History of ozone as a therapeutic agent
1785: ozone was mentioned for the first time in the scientific literature: it was described in an experiment by Martin van Marum, a Dutch physicist
1840: Professor C.F. Schonbein perceived a distinctive smell while studying the slow oxidation of white phosphorus and water electrolysis. This smell was similar to that smelled during a storm; thus he coined the term “ozone” from the Greek ozein (smelling)
1850: first scientific publications in journals such as The Lancet and the British Medical Journal
1896: first ozone generator was patented by Tesla
1897: Major G. Stoker established the Oxygen Hospital in London, for the treatment of ulcers and wounds by oxygen
1932: the Swiss dentist E.A. Fisch understood the enormous advantages of using ozone in local therapies. He treated the surgeon E. Payr for his gangrenous pulpitis using gas injections and ozonated water
1957: H. Wolff and J. Hänsler began to use major autohemotherapy
1980: The advent of ozone therapy in Italy is due to C. Verga: he noticed that myalgic pain disappeared after local injection, and in 1989 he published “New therapeutic approach to lumbar herniations and protrusions”
Recent years: many scientific works written by Cuban, Spanish, German, Russian, Italian, American physicians (and those from other many countries) have been published
The current applications of ozone therapy include many fields of medicine, such as orthopedics (e.g., herniated discs, arthritis, spinal stenosis, tendinitis, peripheral neuropathy from compression), internal medicine (hepatitis, diabetes), cardiology (outcomes of ischemia and infarction, atherosclerosis), bronchopneumology (chronic obstructive pulmonary disease, pulmonary fibrosis, emphysema), rheumatology (rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome), neurology (vasomotor and cluster headaches, multiple sclerosis, dementia of various causes), gastroenterology (Crohn’s disease, ulcerative colitis), ophthalmology (retinal arterial disease, dry eye syndrome), gynecology (vaginitis, dysmenorrhea), surgery (vascular ulcers, diabetic foot, infected wounds), aesthetic medicine (cellulitis, visible capillaries, wrinkles, dystrophic scars).
13.2 Biochemical and Pathophysiological Basis of the Therapeutical Effect of Ozone
13.2.1 Biochemistry
Ozone is detectable at concentrations between 98.16 and 19.63 μg/m3 (0.002 ppm). It is composed of three atoms of oxygen (allotropic form) and is formed by an endothermic process: 3O2 + 68,400 cal → 2O3; it has a PM of 48 and a rate of decomposition of 105–106 mol/s.
In water, ozone is 1.6 times denser and 10 times more soluble than oxygen (49 ml/100 ml of water at 0 °C). Although it is not a radical, it is the third largest oxidant, after fluoride and persulfate.
Ozone is produced from three sources of energy: chemical electrolysis, electric discharge and UV radiation, through a reversible reaction. Ozone half-life depends inversely proportional to the ambient temperature and the salinity of the water, and directly proportional to the pressure, the capacity of the syringe and the concentration of the mixture. For medical purposes, therefore, it can’t be stored, but it must be prepared at the moment of use.
Ozone has the ability to react with the majority of organic and inorganic substances until it reaches complete oxidation. It presents a preferable selectivity for the double and triple bonds present in the cells, fluids or tissues, such as amino acids and unsaturated fatty acids, part of lipoprotein complexes of the plasma and of the double layer of cell membranes, DNA molecules and cysteine residues of the protein. When the gas mixture comes into contact with biological fluids, it dissolve within a few seconds in water. The effectiveness of administration is closely linked to the reaction with phospholipid membranes, determining, after partial initial consumption, the formation of ozonides, aldehydes, reactive oxygen species (ROS), including hydrogen peroxide (H2O2), and lipoperoxides (LOPs), in controlled amounts.
Formation of ROS in plasma is very rapid (less than 1 min), and it is accompanied by a transient decrease in antioxidant capacity (5–25%), returning it to a normal value within 15–20 min. Hydrogen peroxide and other mediators spread within the cells, triggering more pathways into erythrocytes, leukocytes, and platelets.
Considering the small amount of ozone used in the blood, compared with the various systemic actions, a direct action of such products on all the membranes is not possible, but there is a mechanism of induction of the synthesis and activation of various biologically active components. The obtainable effects on the organism determine an improvement in many metabolic processes.
13.2.2 Effects on Oxygen Metabolism and Rheology
Peroxides produced by the interaction of ozone with the phospholipid bilayer enter into erythrocytes, producing controlled oxidative stress. Thus, glycolysis is stimulated in the red blood cells, through the activation of the pentose phosphate pathway, resulting in:
Increased production of adenosine triphosphate (ATP), which stabilizes the membrane potential and improves the mechanical strength
A slow decrease in intracellular pH (Bohr effect)
Increased 2,3-DPG, a direct inhibitor of the affinity of hemoglobin for oxygen
The newly generated red blood cells have an increased G-6PD activity (super gifted erythrocytes), and very gradually they replace only those that have completed their life cycle, without affecting the patient’s hematocrit.
There are also several rheological effects, such as the activation of the nitric oxide (NO) synthase, with subsequent NO production, induction of carbon monoxide (CO) production, and the activity of enzymes such as trypsin, some proteases, and elastase, in a controlled manner. In addition, an increasing negative charge on the membrane surface of red blood cells is induced, improving the elasticity and deformability of these cells. From these biochemical processes a greater oxygen supply for the tissues, a controlled anticoagulant effect, a reduced stacking of erythrocytes, a reduced blood viscosity and platelet aggregation, an increased oxygen partial pressure in arterial blood, and a decrease in oxygen pressure in venous blood, with a consequent decrease in venous and capillary stasis, can be achieved.
13.2.3 Modulation of Oxidative Stress
Ozone is consumed within minutes after administration, because of its high reactivity and solubility. As previously mentioned, hydrogen peroxide and LOPs are formed from it at doses not exceeding the anti-oxidant capacity of the organism. The oxidation products effectively determine a transient increase in oxidative processes, and they induce the activation of anti-oxidant systems after a few minutes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, leading to a rebalancing of the redox components.
Hydrogen peroxide is rapidly converted into water, LOP 4-hydroxynonenal (4-HNE) enhances anti-oxidant enzymes, acting as a trigger: it forms a compound with Cys 34 of albumin and with glutathione, and it induces adaptive responses through the increase in NO and bilirubin, acting as direct anti-oxidants.
4-HNE reacts with the cytosolic Nrf2-Keap1 system, forming a complex that releases Nrf-2, a protein present in all body cells, activated by controlled oxidative stress, and a key compound in the defense against oxidative stress.
This repeated oxidative stress causes a “preconditioning effect,” balancing the redox system, altered by pathogenic stimuli. At ozone concentrations usually employed in medicine, these are transient and controlled processes, compatible with the anti-oxidant capacity in the blood. The redox imbalance is correlated with many diseases, from inflammatory processes to autoimmune diseases. All of these pathological conditions can be treated with ozone, with remarkable results. However, it is very important to know the correct ozone concentration and doses that are effective against a specific pathological condition to be treated and do not exceed the anti-oxidant capacity of the organism [2].
13.2.4 Reactivation of Innate Defense System
After its release, Nrf2 translocates to the nucleus and binds to DNA at the site of the antioxidant response element anti-oxidant response element (ARE; or hARE: human) regulator of the entire antioxidant system.
The activation of Nrf2/ARE causes:
An increase in anti-oxidant enzymes direct (GSH, CO, and bilirubin) and detoxification (catalase, SOD, GPx, GSTR, NADPH-quinone oxidoreductase [NQO1], HO-1, HSP70)
An increase in phase II enzymes (glutathione S-transferase, UDP-glucuronosyltransferase, N-acetyltransferase, and sulfotransferase)
Inhibition of the production of inflammatory cytokines, induction of leukotriene B4 reductase
A reduction of serum iron, and the resulting oxidative stress from high ferritin
Recognition, repair, and removal of damaged proteins
Protection from apoptosis due to oxidative stress
Increased activity of DNA repair
Increase of adrenocorticotropic hormone, cortisol, and corticotropin-releasing hormone
13.2.5 Immunomodulation
Ozone induces in balanced amounts the synthesis of cytokines by monocytes, macrophages, and lymphocytes, the release of cytokines and immunosuppressive immunostimulants (TGF-β1, IFNβ, γ, and δ, TNF, IL-1β, 2, 4, 6, 8, 10), and activation of nonspecific defense systems, humoral and cellular immunity.
Therefore, considering the induced modulation, ozone can be used both in autoimmune diseases and in immune deficiencies.
13.2.6 Bactericidal, Virus Static, and Antifungal Action
According to the literature data, ozone acts against any Gram-positive and Gram-negative bacterium known, including Pseudomonas aeruginosa and Escherichia coli, all lipophilic and hydrophilic viruses, and each fungal spore and protozoa.
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