**6. Discussion and conclusions**

Contrary to all expectations, it is now well demonstrated [68] that combined intradiscal and periganglionic injection of medical ozone allows an excellent outcome in 70.3% of patients treated for disk herniation performed after conservative management failed to respond. In the same vein, it appears very surprising that the application of medical ozone in acute and chronic painful diseases of the joints allows rapid pain relief, disappearance of inflammation and improvement of mobility. Thousands of patients have been successfully treated and the lack of side effects is noteworthy. [69] These positive empiric observations need to be explained. Ozone is indeed a surprising gas that paradoxically, after prolonged administration at low concentrations, induces tolerance, a phenomenon termed 'hormesis' by Goldman [70] to indicate 'a beneficial effect of a low level exposure to an agent that is harmful at high levels'. Thus, at this stage, we use the definition of 'ozone paradox' for explaining these excellent therapeutic results. Immediately after O2\_/O3 administration in the nucleus pulposus or into inflamed endoarticular cavities; a sort of oxidative shock seems to subvert all the traditional rules by inducing an antioxidative response due to several factors, among which is the cholinergic antiinflammatory pathway. [71] A detailed discussion is reported elsewhere. (3)

170 Pharmacology and Nutritional Intervention in the Treatment of Disease

This is another medical specialty where ozone has been recently evaluated with exceedingly interesting results.[72] Primary root carious lesions are being treated with a novel ozone delivery system able to avoid any toxic risk for the mouth cavity and lungs. The tooth's lesion is exposed for 10\_/20 sec to a sort of ozone 'hurricane' based on a gas flow of 615 ml/min of O2\_/O3 at a low concentration (4 mg/ml), perfectly enclosed in a tightly fitting silicone cup enclosing the tooth. It is not surprising that all bacteria, particularly lactobacilli, are destroyed so that the ozone-sterilized dental surface becomes quickly remineralized, becoming hard and resistant to further bacterial attack. This new approach is simple, inexpensive and well tolerated, as opposed to the conventional and painful 'drilling and filling' management of primary root carious lesions. Dermatological, pulmonary, renal, hematological and neurode‐ generative diseases Owing to the ability of ozone to activate a number of biological targets, ozone therapy could be proficiently used in some dermatological, pulmonary, renal, hemato‐ logical and neurodegenerative diseases. However these pathologies so far have not been evaluated in a controlled fashion. Most of the patients with metastatic cancer resistant to radiotherapy and chemotherapy report a striking improvement of the quality of life with prolonged (twice weekly for months) O3-AHT treatments. [25 – 73] This is a constantly

observed result, most probably due to a multifactorial neuroendocrine response.

Finally it must be emphasized that if ozone is judiciously used according to precisely defined guidelines, it causes neither acute, nor chronic side effects. After two decades of practical applications and the results observed in patients after conventional remedies have proved unsatisfactory. One has the feeling that, if ozone therapy could be accepted and used in all

**4.5. Dentistry**

**5. Summary**

There is no doubt that ozone can be toxic, and even today its hazardous employment by charlatans and unprepared physicians has contributed to a poor consideration of ozone therapy. That is one reason why the use of ozone is prohibited in some states of the USA and why this therapy is still regarded with skepticism by orthodox medicine even in Germany, where this approach was first conceived. Moreover, the following data tend to generalize that ozone is always toxic and should not be used in medicine:


#### *But is ozone always toxic?*

As a matter of fact millions of O3-AHT, even if performed in an empirical fashion during the past three decades, has neither yielded acute nor chronic toxic effects. According to Jacobs [76] this procedure has yielded the lowest number of medical complications.

However, four deaths have been recorded due to pulmonary embolism, which occurred during direct intravenous administration of O2\_/O3, an application prohibited by the Euro‐ pean Society of Ozonetherapy since 1983. Thus ozone seems like Janus and his two faces require an explanation. This is now reasonably clear. Since 1988 we have investigated the problem in a scientific way using precise ozone generators, which allow checking ozone concentration in real time by a photometer calibrated with the classical iodometric method. A review [61] and a critical book (3) have extensively clarified the issue but this does not seem sufficient to dispel the dogma that 'ozone is always toxic'. However, we now consider ozone as a real drug that must be used with caution after having carefully defined its therapeutic window. First, the ozone must be calibrated against the antioxidant capacity of the patient's blood in order to control the potential ozone toxicity

Second, expert scientists in free radicals ought to distinguish the chronic intracellular oxidative stress typical of several pathologies by the transitory (5 min) calculated oxidative stress occurring when a precise volume of blood is exposed ex vivo to an equal volume of gas (O2\_/ O3) with well-defined ozone concentrations ranging from 20 up to 40 mg/ml per ml of blood. It needs to be emphasized that the exogenous oxidative stress caused by ozone in blood is due to the fact that ozone, once dissolved in the plasmatic water, instantaneously reacts with biomolecules and disappears but generates ROS, among which are H2O2 and LOPs. These are the effective ozone messengers that interact with a variety of cells and elicit the now-termed 'therapeutic shock' due to the multiform biological responses. That ozone acts as a real chemical drug is proved by the fact that the ozone messengers, to be effective, must reach a threshold because otherwise there are no biological effects and the therapeutic results, if any, are due to a placebo effect. Although we have proven that ozone therapy is not a nebulous approach and has been shown amenable to a precise scientific scrutiny, it is probable that much still remains to be uncovered.

messengers, by acting on different cells, elicit a variety of biological effects that cannot ever be dreamed of with the usual reductionist approach of using a drug for a single target. This consideration can explain the far superior therapeutic effect of parenteral and topical ozone therapy in advanced cases of chronic limb ischemia to the conventional infusion of prostanoids. Another relevant characteristic is that the judicious strategy 'start low, go slow' in using ozone is able to induce in patients the adaptation to the chronic oxidative stress (i.e. ozone) para‐ doxically upregulates the antioxidant defenses. The scientific evaluation of ozone therapy efficacy remains the crucial point: results accrued during the past 20 years show that is very useful in chronic limb ischemia, ARMD, chronic infectious diseases and, most surprising, in orthopedics and even in dentistry after conventional medicine has failed to provide a real advantage. There are no adverse effects and most of the patients report a feeling of wellness. The efficacy remains uncertain in other pathologies such as neurodegenerative, autoimmune

General Aspects of Ozone Therapy http://dx.doi.org/10.5772/57470 173

diseases and cancer because clinical experience is fragmentary and anecdotal.

of Inflammations.

**Author details**

Mediozon Clinics, Istanbul, Turkey

1974;23:181–184.

Ruhi Cakir

**References**

However, orthodox medicine remains skeptical because controlled clinical trials are few and are not considered satisfactory. Unfortunately our good will is not sufficient to overcome prejudice and lack of sponsors. It is distressing to realize that a wrong dogma, commercial interests and the disinterest of Health Authorities delay the application of a medical approach that could help billions of patients, particularly in poor countries. Finally, this paper may serve the purpose of opening a fruitful discussion on the beneficial versus the toxicological actions of ozone, and a referee has proposed that the debate may be hosted as a forum by Mediators

[1] Wolff HH. Die behandlung peripherer durchblutungsstorungen mit ozon. Erfahr Hk

[2] Bocci V, Paulesu L. Studies on the biological effects of ozone: 1. Induction of interfer‐

[3] Bocci V, Luzzi E, Corradeschi F, Paulesu L, Di Stefano A. Studies on the biological effects of ozone: 3. An attempt to define conditions for optimal induction of cyto‐

on gamma on human leucocytes. Haematologica 1990;75:510–515.

kines. Lymphokine Cytokine Res 1993;12:121–126.

Everyone knows that plasma and blood cells contain an almost redundant antioxidant system made up of hydro-liposoluble compounds and antioxidant enzymes. During aging or patho‐ logic conditions, this is not sufficient to correct the intracellular oxidative stress, but normally it is adequate to tame ozone toxicity while allowing the generation of ROS and LOPs. Thus all data emphasizing ozone toxicity can be easily dismissed because the following is now well proven:


Hopefully this discussion should put an end to the confusion between the endogenously constant oxidative stress due to the oxygen and the transitory and occasional therapeutic 'shock' due to precise blood ozonation. A point that should not be overlooked is that ozone messengers, by acting on different cells, elicit a variety of biological effects that cannot ever be dreamed of with the usual reductionist approach of using a drug for a single target. This consideration can explain the far superior therapeutic effect of parenteral and topical ozone therapy in advanced cases of chronic limb ischemia to the conventional infusion of prostanoids. Another relevant characteristic is that the judicious strategy 'start low, go slow' in using ozone is able to induce in patients the adaptation to the chronic oxidative stress (i.e. ozone) para‐ doxically upregulates the antioxidant defenses. The scientific evaluation of ozone therapy efficacy remains the crucial point: results accrued during the past 20 years show that is very useful in chronic limb ischemia, ARMD, chronic infectious diseases and, most surprising, in orthopedics and even in dentistry after conventional medicine has failed to provide a real advantage. There are no adverse effects and most of the patients report a feeling of wellness. The efficacy remains uncertain in other pathologies such as neurodegenerative, autoimmune diseases and cancer because clinical experience is fragmentary and anecdotal.

However, orthodox medicine remains skeptical because controlled clinical trials are few and are not considered satisfactory. Unfortunately our good will is not sufficient to overcome prejudice and lack of sponsors. It is distressing to realize that a wrong dogma, commercial interests and the disinterest of Health Authorities delay the application of a medical approach that could help billions of patients, particularly in poor countries. Finally, this paper may serve the purpose of opening a fruitful discussion on the beneficial versus the toxicological actions of ozone, and a referee has proposed that the debate may be hosted as a forum by Mediators of Inflammations.
