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"This review and others          have documented that the clinical use of hydrogen is quite promising for the treatment of many acute and chronic illnesses and conditions, as well as its utility in support of the maintenance of good health. What started in Japan and the Far East as preliminary results on the clinical use of hydrogen has now continued there and elsewhere, to the point where there are now a critical number of scientific and clinical studies that support the use of hydrogen as a primary or supportive component of clinical care.
With its potent and unique antioxidant properties, gene regulatory abilities, and rapid rates of diffusion across tissue and cellular barriers, as well as its excellent safety record, hydrogen has many unique characteristics that make it very valuable for utilization in medicine and health. Its systemic properties and excellent penetration ab- ilities allow hydrogen to be effective under conditions of poor blood flow and other situations that limit many other types of systemic treatments.
The clinical justification for hydrogen use is growing because:
1) Redox imbalance and the excess production of ROS and RNS (increasing oxidative stress) have been implicated in many, if not all, pathophysiological mechanisms leading to a wide variety of medical conditions and diseases. Hydrogen is useful because of its potent free-radical scavenging properties that significantly reduce strong cellular oxidants, but it does not affect important signaling pathways that depend on mild cellular oxi- dants.
2) Hydrogen is effective in reducing signs and symptoms and improving quality of life in a wide variety of clinical conditions. Because most of its effects are often indirect, such as reducing excess oxidative stress, hy- drogen is useful for many apparently unrelated clinical conditions that are linked to redox imbalances. Often these conditions do not have definitive treatments that eliminate the illness. In such cases, hydrogen can be used in conjunction with less than effective therapies to improve clinical outcomes.
3) Perhaps its most useful property is that hydrogen does not interfere with the underlying mechanisms of most clinical treatments. Thus, its real value may be in adjuvant therapy, along with standard treatments for many clinical conditions.
4) An important factor is the safety of hydrogen and that no adverse effects of hydrogen have been described. This is also very relevant, since many drugs are limited in their use because of toxicity, adverse reactions, and unfavorable dose-response characteristics. Hydrogen does not have these problems.
5) The ease of hydrogen administration is a useful characteristic. This is where H2-enriched water has an ad- vantage over other methods of hydrogen delivery. Drinking H2-enriched water can be done on a long-term basis without any special requirements for administration.
Basic and clinical research on the use of hydrogen for acute and chronic illnesses will continue to improve our understanding of the mechanism of action of hydrogen therapy.
1) Hydrogen is able to promote changes in the expression and levels of particular proteins by regulating gene expression. Of particular importance is that hydrogen can inhibit or change the expression patterns of pro- inflammatory, pro-allergic, pro-apoptotic and pro-oxidative proteins. Many, if not most, of these proteins are over-expressed in a variety of chronic and acute illnesses. How hydrogen changes the expression of particular proteins remains an important question that is currently a topic of research in several laboratories.
2) The cellular receptors for hydrogen and the mechanisms of hydrogen action at the level of cellular mem- branes, enzymes, protein synthesis, and gene regulation will have to be investigated. Little is actually known about these molecular interactions involving hydrogen inside cells and tissues. This will have to also be investi- gated first in simple in vitro models in order to eventually understand more complex in vivo environments.
3) Hydrogen is able to quickly penetrate into tissues and cells. Further investigation is needed to monitor the actual levels of hydrogen in the microcirculation and target tissues, especially when hydrogen is administered for long periods of time. We do not yet know the levels of hydrogen administration which provide steady state and effective concentrations of hydrogen in various tissues and cells.
4) The clinical uses of hydrogen must be further investigated. Most of the published research on hydrogen has utilized animal models. Although this has been extremely useful, it is now time to shift the focus of research to patients with acute and chronic clinical conditions.
5) There are some advantages and disadvantages in the various ways hydrogen is administered, and this should be further investigated. Although inhalation of H2 gas has an advantage in that it is easy to administer; it also has some disadvantages, such as reproducibility of delivering the same dose of H2 in different patients be- cause of variations in the amounts that effectively reach the microcirculation and tissues. It also requires high- pressure containers and pressure regulators to deliver the required amounts of hydrogen gas, and the patient must use a mask or nasal insert. On the other hand, H2-enriched water can be easily and accurately delivered without any special apparatus. With any delivery method there is the problem of knowing the effective concentrations of hydrogen that reach the target tissues, and this will remain an important research topic.
6) The increased use of controlled, randomized clinical trials will improve our knowledge of the benefits of hydrogen for various acute and chronic conditions. Until recently few clinical trials have used rigorous criteria for evaluation of clinical effects. Many trials have been open label in design, and this is expected for initial clin- ical investigations. In the future it is expected that more carefully designed (and more expensive!) placebo-controlled, blinded, randomized clinical trials will be necessary to confirm the clinical benefits of hydrogen. Finally, the use of hydrogen for acute and chronic medical conditions is rapidly being eclipsed by the use of hydrogen for health maintenance, exercise and physical performance, as well as aging. These areas of hydrogen use will continue to grow and will ultimately dwarf the current clinical uses of hydrogen in our society."