that of oxidized albumin (ƒ(HNA-1) (B) and ƒ(HNA-2)) (C) was significantly lower in H2-enriched dialysate than in standard dialysate.

Table 2

The results of serum creatinine value, fast PET and effluent test

Standard dialysate H2-enriched dialysate
Creatinine mg/dL


10.53 ± 2.27


10.03 ± 2.19


Parameter of fast PET




   D/P-Cre


0.71 ± 0.12


0.66 ± 0.11


   Drained volume mL/4 hr


470 ± 184


442 ± 130


Effluent test




   Albumin mg/L


408 ± 175


402 ± 145


   Interleukin-6 pg/mL


6.0 ± 3.3


5.5 ± 2.3


   CA125 U/mL 18.8 ± 8.5 19.5 ± 5.0

Figure 4 shows the redox state of albumin in serum before and after fast PET. The serum ƒ(HMA) level after administration of H2-enriched dialysate (65.75 ± 7.52%) was significantly higher than that after standard dialysate (62.44 ± 7.66%). In contrast, ƒ(HNA-1) after administration of H2-enriched dialysate (31.12 ± 6.73%) was significantly lower than that of standard dialysate (34.73 ± 7.02%). These results suggest that use of H2-enriched dialysate reduced not only peritoneal, but also systemic OS. No significant difference was seen between effluent and serum ƒ(HMA) levels after administration of H2-enriched dialysate (65.31 ± 11.10% and 62.71 ± 7.52%, respectively), while effluent ƒ(HMA) after administration of standard dialysate was significantly lower than serum ƒ(HMA) before administration of standard dialysate (54.70 ± 13.08% and 62.96 ± 8.34%, respectively; P = 0.0339), suggesting that intraperitoneal oxidation of albumin was suppressed by H2-enriched dialysate.

An external file that holds a picture, illustration, etc. Object name is 2045-9912-3-14-4.jpg

Redox state of albumin in serum before and after fast PET. The mean proportion of reduced albumin (ƒ(HMA)) was significantly higher after fast PET using H2-enriched dialysate than after that using standard dialysate (A). Conversely, the mean proportion of reversibly oxidized albumin (ƒ(HNA-1)) was significantly lower after fast PET using H2-enriched dialysate than that after using standard dialysate (B). No significant changes were found in irreversibly oxidized albumin (ƒ(HNA-2)) in the both groups (C).

Discussion

Several reports have suggested that OS participates in peritoneal deterioration, with findings such as strong cytoplasmic staining of 8-hydroxy-2′-deoxyguanosine in peritoneal biopsy specimens of long-term PD patients [], amplified protein kinase C signaling and fibronectin expression due to enhanced ROS in cultured human mesothelial cells []. In terms of the central role of enhanced OS in PD peritoneal damage, Gunal et al. [] showed that oral supplementation with the anti-oxidative agent trimetazidine inhibited morphological and functional deterioration of the peritoneum in a PD rat model. However, regarding suppressing OS, no clinical approaches have been available for PD treatment so far.

The present study aimed to test the therapeutic possibility of using dissolved hydrogen in the dialysate to suppress intra-cavity OS in the clinical setting. This study examined the redox state of albumin as a marker of OS. Since the change in redox state of albumin is a physiological and direct reaction, it is appropriate when evaluating real-time OS and/or detecting rapid changes in OS, as compared to other OS markers such as 8-hydroxy-2′–deoxyguanosine, oxidized low-density lipoprotein and F2 isoprotanes, all of which are in vivo by-products during the process of oxidation.

This pilot study of 6 patients clearly demonstrated that single administration of H2-enriched dialysate increased levels of both peritoneal and plasma ƒ(HMA) without any detrimental effects.

Intraperitoneal administration of H2 altered the local redox state, which may indicate the therapeutic potential of delivering H2 directly to the abdominal cavity in respect to the amelioration of peritoneal damage by PD treatment. On the other hand, interestingly, significant increases in serum ƒ(HMA) levels were seen on intraperitoneal administration of H2. Rapid changes in hydrogen concentration of expired gas after the administration of H2-enriched dialysate may mean that molecular hydrogen in dialysate is rapidly distributed to the body to suppress systemic OS. Another possibility is that increased ƒ(HMA) in the cavity may be recruited into systemic circulation through the abdominal lymphatic drainage. The exact mechanisms underlying increased serum ƒ(HMA) need to be addressed in the future.

In addition, the mechanisms of increased ƒ(HMA) and decreased ƒ(HMA1) by H2 have remained unclear in this study. However, molecular hydrogen is known to directly reduce levels of the cytotoxic hydroxyl radical [], through several possible mechanisms, such as regulation of particular metalloproteins by bonding, or metalloprotein-hydrogen interactions []. Whether H2 directly reacts with the mercapto-residue of albumin, or H2 indirectly modifies it, should be clarified in the future.

Satisfactory anti-oxidative capability of drinking H2-enriched water without any detrimental effects has been reported, in both experimental [] and clinical settings, e.g., type II diabetes mellitus [], metabolic syndrome [], myopathies (progressive muscular dystrophy and polymyositis/dermatomyositis) [], and rheumatoid arthritis []. In addition, we also reported the clinical feasibility of applying H2-enriched water as dialysate for hemodialysis treatment [,]. Given these reports and our present findings, H2-enriched peritoneal dialysate could be of interest in clinical trials with respect to peritoneal preservation. Furthermore, therapeutic effects seem plausible in terms of the prevention of cardiovascular events in patients, since low f(HMA) has been a significant risk factor for cardiovascular mortality among patients treated with PD [] and HD [].

In summary, single administration of H2-enriched dialysate reduced peritoneal and systemic OS without any detrimental effects. A longitudinal study is warranted to ensure clinically beneficial effects, such as suppression of peritoneal deterioration and cardiovascular damage.

 

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Link to Publisher's site
. 2013; 3: 14.
Published online 2013 Jul 1. doi: 10.1186/2045-9912-3-14
PMCID: PMC3734057
PMID: 23816239
Transperitoneal administration of dissolved hydrogen for peritoneal dialysis patients: a novel approach to suppress oxidative stress in the peritoneal cavity
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

HT, YH, and WJZ carried out the selections of patients, and the sample collections. HT drafted the manuscript. YM, TT, and SE carried out the measurements of samples. SK, and TW contributed to the study as senior advisers. BS carried out the set-up of equipment system for study. MN organized the study project, and drafted the final manuscript. All authors read and approved the final manuscript.

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molecular hydrogen water for VASCULAR ENDOTHELIAL FUNCTION

The redox imbalance between nitric oxide and superoxide generated in the endothelium is thought to play a pivotal role in the development of endothelial dysfunction. A third reactive oxygen species (ROS), H2O2, is known to have both beneficial and detrimental effects on the vasculature. Nonetheless, the influence of the hydroxyl radical, a byproduct of H2O2 decay, is unclear, and there is no direct evidence that the hydroxyl radical impairs endothelial function in conduit arteries. Molecular hydrogen (H2) neutralizes detrimental ROS, especially the hydroxyl radical.

OBJECTIVES:

To assess the influence of the hydroxyl radical on the endothelium and to confirm that a gaseous antioxidant, molecular hydrogen H2, can be a useful modulator of blood vessel function.

METHODS:

The efficacy of water containing a high concentration of  molecular hydrogen H2 was tested by measuring flow-mediated dilation (FMD) of the brachial artery (BA). The subjects were randomly divided into two groups: the high- molecular hydrogen H2 water group, who drank high- molecular hydrogen H2 water containing 7 ppm molecular hydrogen H2 (3.5 mg molecular hydrogen H2 in 500 mL water); and the placebo group. Endothelial function was evaluated by measuring the FMD of the BA. After measurement of diameter of the BA and FMD at baseline, volunteers drank the high- molecular hydrogen H2 water or placebo water immediately and with a 30-minute interval; FMD was compared to baseline.

RESULTS:

FMD increased in the high- molecular hydrogen H2 water group (eight males; eight females) from 6.80%±1.96% to 7.64%±1.68% (mean ± standard deviation) and decreased from 8.07%±2.41% to 6.87%±2.94% in the placebo group (ten males; eight females). The ratio to the baseline in the changes of FMD showed significant improvement (P<0.05) in the high- molecular hydrogen H2 water group compared to the placebo group.

CONCLUSION:

molecular hydrogen H2 water may protect the vasculature from shear stress-derived detrimental ROS, such as the hydroxyl radical, by maintaining the nitric oxide-mediated vasomotor response.

https://www.ncbi.nlm.nih.gov/pubmed/25378931

references:

PMID:25378931
PMCID:PMC4207582
DOI:10.2147/VHRM.S68844
 2014 Oct 17;10:591-7. doi: 10.2147/VHRM.S68844. eCollection 2014.
Consumption of water containing over 3.5 mg of dissolved molecular hydrogen could improve vascular endothelial function.

Author information

1
Department of Cardiology, Haradoi Hospital, Fukuoka, Japan.
2
MiZ Company Limited, Fujisawa, Kanagawa, Japan.
3
Department of Internal Medicine, Haradoi Hospital, Fukuoka, Japan.
4
Midorino Clinic, Aoba, Higashi-ku, Fukuoka, Japan.
5
Department of Rheumatology and Orthopedic Surgery, Haradoi Hospital, Fukuoka, Japan.

Molecular hydrogen affects body composition, metabolic profiles, and mitochondrial function in middle-aged OVERWEIGTH women

 

1 Faculty of Sport and Physical Education, University of Novi Sad, Novi Sad, Serbia.
2 Faculty of Sport and Physical Education, University of Novi Sad, Novi Sad, Serbia. sergej.ostojic@chess.edu.rs.
3 University of Belgrade School of Medicine, Belgrade, Serbia. sergej.ostojic@chess.edu.rs.
4 Applied Bioenergetics Laboratory, Faculty of Sport and PE, University of Novi Sad, Lovcenska 16, Novi Sad, 21000, Serbia. sergej.ostojic@chess.edu.rs.
PMID: 28560519
DOI: 10.1007/s11845-017-1638-4
 2018 Feb;187(1):85-89. doi: 10.1007/s11845-017-1638-4. Epub 2017 May 30.

Abstract

BACKGROUND:

Molecular hydrogen (H2) effectively treats obesity-related disorders in animal models, yet no studies have investigated the effectiveness and safety of Molecular hydrogen H2 for improving biomarkers of obesity in humans.

AIM:

In this double blind, placebo-controlled, crossover pilot trial, we evaluated the effects of Molecular hydrogen H2 intervention on body composition, hormonal status, and mitochondrial function in ten (n = 10) middle-aged overweight women.

METHODS:

Volunteers received either hydrogen-generating minerals (supplying ~6 ppm of Molecular hydrogen H2 per day) or placebo by oral administration of caplets for 4 weeks. The primary end-point of treatment efficacy was the change in the body fat percentage from baseline to 4 weeks. In addition, assessment of other body composition indices, screening laboratory studies, and evaluation of side effects were performed before and at follow-up. Clinical trial registration www.clinicaltrials.gov , ID number NCT02832219.

RESULTS:

No significant differences were observed between treatment groups for changes in weight, body mass index, and body circumferences at 4-week follow-up (P > 0.05). Molecular hydrogen H2 treatment significantly reduced body fat percentage (3.2 vs. 0.9%, P = 0.05) and arm fat index (9.7 vs. 6.0%, P = 0.01) compared to placebo administration, respectively. This was accompanied by a significant drop in serum triglycerides after Molecular hydrogen H2 intervention comparing to placebo (21.3 vs. 6.5%; P = 0.04), while other blood lipids remained stable during the study (P > 0.05). Fasting serum insulin levels dropped by 5.4% after Molecular hydrogen H2 administration, while placebo intervention augmented insulin response by 29.3% (P = 0.01).

CONCLUSIONS:

It appears that orally administered Molecular hydrogen H2 as a blend of hydrogen-generating minerals might be a beneficial agent in the management of body composition and insulin resistance in obesity.

Should molecular hydrogen therapy be included in a musculoskeletal medicine routine?

Molecular hydrogen (H 2) has recently been recognized as a potential novel therapeutic agent in biomedicine. Initially proposed to be a possible treatment for certain types of neuromuscular disorders, cardio-metabolic diseases and cancer,molecular hydrogen  H 2 improved clinical end-points and surrogate markers in several clinical trials, mainly acting as an anti-inflammatory agent and powerful antioxidant. In this paper, the medicinal properties of molecular hydrogen H 2 in musculoskeletal medicine are discussed with the aim to provide an updated and practical overview for health professionals working in this field.

Background

As the oldest and the most abundant molecule in the universe, molecular hydrogen (H 2) has been traditionally recognized as a biologically inert gas. However, several trials in the past 10 years reported beneficial effects of molecular hydrogen H 2 in the clinical environment, revealing its possible role as a novel therapeutic agent in medicine – . Usually administered orally or via inhalation, molecular hydrogen H 2 improves both patient- and clinician-reported outcomes, and biomarkers of different pathologies and disorders, from metabolic diseases to chronic systemic inflammatory disorders to cancer [for detailed review see Ref. ].

Its clinical relevance seems to be particularly notable in the musculoskeletal medicine, with several small-scale short-term studies –  reporting that molecular H 2 was able to restore the health and functional abilities of patients after acute injuries or chronic illnesses affecting the muscles and bones. Since musculoskeletal conditions account for a large proportion of a general practitioner’s workload , one might consider molecular hydrogen  H 2 as a promising medication or adjuvant that could alleviate these prevalent conditions. In this opinion paper, the medicinal properties of molecular hydrogen H 2 in musculoskeletal medicine are discussed to provide an updated and practical overview for health professionals working in this field.

Promising results from preliminary studies

Being prompted by the prominent effects of molecular hydrogen H 2 on disuse muscle atrophy, cartilage trauma, and osteopenia in animal studies – , a number of clinical investigators from 2010 onwards evaluated the effectiveness of molecular hydrogen H 2 in patients suffering from different muscle and bone ailments – from sprains and strains to chronic joint disorders to myopathies – . Typically, these studies were designed as single-blind pilot trials, with small sample sizes (< 40 participants) and of short duration (≤ 12 weeks). Although limited in size and scope, those studies can provide early support for specific therapeutic claims about molecular hydrogen H 2 in musculoskeletal medicine. In a first trial, a combination of oral and topical molecular hydrogen H 2 resulted in a faster return to normal joint flexibility in 36 young men who had suffered sports-related soft tissue injuries, when administered for 14 days as a complementary treatment to a traditional medical protocol for soft tissue injuries 7.molecular  hydrogen  H 2intervention (hydrogen-rich packs 6 times per day for 20 min and 2 g of oral molecular hydrogen H 2 daily) was found to augment plasma viscosity decrease after an injury, while other biomarkers of inflammation (C-reactive protein, interleukin-6) and clinical outcomes (pain scores at rest and at walking, degree of limb swelling) were not affected by the intervention 7.

Another study in Japan reported that drinking 530 ml of a liquid containing 4 to 5 ppm of molecular hydrogen H  (dissolved in water) every day for 4 weeks significantly reduced disease activity in 20 patients with rheumatoid arthritis, as evaluated by changes in the degree of tenderness and swelling in 28 joints and C-reactive protein levels 8.  Molecular hydrogen H 2 was administered as an adjuvant to regular disease-modifying anti-rheumatic drugs and biological drugs, with the efficacy of molecular hydrogen H 2 found to be not inferior comparing to abatacept, methotrexate or a combination of two. In total, 47.4% of patients went into remission, with anti-citrullinated protein antibody (ACPA)-positive patients (ACPA levels above 300 U/mL; patients with worse prognosis and higher rates of erosive damage) responding best to the treatment.

Finally, the consumption of water containing a high concentration of moleucular hydrogen H 2 (31% saturation) for up to 12 weeks improved surrogate markers of muscle pain and fatigability in 22 patients with inherited and acquired myopathies treated with low-dose prednisone .

Taken together, the above studies seem to pave the way for a future use of molecular hydrogen H 2 therapy in musculoskeletal medicine.

please note that although the article above adds  little salt regarding molecular hydrogen safety due to it’s novelty ,one of the best parts about molecular hydrogen water is that it has been shown to have a tremendous safety profile. This has been demonstrated in a few ways:

  • Out of 600-plus scientific studies, molecular hydrogen  H2 has shown no cytotoxic effects or cytotoxic by-products in the human body. 22
  • We have a basal level of molecular hydrogen  H2 in our blood stream at all times, around 1~5 micromolar or less. 23
  • Humans can produce up to 10 liters of molecular hydrogen  H2 a day with a good diet containing fruits, vegetables, and fiber-rich foods. This is due to the production of molecular hydrogen  H2 by our gut flora (gut bacteria). 24
  • Another reason we know molecular hydrogen H2 is safe is because it has been used to ameliorate decompression sickness in deep sea diving since 1945. 25 The molecular hydrogen H2 concentration has been as high 98.87 percent molecular hydrogen  H2 and 1.26 percent of O2, at 19.1 atm with minimal to no adverse or cytotoxic effects. 26 The United States military also has been using molecular hydrogen H2 for deep sea diving since the 60s. 27 Molecular hydrogen has been demonstrated to be extremely safe for the human body. 28

 

This information tells us that molecular hydrogen-rich water is safe for consumption in all age groups, from children to adults, as a preventive beverage that has the potential to reduce oxidative stress and so much more. Everyone, including children, is exposed to oxidative stress, which has been linked to the pathogenesis of nearly all disease conditions, including cancer. 29 Consuming water infused with molecular hydrogen is exactly what our society needs to aid in the battle against degenerative diseases.

Please note that most studies and research with molecular hydrogen gas were performed using molecular hydrogen rich water

References

1. Kajiyama S, Hasegawa G, Asano M, et al. : Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res.2008;28(3):137–43. 10.1016/j.nutres.2008.01.008 [PubMed] [Cross Ref]
2. Nakao A, Toyoda Y, Sharma P, et al. : Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot study. J Clin Biochem Nutr.2010;46(2):140–9. 10.3164/jcbn.09-100 [PMC free article] [PubMed] [Cross Ref]
3. Nakayama M, Nakano H, Hamada H, et al. : A novel bioactive haemodialysis system using dissolved dihydrogen (H 2) produced by water electrolysis: a clinical trial. Nephrol Dial Transplant.2010;25(9):3026–33. 10.1093/ndt/gfq196 [PubMed] [Cross Ref]
4. Yoritaka A, Takanashi M, Hirayama M, et al. : Pilot study of H 2 therapy in Parkinson’s disease: a randomized double-blind placebo-controlled trial. Mov Disord. 2013;28(6):836–9. 10.1002/mds.25375[PubMed] [Cross Ref]
5. Xia C, Liu W, Zeng D, et al. : Effect of hydrogen-rich water on oxidative stress, liver function, and viral load in patients with chronic hepatitis B. Clin Transl Sci. 2013;6(5):372–5. 10.1111/cts.12076[PMC free article] [PubMed] [Cross Ref]
6. Ostojic SM: Molecular hydrogen: An inert gas turns clinically effective. Ann Med. 2015;47(4):301–4. 10.3109/07853890.2015.1034765 [PubMed] [Cross Ref]
7. Ostojic SM, Vukomanovic B, Calleja-Gonzalez J, et al. : Effectiveness of oral and topical hydrogen for sports-related soft tissue injuries. Postgrad Med. 2014;126(5):187–95. 10.3810/pgm.2014.09.2813[PubMed] [Cross Ref]
8. Ishibashi T, Sato B, Rikitake M, et al. : Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: an open-label pilot study. Med Gas Res. 2012;2(1):27. 10.1186/2045-9912-2-27 [PMC free article] [PubMed][Cross Ref]
9. Ito M, Ibi T, Sahashi K, et al. : Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies. Med Gas Res.2011;1(1):24. 10.1186/2045-9912-1-24 [PMC free article] [PubMed] [Cross Ref]
10. Hunter DJ, Reddy KS: Noncommunicable diseases. N Engl J Med. 2013;369(14):1336–43. 10.1056/NEJMra1109345 [PubMed] [Cross Ref]
11. Fujita R, Tanaka Y, Saihara Y, et al. : Effect of molecular hydrogen saturated alkaline electrolyzed water on disuse muscle atrophy in gastrocnemius muscle. J Physiol Anthropol. 2011;30(5):195–201. 10.2114/jpa2.30.195 [PubMed] [Cross Ref]
12. Guo JD, Li L, Shi YM, et al. : Hydrogen water consumption prevents osteopenia in ovariectomized rats. Br J Pharmacol. 2013;168(6):1412–20. 10.1111/bph.12036 [PMC free article] [PubMed] [Cross Ref]
13. Hanaoka T, Kamimura N, Yokota T, et al. : Molecular hydrogen protects chondrocytes from oxidative stress and indirectly alters gene expressions through reducing peroxynitrite derived from nitric oxide. Med Gas Res. 2011;1(1):18. 10.1186/2045-9912-1-18 [PMC free article] [PubMed] [Cross Ref]
14. Derry S, Wiffen P, Moore A: Topical Nonsteroidal Anti-inflammatory Drugs for Acute Musculoskeletal Pain. JAMA. 2016;315(8):813–4. 10.1001/jama.2016.0249 [PubMed] [Cross Ref]
15. Strehl C, Bijlsma JW, de Wit M, et al. : Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force. Ann Rheum Dis. 2016;75(6):952–7. 10.1136/annrheumdis-2015-208916[PubMed] [Cross Ref]
16. The Food and Drug Administration (FDA): Agency Response Letter GRAS Notice No. 520. (Assessed at October 28, 2016). Reference Source
17. The Food and Drug Administration (FDA): Inspections, Compliance, Enforcement, and Criminal Investigations. (Assessed at October 28, 2016). Reference Source

Approved

1Department of Neurology and Psychiatry, Saint Louis University School of Medicine, Saint Louis, MO, USA
Competing interests: No competing interests were disclosed.
Review date: 2016 Dec 8. Status: Approved

The title is appropriate with reference to the content of the article.

The article is a review of the literature with reference to utilizing molecular hydrogen to enhance sports related injuries.

After a detailed review of the literature, the conclusion is there is not enough information to make any solid recommendation concerning utilizing molecular hydrogen to treat sports related injuries, so the implication is probably molecular hydrogen doesn’t improve recovery from sports related injuries enough to make any difference.

This appears to be a good review of the related literature.

I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Approved

Xiaoli SunReferee1 and Ning ZhangCo-referee2
1Department of Diving Medicine, Second Military Medical University, Shanghai, China
2Department of Naval Aeromedicine, Second Military Medical University, Shanghai, China
Competing interests: No competing interests were disclosed.
Review date: 2016 Dec 8. Status: Approved

This opinion paper provides an undated and practical overview on the properties of molecular hydrogen in musculoskeletal medicine. The paper focuses on the preliminary studies of H2 on musculoskeletal medicine, and the concerns over the general use of products containing H2. I sympathize the author’s prudent attitudes, which toward the hydrogen should be regarded as an experimental agent and not recommended to general use provisionally. However, I think this paper should also mention the long-term diving practices which high pressure hydrogen inhalation involved to prove the possible safe use of H2 gas.

We have read this submission. We believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Articles from F1000Research are provided here courtesy of F1000 Research Ltd
Logo of f1000res
Version 1. . 2016; 5: 2659.
Published online 2016 Nov 10. doi:  10.12688/f1000research.9758.1
PMCID: PMC5147523
Should hydrogen therapy be included in a musculoskeletal medicine routine?
1Faculty of Sport and PE, University of Novi Sad, Novi Sad, Serbia
2University of Belgrade School of Medicine, Belgrade, Serbia
Competing interests: No competing interests were disclosed.

molecular hydrogen water for patients with RHEUMATOID ARTHRITIS : an open-label pilot study

Recently, molecular hydrogen (H2) was demonstrated to be a selective scavenger for the hydroxyl radical.

Although its etiology is unknown, the hydroxyl radical has been suggested to be involved in the pathogenesis of Rheumatoid arthritis( a chronic inflammatory disease characterized by the destruction of bone and cartilage..).

We hypothesized that molecular hydrogen H2 in the water could complement conventional therapy by reducing the oxidative stress in Rheumatoid arthritis

The method to prepare water containing extremely high concentration of molecular hydrogen H2 has been developed.

20 patients with rheumatoid arthritis (RA) drank 530 ml of water containing 4 to 5 ppm molecular hydrogen (high H2) water every day for 4 weeks. After a 4-week wash-out period, the patients drank the high molecular hidrogen H2 water for another 4 weeks.

Urinary 8-hydroxydeoxyguanine (8-OHdG) and disease activity (DAS28, using C-reactive protein [CRP] levels) was estimated at the end of each 4-week period.

Results:

Drinking high molecular hydrogen H2 water seems to raise the concentration of molecular hydrogen H2 more than the H2 molecular hydrogen saturated (1.6 ppm) water in vivo.

Urinary 8-OHdG was significantly reduced by 14.3% (p < 0.01) on average. DAS28 also decreased from 3.83 to 3.02 (p < 0.01) during the same period.

After the wash-out period, both the urinary 8-OHdG and the mean
DAS28 decreased, compared to the end of the drinking period.

During the second drinking period, the mean DAS28 was reduced from 2.83 to 2.26 (p < 0.01). Urinary 8-OHdG was not further reduced but remained below the baseline value.

All the 5 patients with early rheumatoid arthritis (duration < 12 months) who did not show antibodies against cyclic citrullinated peptides (ACPAs) achieved remission, and 4 of them became symptom-free at the end of the study.

Conclusions: The results suggest that the hydroxyl radical scavenger -molecular hydrogen H2(dissolved in water) effectively reduces oxidative stress in patients with rheumatoid arthritis. The symptoms of rheumatoid arthritis were significantly improved with high molecular hidrogen H2 water.

 

  • diatomic molecular hydrogen H2- Water Products 

 

 

Consumption of water containing a high
concentration of molecular hydrogen reduces
oxidative stress and disease activity in patients
with rheumatoid arthritis: an open-label pilot
study
Toru Ishibashi1*, Bunpei Sato2
, Mariko Rikitake1
, Tomoki Seo2
, Ryosuke Kurokawa2
, Yuichi Hara1
, Yuji Naritomi1
,
Hiroshi Hara1 and Tetsuhiko Nagao3

* Correspondence: toruishi@haradoi-hospital.com 1
Haradoi Hospital, Department of Rheumatology and Orthopaedic Surgery,
6-40-8 Aoba, Higashi-ku, Fukuoka 813-8588, Japan
Full list of author information is available at the end of the article
MEDICAL GAS
RESEARCH
© 2012 Ishibashi et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

doi:10.1186/2045-9912-2-27
Cite this article as: Ishibashi et al.: Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: an open-label pilot study. Medical Gas Research 2012 2:27.