Therapeutic Inhalation of Hydrogen Gas for Alzheimer's Disease Patients and Subsequent Long-Term Follow-Up as a Disease-Modifying Treatment: An Open Label Pilot Study.

(1) Background: Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. Hydrogen gas (H2) is a therapeutic medical gas with multiple functions such as anti-oxidant, anti-inflammation, anti-cell death, and the stimulation of energy metabolism. To develop a disease-modifying treatment for AD through multifactorial mechanisms, an open label pilot study on H2 treatment was conducted. (2) Methods: Eight patients with AD inhaled 3% H2 gas for one hour twice daily for 6 months and then followed for 1 year without inhaling H2 gas. The patients were clinically assessed using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). To objectively assess the neuron integrity, diffusion tensor imaging (DTI) with advanced magnetic resonance imaging (MRI) was applied to neuron bundles passing through the hippocampus. (3) Results: The mean individual ADAS-cog change showed significant improvement after 6 months of H2 treatment (-4.1) vs. untreated patients (+2.6). As assessed by DTI, H2 treatment significantly improved the integrity of neurons passing through the hippocampus vs. the initial stage. The improvement by ADAS-cog and DTI assessments were maintained during the follow-up after 6 months (significantly) or 1 year (non-significantly). (4) Conclusions: This study suggests that H2 treatment not only relieves temporary symptoms, but also has disease-modifying effects, despite its limitations.

Hydrogen Gas Inhalation Treatment in Acute Cerebral Infarction: A Randomized Controlled Clinical Study on Safety and Neuroprotection.

BACKGROUND: Molecular hydrogen (H2) acts as a therapeutic antioxidant. Inhalation of H2 gas (1-4%) was effective for the improvement of cerebral infarction in multiple animal experiments. Thus, for actual applications, a randomized controlled clinical study is desired to evaluate the effects of inhalation of H2 gas. Here, we evaluate the H2 treatment on acute cerebral infarction. METHODS: Through this randomized controlled clinical study, we assessed the safety and effectiveness of H2 treatment in patients with cerebral infarction in an acute stage with mild- to moderate-severity National Institute of Health Stroke Scale (NIHSS) scores (NIHSS = 2-6). We enrolled 50 patients (25 each in the H2 group and the control group) with a therapeutic time window of 6 to 24 hours. The H2 group inhaled 3% H2 gas (1 hour twice a day), and the control group received conventional intravenous medications for the initial 7 days. The evaluations included daily vital signs, NIHSS scores, physical therapy indices, weekly blood chemistry, and brain magnetic resonance imaging (MRI) scans over the 2-week study period. RESULTS: The H2 group showed no significant adverse effects with improvements in oxygen saturation. The following significant effects were found: the relative signal intensity of MRI, which indicated the severity of the infarction site, NIHSS scores for clinically quantifying stroke severity, and physical therapy evaluation, as judged by the Barthel Index. CONCLUSIONS: H2 treatment was safe and effective in patients with acute cerebral infarction. These results suggested a potential for widespread and general application of H2 gas.

Soluble Epoxide Hydrolase in Hydrocephalus, Cerebral Edema, and Vascular Inflammation After Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Acute communicating hydrocephalus and cerebral edema are common and serious complications of subarachnoid hemorrhage (SAH), whose causes are poorly understood. Using a mouse model of SAH, we determined whether soluble epoxide hydrolase (sEH) gene deletion protects against SAH-induced hydrocephalus and edema by increasing levels of vasoprotective eicosanoids and suppressing vascular inflammation. METHODS: SAH was induced via endovascular puncture in wild-type and sEH knockout mice. Hydrocephalus and tissue edema were assessed by T2-weighted magnetic resonance imaging. Endothelial activation was assessed in vivo using T2*-weighted magnetic resonance imaging after intravenous administration of iron oxide particles linked to anti-vascular cell adhesion molecule-1 antibody 24 hours after SAH. Behavioral outcome was assessed at 96 hours after SAH with the open field and accelerated rotarod tests. RESULTS: SAH induced an acute sustained communicating hydrocephalus within 6 hours of endovascular puncture in both wild-type and sEH knockout mice. This was followed by tissue edema, which peaked at 24 hours after SAH and was limited to white matter fiber tracts. sEH knockout mice had reduced edema, less vascular cell adhesion molecule-1 uptake, and improved outcome compared with wild-type mice. CONCLUSIONS: Genetic deletion of sEH reduces vascular inflammation and edema and improves outcome after SAH. sEH inhibition may serve as a novel therapy for SAH.

A basic study on molecular hydrogen (H2) inhalation in acute cerebral ischemia patients for safety check with physiological parameters and measurement of blood H2 level.

BACKGROUND: In animal experiments, use of molecular hydrogen ( H2) has been regarded as quite safe and effective, showing benefits in multiple pathological conditions such as ischemia-reperfusion injury of the brain, heart, kidney and transplanted tissues, traumatic and surgical injury of the brain and spinal cord, inflammation of intestine and lung , degenerative striatonigral tissue and also in many other situations. However, since cerebral ischemia patients are in old age group, the safety information needs to be confirmed. For the feasibility of H2 treatment in these patients, delivery of H2 by inhalation method needs to be checked for consistency. METHODS: Hydrogen concentration (HC) in the arterial and venous blood was measured by gas chromatography on 3 patients, before, during and after 4% (case 1) and 3% (case2,3) H2 gas inhalation with simultaneous monitoring of physiological parameters. For a consistency study, HC in the venous blood of 10 patients were obtained on multiple occasions at the end of 30-min H2 inhalation treatment. RESULTS: The HC gradually reached a plateau level in 20 min after H2 inhalation in the blood, which was equivalent to the level reported by animal experiments. The HC rapidly decreased to 10% of the plateau level in about 6 min and 18 min in arterial and venous blood, respectively after H2 inhalation was discontinued. Physiological parameters on these 3 patients were essentially unchanged by use of hydrogen. The consistency study of 10 patients showed the HC at the end of 30-min inhalation treatment was quite variable but the inconsistency improved with more attention and encouragement. CONCLUSION: H2 inhalation of at least 3% concentration for 30 min delivered enough HC, equivalent to the animal experiment levels, in the blood without compromising the safety. However, the consistency of H2 delivery by inhalation needs to be improved.

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.

BACKGROUND: We have treated 4 patients of acute erythematous skin diseases with fever and/or pain by H2 enriched intravenous fluid. We also added data from two volunteers for assessing the mode of H2 delivery to the skin for evaluation of feasibility of H2 treatment for this type of skin diseases. METHODS: All of the four patients received intravenous administration of 500 ml of H2 enriched fluid in 30 min for more than 3 days except in one patient for only once. From two volunteers (one for intravenous H2 administration and the other for H2 inhalation), blood samples were withdrawn serially and air samples were collected from a heavy duty plastic bag covering a leg, before, during and after H2 administration. These samples were checked for H2 concentration immediately by gas chromatography. Multiple physiological parameters and blood chemistry data were collected also. RESULTS: Erythema of these 4 patients and associated symptoms improved significantly after the H2 treatment and did not recur. Administration of H2 did not change physiological parameters and did not cause deterioration of the blood chemistry. The H2 concentration in the blood from the volunteers rapidly increased with H2 inhalation and slowly decreased with cessation of H2 particularly in the venous blood, while H2 concentration of the air from the surface of the leg showed much slower changes even after H2 inhalation was discontinued, at least during the time of sample collection. CONCLUSION: An improvement in acute erythemtous skin diseases followed the administration of H2 enriched fluid without compromising the safety. The H2 delivery study of two volunteers suggested initial direct delivery and additional prolonged delivery possibly from a slowly desaturating reservoir in the skin to the surface.

Improved brain MRI indices in the acute brain stem infarct sites treated with hydroxyl radical scavengers, Edaravone and hydrogen, as compared to Edaravone alone. A non-controlled study.

BACKGROUND: In acute stage of cerebral infarction, MRI indices (rDWI & rADC) deteriorate during the first 3-7 days after the ictus and then gradually normalize in approximately 10 days (pseudonormalization time), although the tissue is already infarcted. Since effective treatments improve these indices significantly and in less than the natural pseudonormalization time, a combined analysis of these changes provides an opportunity for objective evaluation on the effectiveness of various treatments for cerebral infarction. Hydroxyl radicals are highly destructive to the tissue and aggravate cerebral infarction. We treated brainstem infarction patients in acute stage with hydroxyl radical scavengers (Edaravone and hydrogen) by intravenous administration and evaluated the effects of the treatment by a serial observation and analysis of these MRI indices. The effects of the treatment were evaluated and compared in two groups, an Edaravone alone group and a combined group with Edaravone and hydrogen, in order to assess beneficial effects of addition of hydrogen. METHODS: The patients were divided in Edaravone only group (E group. 26 patients) and combined treatment group with Edaravone and hydrogen enriched saline (EH group. 8 patients). The extent of the initial hump of rDWI, the initial dip of rADC and pseudo-normalization time were determined in each patient serially and averages of these data were compared in these two groups and also with the natural course in the literatures. RESULTS: The initial hump of rDWI reached 2.0 in the E group which was better than 2.5 of the natural course but was not as good as 1.5 of the EH group. The initial dip of rADC was 0.6 in the E group which was close to the natural course but worse than 0.8 of the EH group. Pseudonormalization time of rDWI and rADC was 9 days only in EH group but longer in other groups. Addition of hydrogen caused no side effects. CONCLUSIONS: Administration of hydroxyl radical scavengers in acute stage of brainstem infarction improved MRI indices against the natural course. The effects were more obvious and significant in the EH group. These findings may imply the need for more frequent daily administration of hydroxyl scavenger, or possible additional hydrogen effects on scavenger mechanisms.