Evidenze Scientifiche

Med Biol Eng Comput. 2016 Oct 12.

Cerebrovascular pattern improved by ozone autohemotherapy: an entropy-based study on multiple sclerosis patients.


Ozone major autohemotherapy is effective in reducing the symptoms of multiple sclerosis (MS) patients, but its effects on brain are still not clear. In this work, we have monitored the changes in the cerebrovascular pattern of MS patients and normal subjects during major ozone autohemotherapy by using near-infrared spectroscopy (NIRS) as functional and vascular technique. NIRS signals are analyzed using a combination of time, time-frequency analysis and nonlinear analysis of intrinsic mode function signals obtained from empirical mode decomposition technique. Our results show that there is an improvement in the cerebrovascular pattern of all subjects indicated by increasing the entropy of the NIRS signals. Hence, we can conclude that the ozone therapy increases the brain metabolism and helps to recover from the lower activity levels which is predominant in MS patients.

Eur J Pharmacol. 2016 Oct 15;789:313-8. doi: 10.1016/j.ejphar.2016.07.031. Epub 2016 Jul 20.

Medical ozone increases methotrexate clinical response and improves cellular redox balance in patients with rheumatoid arthritis.


Medical ozone reduced inflammation, IL-1β, TNF-α mRNA levels and oxidative stress in PG/PS-induced arthritis in rats. The aim of this study was to investigate the medical ozone effects in patients with rheumatoid arthritis treated with methotrexate and methotrexate+ozone, and to compare between them. A randomized clinical study with 60 patients was performed, who were divided into two groups: one (n=30) treated with methotrexate (MTX), folic acid and Ibuprophen (MTX group) and the second group (n=30) received the same as the MTX group+medical ozone by rectal insufflation of the gas (MTX+ozone group). The clinical response of the patients was evaluated by comparing Disease Activity Score 28 (DAS28), Health Assessment Questionnaire Disability Index (HAQ-DI), Anti-Cyclic Citrullinated (Anti-CCP) levels, reactants of acute phase and biochemical markers of oxidative stress before and after 20 days of treatment. MTX+ozone reduced the activity of the disease while MTX merely showed a tendency to decrease the variables. Reactants of acute phase displayed a similar picture. MTX+ozone reduced Anti-CCP levels as well as increased antioxidant system, and decreased oxidative damage whereas MTX did not change. Glutathione correlated with all clinical variables just after MTX+ozone. MTX+ozone increased the MTX clinical response in patients with rheumatoid arthritis. No side effects were observed. These results suggest that ozone can increase the efficacy of MTX probably because both share common therapeutic targets. Medical ozone treatment is capable of being a complementary therapy in the treatment of rheumatoid arthritis.

J Vasc Interv Radiol. 2016 Aug;27(8):1242-1250.e3. doi: 10.1016/j.jvir.2016.04.012. Epub 2016 Jun 28.

Percutaneous Treatment of Herniated Lumbar Discs with Ozone: Investigation of the Mechanisms of Action.



To elucidate the mechanism of action of intradiscal oxygen-ozone therapy for herniated intervertebral disc therapy.


Ozone‘s mechanism of action was investigated using 3 approaches: mathematical models of intervertebral disc space to explore the relationship between disc pressure and volume; ozonolysis experiments using glycosaminoglycans (GAGs) from a Chinese hamster ovary cell line that were similar in composition to GAGs found in human nucleus pulposus; and experiments in which live Yucatan miniature pigs received various concentrations of percutaneous, image-guided intradiscal oxygen-ozone treatment and were examined (after sacrifice) with histology and semiquantitative analysis of disc cytokine concentrations.


Engineering calculations support observations that a small (6%) disc volume reduction can result in considerable (9.84%) intradiscal pressure reduction. Porcine disc histology and Chinese hamster ovary GAG ozonolysis results showed that administered ozone reacted with and fragmented disc proteoglycans, reducing disc volume through disc dehydration. Cytokine analysis of porcine discs found that each of 4 cytokines measured (interleukin [IL]-1β, IL-6, IL-8, and tumor necrosis factor α) increased in concentration after 2 wt% ozone treatment.


Oxygen-ozone therapy breaks down proteoglycan GAGs that maintain disc osmotic pressure, dehydrating the nucleus pulposus and reducing intervertebral disc volume. This is likely a primary mechanism by which ozone relieves nerve root compression and alleviates herniated disc-related pain. Additionally, 2 wt% ozoneappears to interact with intradiscal cytokines, generating an antiinflammatory response that may contribute to symptom improvement.

[The results of combined surgical treatment of thromboangiitis obliterans and critical lower limb ischemia using prolonged epidural analgesia and autohemotherapy with ozone].

[Article in Russian]



to evaluate the results of combined treatment of thromboangiitis obliterans with severe lower limb ischemia using prolonged epidural anaesthesia and autohemotherapy with ozone.


It was analyzed treatment of 125 patients with thromboangiitis obliterans and severe lower limb ischemia. Patients were divided into 2 groups. Control group consisted of 60 patients who underwent conventional perioperative therapy with anticoagulants, antiplatelet agents, dextrans, metabolic drugs, glucocorticoids, angioprotectors, narcotic and non-narcotic analgesics. Study group included 65 patients in whom prolonged epidural anaesthesia and autohemotherapy with ozone was applied additionally.


In early postoperative period (up to 30 days) the incidence of secondary lower leg amputation was 10% and 1.5% in both groups respectively (p<0.05). Primary healing after limited foot amputation was achieved in 63.6% and 83.3% in control and stugy groups respectively (p<0.05). Ulcerative defect recovery was observed in 62.2% and 76.2% in both groups respectively (p<0.01). Satisfactory result of treatment was obtained in 61.7% and 80.0% of patients.


Restoration of magistral and collateral blood flow combined with prolonged epidural anaesthesia and autohemotherapy with ozone improves surgical outcomes and rehabilitation of patients with thromboangiitis obliterans and severe lower limb ischemia.

 Biol Regul Homeost Agents. 2016 Apr-Jun;30(2):621-5.

Comparison between intrarticular injection of hyaluronic acid, oxygen ozone, and the combination of both in the treatment of knee osteoarthrosis.


This study aimed to compare short-term clinical outcomes between intra-articular injection of hyaluronic acid (HA), oxygen ozone (O2O3), and the combination of both, in patients affected by osteoarthrosis (OA) of the knee. Seventy patients (age 45-75 years) with knee OA were randomized to intra-articular injections of HA (n=23), or O2O3 (n=23) or combined (n=24) one per week for 5 consecutive weeks. KOOS questionnaire and visual analog scale (VAS), before treatment (pre) at the end (post), and at 2 months after treatment ended (follow-up) were used as outcome measures. Analysis showed a significant effect (P < 0.05) of the conditions (pre, post and follow-up) in all parameters of the KOOS score and a significant effect (P < 0.05) of groups (HA, O2O3 and combined) for pain, symptoms, activities of daily living and quality of life. The combined group scores were higher compared to the HA and O2O3 groups, especially at follow-up. The combination of O2O3 and HA treatment led to a significantly better outcome especially at 2-month follow-up compared to HA and O2O3 given separately to patients affected by OA of the knee.

Wiad Lek. 2016;69(1):7-9.

Ozone therapy effectiveness in patients with ulcerous lesions due to diabetes mellitus.



Development of purulo-necrotic foot lesions is one of the most dangerous surgical complications of diabetes mellitus, it causes high lethality, early disability, considerable economical expenses on treatment and rehabilitation. Mentioned above determine substantial actuality of diabetic foot problem and condition the necessity of further search of new ways and effective methods of lower extremities lesions complex treatment.


of our research was to study the effectiveness of ozone use in complex therapy among patients with diabetic foot.


Under our observation were 47 patients with I and II stages of diabetic foot that correspond to superficial and deep ulcers without involving of subcutaneous tissue, ligaments, tendons and muscles into the process, without bone lesion, phlegmons and abscess forming according to Meggit-Wagner (1978) classification. Depending on treatment every group of patients was divided into subgroups. B group composed patients that received traditional therapy.A group composed patients that along with traditional therapy course received course of systemic and regional ozone therapy for 12-14 days, one session per day. Cytological examination of discharge from wounds was carried, lipid peroxidation state and antioxidant protection state was assessed.


Ozone use has more evident clinical effect, significantly affects the phase course of wound process, promotes the improvement of lipid peroxidation and antioxidant protection indexes, reduces the length of hospital stay and term of treatment of patients with diabetic foot. СONCLUSIONS: Studies conducted showed that including of ozone therapy into complex surgical treatment has positive effect on wound process.

Interv Neuroradiol. 2016 Aug;22(4):466-72. doi: 10.1177/1591019916637356. Epub 2016 Apr 11.

Herniated disks unchanged over time: Size reduced after oxygen-ozone therapy.


The spontaneous regression of disk herniation secondary to dehydration is a much-debated topic in medicine. Some physicians wonder whether surgical removal of the extruded nucleus pulposus is really necessary when the spontaneous disappearance of a herniated lumbar disk is a well-known phenomenon. Unfortunately, without spontaneous regression, chronic pain leads to progressive disability for which surgery seems to be the only solution. In recent years, several studies have demonstrated the utility of oxygen-ozone therapy in the treatment of disk herniation, resulting in disk shrinkage. This retrospective study evaluates the outcomes of a series of patients with a history of herniated disks neuroradiologically unchanged in size for over two years, treated with oxygen-ozonetherapy at our center over the last 15 years. We treated 96 patients, 84 (87.5%) presenting low back pain complicated or not by chronic sciatica. No drug therapy had yielded significant benefits. A number of specialists had been consulted in two or more years resulting in several neuroradiological scans prior to the decision to undertake oxygen-ozone therapy. Our study documents how ozone therapy for slipped disks “unchanged over time” solved the problem, with disk disruption or a significant reduction in the size of the prolapsed disk material extruded into the spinal canal.


Lumbar disk herniation; ozone therapy


Oxid Med Cell Longev. 2015;2015:190640. doi: 10.1155/2015/190640. Epub 2015 Jul 21.

Daily Oxygen/O₃ Treatment Reduces Muscular Fatigue and Improves Cardiac Performance in Rats Subjected to Prolonged High Intensity Physical Exercise.


Rats receiving daily intraperitoneal administration of O2 and running on a treadmill covered an average distance of 482.8 ± 21.8 m/week as calculated during 5-week observation. This distance was increased in rats receiving daily intraperitoneal administration of an oxygen/O3 mixture at a dose of 100; 150; and 300 μg/kg with the maximum increase being +34.5% at 300 μg/kg and still present after stopping the administration of oxygen/O3. Oxygen/O3 decreased the mean arterial blood pressure (-13%), the heart rate (-6%), the gastrocnemius and cardiac hypertrophy, and fibrosis and reduced by 49% the left ventricular mass and relative wall thickness measurements. Systolic and diastolic functions were improved in exercised oxygen/O3 rats compared to O2 rats. Oxygen/O3 treatment led to higher MPI index starting from the dose of 150 μg/kg (p < 0.05) and more effective (+14%) at a dose of 300 μg/kg oxygen/O3. Oxygen/O3 dose-dependently increased the expression of the antioxidant enzymes Mn-SOD and GPx1 and of eNOS compared to the exercised O2 rats. The same doses resulted in decrease of LDH levels, CPK, TnI, and nitrotyrosine concentration in the heart and gastrocnemius tissues, arguing a beneficial effect of the ozone molecule against the fatigue induced by a prolonged high intensity exercise

Eur J Histochem. 2015 Apr 21;59(2):2515. doi: 10.4081/ejh.2015.2515.

Low ozone concentrations stimulate cytoskeletal organization, mitochondrial activity and nuclear transcription.


Ozone therapy is a modestly invasive procedure based on the regeneration capabilities of low ozone concentrations and used in medicine as an alternative/adjuvant treatment for different diseases. However, the cellular mechanisms accounting for the positive effects of mild ozonization are still largely unexplored. To this aim, in the present study the effects of low ozone concentrations (1 to 20 µg O3/mL O2) on structural and functional cell features have been investigated in vitro by using morphological, morphometrical, cytochemical and immunocytochemical techniques at bright field, fluorescence and transmission electron microscopy. Cells exposed to pure O2 or air served as controls. The results demonstrated that the effects of ozoneadministration are dependent on gas concentration, and the cytoskeletal organization, mitochondrial activity and nuclear transcription may be differently affected. This suggests that, to ensure effective and permanent metabolic cell activation, ozone treatments should take into account the cytological and cytokinetic features of the different tissues.

Validity of Oxygen-Ozone Therapy as Integrated Medication Form in Chronic Inflammatory Diseases.


The state-of-the-art of oxygen-ozone therapy is now clarified and all the mechanisms of action of medical ozone are within classical biochemistry and molecular biology. The outcomes of standard treatments in peripheral arterial occlusive disease (PAOD) and dry-form of age-related macular degeneration (AMD) have been compared with the documented therapeutic results achieved with ozonated autohemotherapy (O-AHT). On the other hand, the clinical data of O-AHT on stroke remain indicative. As the cost of O-AHT is almost irrelevant, its application in all public hospitals, especially those of poor Countries, would allow two advantages: the first is for the patient, who will improve her/his conditions, and the second is for Health Authorities burdened with increasing costs. The aim of this paper is to report to clinical scientists that O-AHT is a scientific-based therapeutic approach without side effects. The integration of O-AHT with effective approved drugs is likely to yield the best clinical results in several chronic inflammatory diseases.

[PubMed – indexed for MEDLINE]
Drug Des Devel Ther. 2015 May 15;9:2677-85. doi: 10.2147/DDDT.S74518. eCollection 2015.

The usefulness of ozone treatment in spinal pain.



The aim of this review is to elucidate the biochemical, molecular, immunological, and pharmaceutical mechanisms of action of ozone dissolved in biological fluids. Studies performed during the last two decades allow the drawing of a comprehensive framework for understanding and recommending the integration of ozone therapy for spinal pain.


An in-depth screening of primary sources of information online – via SciFinder Scholar, Google Scholar, and Scopus databases as well as Embase, PubMed, and the Cochrane Database of Systemic Reviews – was performed. In this review, the most significant papers of the last 25 years are presented and their proposals critically evaluated, regardless of the bibliometric impact of the journals.


The efficacy of standard treatments combined with the unique capacity of ozone therapy to reactivate the innate antioxidant system is the key to correcting the oxidative stress typical of chronic inflammatory diseases. Pain pathways and control systems of algesic signals after ozone administration are described.


This paper finds favors the full insertion of ozone therapy into pharmaceutical sciences, rather than as either an alternative or an esoteric approach.


antioxidants; oxidants; oxidative stress


J Physiol Pharmacol. 2015 Apr;66(2):267-72.

Ozonation of human blood increases sphingosine-1-phosphate in plasma.


Ozonated blood therapy is used in the treatment of several diseases, including superficial infections, burns, dental and intestinal conditions. Except that, the possibility of using ozone to sterilize blood supplies is under promising investigation. However, still little is known regarding the impact of blood ozonation, especially on biologically active serum sphinoglipids. In the present work we sought to investigate the contents of sphingolipids, such as sphingosine, sphingosine-1-phosphate (S-1-P), sphinganine, and ceramide (CER) in the plasma, after immediate and prolonged (1 h) ozonation of human whole blood. For the measurements liquid chromatography hyphenated with the mass spectrometry was applied. We demonstrated that only the content of sphingosine-1-phosphate in the plasma was increased significantly, possibly exerting its beneficial effect for various physiological and clinical events.

Ann Transl Med. 2014 Dec; 2(12): 117. 
PMCID: PMC4260055

It is time to integrate conventional therapy by ozone therapy in type-2 diabetes patients

We read the article written by Gregg et al. [2014] (1). It is an excellent paper and describes that rates of type-2 diabetes related complications have deeply declined during the last fifteen years in spite of a tripled increase of the number of diabetic patients. The reduction of acute myocardial infarction, stroke, amputation and end-stage renal disease are certainly due to an improved clinical care, performance of the healthcare system, and patient education in disease management. A far more effective glycemic control, the use of statins as well as coronary revascularization have been the most critical factors but nonetheless acute myocardial infarction, death from hyperglycemia, stroke and amputation the frequency of which halved remain the most stubborn affections dominated by a chronic oxidative stress. This is due to an increased production of reactive oxygen species (ROS), a decreased GSH synthesis, a decreased antioxidant system, production of phase 2 enzymes and HO-1 incapable of neutralizing the excess of oxidants (2).

Although orthodox medicine disposes of excellent drugs, they cannot re-establish a normal redox system because these drugs are not able to reactivate the cellular antioxidant system. In order to interrupt this vicious circle, we propose that now it is time to integrate orthodox medicine with ozone therapy. During the last two decades we have clarified all the biochemical, pharmacological, and molecular aspects of this procedure which is absolutely free of side effects due to the minimal dosages of ozone acting as a prodrug and to the mechanism of action of the ozone messengers. In detail, the latters are hydrogen peroxide and alkenal adducts transferred to billions of cells of the organism able to upregulate the antioxidant system and to normalize the redox system (3,4). The activation of the Nrf2 protein and the upregulation of the synthesis of some 220 genes allow the enzymatic activation of the defence system in all organs.

Type-2 diabetes, even if treated with good orthodox drugs, induces a micro- and macro-vascular dysfunction leading to a great number of complications. By considering the diabetic epidemiology and the need to fully correct the complex dysfunction, it appears urgent to integrate orthodox medications with ozone therapy (5). One treatment weekly performed for several years may definitively improve the diabetic patient recovery.


Disclosure: The authors declare no conflict of interest.


1. Gregg EW, Li Y, Wang J, et al.  Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med 2014;370:1514-23.  [PubMed]
2. Feldman EL.. Oxidative stress and diabetic neuropathy: a new understanding of an old problem. J Clin Invest 2003;111:431-3. [PMC free article]  [PubMed]
3. Pecorelli A, Bocci V, Acquaviva A, et al.  NRF2 activation is involved in ozonated human serum upregulation of HO-1 in endothelial cells. Toxicol Appl Pharmacol2013;267:30-40.  [PubMed]
4. Bocci V, Valacchi G. Free radicals and antioxidants: how to reestablish redox homeostasis in chronic diseases? Curr Med Chem 2013;20:3397-415.  [PubMed]
5. Bocci V, Zanardi I, Huijberts MS, et al.  An integrated medical treatment for type-2 diabetes. Diabetes Metab Syndr 2014;8:57-61.  [PubMed]

Articles from Annals of Translational Medicine are provided here courtesy of AME Publications
nterv Neuroradiol. 2014 Oct 31;20(5):632-6. doi: 10.15274/INR-2014-10083. Epub 2014 Oct 17.

Ozone therapy in dentistry. A brief review for physicians.


The 21(st) century dental practice is quite dynamic. New treatment protocols and new materials are being developed at a rapid pace. Ozone dental therapy falls into the category of new treatment protocols in dentistry, yet ozone is not new at all. Ozone therapy is already a major treatment modality in Europe, South America and a number of other countries. What is provided here will not be an exhaustive scientific treatise so much as a brief general introduction into what dentists are now doing with ozone therapies and the numerous oral/systemic links that make this subject so important for physicians so that, ultimately, they may serve their patients more effectively and productively.


Ozone; caries; dentistry; infection; oral/systemic; periodontal disease





1Biolab, Department of Electronics and Telecommunications, Politecnico di Torino, Torino, Italy; 2Kaos ONLUS Foundation, Torino, Italy; 3Italian Society for Oxygen and Ozone Therapy, Bergamo, Italy; 4“Un passo insieme” ONLUS Foundation, Torino, Italy

Received March 26, 2014 – Accepted June 30, 2014

Ozone autohemotherapy is an emerging therapeutic technique that is gaining increasing impor- tance in treating neurological disorders. A validated and standard methodology to assess the effect of such therapy on brain metabolism and circulation is however still lacking. We used a near-infrared spectroscopy (NIRS) system to monitor the cerebral metabolism and a transcranial Doppler (TCD) to monitor the blood ow velocity in the middle cerebral arteries. Fifty-four subjects (32 neurological patients and 22 controls) were tested before, during, and after ozone autohemotherapy. We monitored the concentration changes in the level of oxygenated and deoxygenated haemoglobin, and in the level of the Cytochrome-c-oxidase (CYT-c). As a primary endpoint of the work, we showed the changes in the brain metabolism and circulation of the entire population. The concentration of oxygenated hemoglobin increased after the reinjection of the ozoned blood and remained higher than the beginning for another 1.5 hours. The concentration of the deoxygenated haemoglobin decreased during the therapy and the CYT-c concentration markedly increased about 1 hour after the reinjection. No signi cant changes were observed on the blood ow velocity. As secondary endpoint, we compared the NIRS metabolic pattern of 20 remitting-relapsing multiple sclerosis (MS) patients against 20 controls. We showed that by using only 7 NIRS variables it was possible to characterize the metabolic brain pattern of the two groups of subjects. The MS subjects showed a marked increase of the CYT-c activity and concentration about 40 minutes after the end of the autohemotherapy, possibly revealing a reduction of the chronic oxidative stress level typical of MS sufferers. From a technical point of view, this preliminary study showed that NIRS could be useful to show the effects of ozone autohemotherapy at cerebral level, in a long-term monitoring. The clinical result of this study is the quantitative measurement of the CYT-c level changes in MS induced by ozone autohemotherapy.

 Nat Sci Biol Med. 2011 Jan-Jun; 2(1): 66–70. 
PMCID: PMC3312702

Ozone therapy: A clinical review


Ozone (O3) gas discovered in the mid-nineteenth century is a molecule consisting of three atoms of oxygen in a dynamically unstable structure due to the presence of mesomeric states. Although O3 has dangerous effects, yet researchers believe it has many therapeutic effects. Ozone therapy has been utilized and heavily studied for more than a century. Its effects are proven, consistent, safe and with minimal and preventable side effects. Medical O3 is used to disinfect and treat disease. Mechanism of actions is by inactivation of bacteria, viruses, fungi, yeast and protozoa, stimulation of oxygen metabolism, activation of the immune system. Medication forms in a gaseous state are somewhat unusual, and it is for this reason that special application techniques have had to be developed for the safe use of O3. In local applications as in the treatment of external wounds, its application in the form of a transcutaneous O3 gas bath has established itself as being the most practical and useful method, for example at low (sub-atmospheric) pressure in a closed system guaranteeing no escape of O3 into the surrounding air. Ozonized water, whose use is particularly known in dental medicine, is optimally applied as a spray or compress. Diseases treated are infected wounds, circulatory disorders, geriatric conditions, macular degeneration, viral diseases, rheumatism/arthritis, cancer, SARS and AIDS.

Keywords: Allodynia, autohemotherapy, lipid ozonation products, ozone


Ozone (O3), a gas discovered in the mid-nineteenth century, is a molecule consisting of three atoms of oxygen in a dynamically unstable structure due to the presence of mesomeric states. The gas is colorless, acrid in odour and explosive in liquid or solid form. It has a half-life of 40 min at 20°C and about 140 min at 0°C. Its basic function is to protect humans from harmful effects of UV radiation. Ozone occurs at less than 20 μg/m3 from the Earth’s surface at concentrations that are perfectly compatible with life. Although O3 has dangerous effects, yet researchers believe it has many therapeutic effects.[13] The beginning of precise medical O3 generators has only recently allowed the mechanisms, action and possible toxicity of O3 to be evaluated by clinical trials.[2] Ozone has a capacity to oxidize organic compounds,[4] and has well-known toxic effects on the respiratory tract when present in smog.[56] In medical use the gas produced from medical grade oxygen is administered in precise therapeutic doses, and never via inhalation, and advocates that it has excellent health benefits in dental caries, decrease blood cholesterol and stimulation of antioxidative responses, modifies oxygenation in resting muscle and is used in complementary treatment of hypoxic and ischemic syndromes.[710]


Ozone therapy has been utilized and extensively studied for many decades altogether. Its effects are proven, consistent and with minimal side effects. Medical O3, used to disinfect and treat disease, has been around for over 150 years. Used to treat infections, wounds and multiple diseases, O3’s effectiveness has been well-documented. It has been used to disinfect drinking water before the turn of the last century. Ozone was known to treat as many as 114 diseases.[11] Ozone therapy has been in use since the 1800s and in 1896 the genius Nikola Tesla patented the first O3 generator in the US, later forming the “Tesla Ozone Company.”[12] During the first world war (1914-18) doctors familiar with O3’s antibacterial properties, and with few other medical resources available to them applied it topically to infected wounds and discovered O3 not only remedied infection, but also had hemodynamic and anti-inflammatory properties.[13] In the late 1980s, reports had emerged that German physicians were successfully treating HIV patients with 03-AHT (Autohemotherapy). There was then no pharmaceutical treatment for HIV and a pandemic was feared, so Canadian authorities authorized the study to test safety and efficacy of 03-AHT in AIDS patients. Ozone had shown promise in in vitro testing. Ozone was seen effective at disinfecting extracorporeal blood samples of HIV; unfortunately for AIDS patients, 03-AHT proved to be an in vivoineffective treatment[1415] [Table 1].

Table 1

The chronological use of ozone in medicine


Ozone is a naturally occurring energy-rich molecule embodying unique physico-chemical and biological properties suggesting a possible role in the therapy of SARS, either as a monotherapy or, more realistically, as an adjunct to standard treatment regimens. Owing to the excess energy contained within the O3molecule, it is theoretically likely that O3, unlike organism-specific antiviral options available today, will show effectiveness across the entire genotype and subtype spectrum of SARS.[25]


Inactivation of bacteria, viruses, fungi, yeast and protozoa: Ozone therapy disrupts the integrity of the bacterial cell envelope through oxidation of the phospholipids and lipoproteins. In fungi, O3 inhibits cell growth at certain stages. With viruses, the O3 damages the viral capsid and upsets the reproductive cycle by disrupting the virus-to-cell contact with peroxidation. The weak enzyme coatings on cells which make them vulnerable to invasion by viruses make them susceptible to oxidation and elimination from the body, which then replaces them with healthy cells.[26]

Stimulation of oxygen metabolism: Ozone therapy causes an increase in the red blood cell glycolysis rate. This leads to the stimulation of 2,3-diphosphoglycerate which leads to an increase in the amount of oxygen released to the tissues. Ozone activates the Krebs cycle by enhancing oxidative carboxylation of pyruvate, stimulating production of ATP. It also causes a significant reduction in NADH and helps to oxidize cytochrome C. There is a stimulation of production of enzymes which act as free radical scavengers and cell-wall protectors: glutathione peroxidase, catalase and superoxide dismutase. Production of prostacyline, a vasodilator, is also induced by O3 [Figure 1].[25]

Figure 1

Action of ozone on RBC Metabolism[27]

Activation of the immune system: Ozone administered at a concentration of between 30 and 55 μg/cc causes the greatest increase in the production of interferon and the greatest output of tumor necrosis factor and interleukin-2. The production of interleukin-2 launches an entire cascade of subsequent immunological reactions.[27]

Mechanism of action of O3 on the human lung: Ozone exposure induces a significant mean decrement in vital capacity. It significantly increases mean airway resistance and specific airway resistance but does not change dynamic or static pulmonary compliance or viscous or elastic work. It also significantly reduces maximal transpulmonary pressure. And further more significantly increases respiratory rate and decreased tidal volume.[27]


The study to evaluate effect of bimosiamose on O3-induced sputum neutrophilia: Biomosiamose is an anti-inflammatory glycomimetic and selectin inhibitor.[28] It is found effective against disease states involving inflammatory cells like for example for asthma.[29] This drug, as per last updation, was in phase 2 trials and being evaluated for its efficacy and safety in treating chronic pulmonary obstructive disease (COPD), the study is sponsored by Revotar Biopharmaceuticals AG and was carried out by NCT00962481(ClinicalTrials.gov Identifier).[30]

Evaluate the effects of the drug (SB-656933-AAA) on the body after a single dose in subjects who have inhaled O3: Drug SB-656933-AAA was developed by GlaxoSmithKline which was found to exhibit good activity in treating COPD as well as cystic fibrosis. This action was found to be enhanced by administration of a single dose of O3 before administration of the aforementioned drug. This drug until latest updated data was in phase 1 stage, study was carried out by NCT00551811.[31]

Intraarticular O3 therapy for pain control in osteoarthritis of the knee: Ozone is being currently tested for its effectiveness in relieving the pain in patients suffering from osteoarthritis of the knee. The current status of the study is phase 2 which is sponsored by Ben-Gurion University of the Negev and the study being conducted by NCT00832312.[32]

The Effect of Ozone Therapy for Lumbar-Herniated Disc: Ozone is also being evaluated for its efficacy infiltration and its effectiveness in comparison with microdiscectomy in the treatment of lumbar-herniated disc with criteria for surgery. The study is currently in its phase 2 studies, which is sponsored by Kovacs Foundation and trials being carried out by NCT00566007. The study also evaluates the efficacy of infiltration in presence of corticoids, anesthetics, which is being compared by replacing O3 by oxygen.[3335]


Diabetic complications are attributed to the oxidative stress in the body, O3 was found to activate the antioxidant system affecting the level of glycemia. Ozone prevented oxidative stress by normalizing the organic peroxide levels by activating superoxide dismutase.[3637] Ozone was found to completely inactivate the HIV in vitro, this action of O3 was dose-dependent. Concentration used for inactivation was found to be non-cytotoxic. The inactivation was owing to the reduction of the HIV p24 core protein.[38] Ozone was also found to increase the host immunity by increasing the production of cytokine.[39] In an in vitro study, it was observed that O3 is very effective in reducing the concentrations of Acinetobacter baumannii, Clostridium difficile and methicillin-resistant Staphylococcus aureus in dry as well as wet samples, hence it can be used as a disinfectant. Oxygen/ O3 mixture was also found to prolong the appearance of arrhythmia induced by potassium chloride, aconitine, etc., in laboratory animals like rats.[40]


An array of ill-effects are observed owing to the reactivity of O3 viz oxidation, peroxidation or generation of free radicals and giving rise to cascade of reactions like peroxidation of lipids leading to changes in membrane permeability,[41] lipid ozonation products (LOP) act as signal transducer molecules.[42] The main reason for this being presence of unsaturated fatty acids in both lung lining fluid and pulmonary cell bilayers, O3 reacts with unsaturated fatty acids to give their specific products i.e., LOP, which activates the lipases triggering the release of endogenous mediators of inflammation.[43] The loss of functional groups in enzymes leading to enzyme inactivation. These reactions further results in cell injury or eventual cell death. Combinations of O3 and NO2 occur in photochemical smog, have hazardous effects on lung alveoli and act additively or synergistically. Dietary antioxidants or free radical scavengers like vitamin E, C, etc., can prevent aforementioned effects of O3.[4445]

In an in vitro study it was observed that arachidonic acid was oxidized in presence to O3 to give peroxides, viz. arachidonic acid peroxides (AAP), having activity comparable to prostaglandin endoperoxides. These peroxides were fond to show following actions contraction of rabbit aortic strips and rat fundus strips in presence on indomethacin and Vane’s mixture of vasoactive hormones at doses comparable to naturally formed prostaglandin peroxides. AAP also caused aggregation of human platelets in platelet-rich plasma, but these effects were not observed in presence of indomethacin and vitamin E, which indicated that these can be used to treat such toxicity of O3.[46]


Ozone was effectively used as an antibacterial agent to treat oral infections caused by Actinomyces naeslundii, Lactobacilli casei and Streptococcus mutans. Exposure of about 60 s exhibited 99.9% killing efficiency, but exposure for such a long period showed degradation of saliva proteins. So exposure of 10 s to 30 s was proved effective to kill significant number of bacteria.[47]

A single subcutaneous injection of O3 in mouse with spared nerve injury of the sciatic nerve was found to decrease the neuropathic pain-type behavior. Mechanism of this action is yet unclear but O3 was observed to regulate the expression of the genes that play vital role in onset and maintenance of allodynia.[48]


The authors would like to thank Mr. Deepak Ahire, Ex-lecturer of Pharmaceutical Chemistry, V.E.S. College of Pharmacy, for enlightening us with some key points on Ozone Therapy and for successful completion of the article.


Source of Support: Nil.

Conflict of Interest: None declared.


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Minimally Invasive Oxygen-Ozone Therapy for Lumbar Disk Herniation

  1. Cosma F. Andreulab,
  2. Luigi Simonettia,
  3. Fabio de Santisa,
  4. Raffaele Agatia,
  5. Renata Riccia and
  6. Marco Leonardia

+Author Affiliations

  1. aDepartment of Neuroradiology, Ospedale Bellaria, Bologna, Italy

  2. bOspedale Policlinico, Bari, Italy
  1. Address reprint requests to Marco Leonardi, MD, Servizio di Neuroradiologia, Ospedale Bellaria, Via Altura 3, 40139 Bologna, Italy


BACKGROUND AND PURPOSE: Oxygen-ozone therapy is a minimally invasive treatment for lumbar disk herniation that exploits the biochemical properties of a gas mixture of oxygen and ozone. We assessed the therapeutic outcome of oxygen-ozone therapy and compared the outcome of administering medical ozone alone with the outcome of medical ozone followed by injection of a corticosteroid and an anesthetic at the same session.

METHODS: Six hundred patients were treated with a single session of oxygen-ozone therapy. All presented with clinical signs of lumbar disk nerve root compression, with CT and/or MR evidence of contained disk herniation. Three hundred patients (group A) received an intradiscal (4 mL) and periganglionic (8 mL) injection of an oxygen-ozone mixture at an ozone concentration of 27 μg/mL. The other 300 patients (group B) received, in addition, a periganglionic injection of corticosteroid and anesthetic. Therapeutic outcome was assessed 6 months after treatment by using a modified MacNab method. Results were evaluated by two observers blinded to patient distribution within the two groups.

RESULTS: A satisfactory therapeutic outcome was obtained in both groups. In group A, treatment was a success (excellent or good outcome) in 70.3% and deemed a failure (poor outcome or recourse to surgery) in the remaining 29.7%. In group B, treatment was a success in 78.3% and deemed a failure in the remaining 21.7%. The difference in outcome between the two groups was statistically significant (P < .05).

CONCLUSION: Combined intradiscal and periganglionic injection of medical ozone and periganglionic injection of steroids has a cumulative effect that enhances the overall outcome of treatment for pain caused by disk herniation. Oxygen-ozone therapy is a useful treatment for lumbar disk herniation that has failed to respond to conservative management.

Noninvasive procedures, minimally invasive percutaneous injection, and surgery represent the gamut of treatments available in the management of lumbar disk herniation. Noninvasive treatments are plainly the first choice in most cases (1), but when patients fail to respond, minimally invasive percutaneous injection or surgery is warranted. Minimally invasive treatments were developed to offer good clinical results combined with a well-tolerated, low-cost procedure. In recent years, these procedures were further boosted by a growing number of reports of 5–20% treatment failure rate after surgical diskectomy, with failed back surgery syndrome in 15% of cases (29).

Oxygen-ozone therapy is one of the different minimally invasive treatments currently available (1013). It is used in medicine to treat different conditions (1415) and is based on exploiting the chemical properties of ozone, an unstable allotropic form of oxygen with the symbol O3 and a molecular weight of 48 kDa. A vast bibliography on the topic can be found in a recent study on how oxygen-ozone therapy works (16).

A reduction in herniated disk volume is one of the therapeutic aims of intradiscal administration of medical ozone, as disk shrinkage may reduce nerve root compression (17). Another reason for using medical ozone to treat disk herniation is its analgesic and antiinflammatory effects (1518).

In the wake of reports on the efficacy of periganglionic administration of steroids to treat pain from disk herniation (1922), we combined an intradiscal injection of medical ozone with subsequent periganglionic injection of a mixture containing a corticosteroid and an anesthetic in one group of patients.

We assessed the results obtained in treating 600 patients with oxygen-ozone therapy and compared the outcome in patients receiving medical ozone alone with that in patients who also received a corticosteroid and anesthetic mixture injected at the same session.


From January 1999 to March 2001, 600 patients aged 20–80 years were treated with a single session of oxygen-ozone therapy. The patients observed in this multicenter study had not been randomized, nor was the treatment compared with an accepted reference standard since ethical constraints precluded a randomized blind study design (23). These patients represent a consecutive sequence of patients who presented with lumbar disk herniation during the 2 years and who were judged not to be surgical candidates for clinical or anatomic reasons. Informed consent was obtained from all patients.

Three hundred patients (group A, Bellaria Hospital, Bologna, Italy) received an intradiscal (4 mL) and periganglionic (8 mL) injection of an oxygen-ozone mixture with an ozone concentration of 27 μg/mL. The other 300 patients (group B, Anthea Hospital, Bari, Italy) received identical oxygen-ozone injections, followed by a periganglionic injection of corticosteroid (1 mL of Depo-Medrone 40 mg [Pharmacia & Upjohn, Milan, Italy]) and anesthetic (2 mL of Marcain 0.5% [Biologici Italia Laboratories, Novate Milanese, MI, Italy]) at the same session. The oxygen-ozone gas mixture was obtained by using a Multiossigen PM95 generator (Multiossigen s.r.l., Gorle, BG, Italy).

Intradiscal and periganglionic injection was administered by means of an extraspinal lateral approach, using a 22-gauge 17.78-cm Becton Dickinson spinal needle (Quincke Type Point; Becton Dickinson & Co., Franklin Lakes, NJ), as used for discography under fluoroscopic guidance (group A) (122425) or CT guidance (group B) (26) (Fig 1), from the same side as the main location of symptoms. The gas mixture was injected by using a polypropylene syringe with the interconnection of a millipore filter (Fig 2). Time for injection was globally 15 seconds. A longer time is not suitable because of the unstable condition of medical ozone, which starts decaying (2 μg/mL) after about 20 seconds. No premedication or anesthesia was given to either group, and the procedure was performed at an outpatient facility. The L4–5 level was the most frequently treated (61.8%); L1–2, 0.7%; L2–3, 1.2%; L3–4, 8.7%; L5-S1, 27.6%.

FIG 1.

Puncture at L4-L5 performed under CT guidance.

FIG 2.

Injection of the oxygen-ozone mixture through a millipore filter.

Selection criteria for oxygen-ozone therapy were the following. Clinical criterion was low back pain resistant to conservative management (drugs, physiotherapy, and others), lasting at least 3 months. Neurologic criterion was low back pain with positive signs of nerve root involvement, with or without paraesthesia or hypaesthesia, with appropriate dermatome distribution. Neuroradiologic criteria were CT and/or MR evidence of contained disk herniation, in line with the patient’s clinical symptoms, with or without disk degeneration, and residues of surgical microdiskectomy with recurrent herniation.

Exclusion criteria for oxygen-ozone therapy were neuroradiologic evidence of disk prolapse or free fragments of herniated disk, and major neurologic deficit correlated to disk disease. In these cases, the patients underwent surgical treatment.

At the end of treatment, patients were advised to rest in supine decubitus position for 2 hours. All patients were discharged on the same day as treatment. On discharge, patients were instructed to gradually resume motor activity. All patients underwent follow-up examinations 2 weeks, 2 months, and 6 months after treatment.

Clinical outcome was assessed 6 months after treatment by applying the modified MacNab method (Table ) (827). Results were evaluated by two observers (R.R., F.d.S.) who were blinded to patient distribution within the two groups, by using a questionnaire and direct patient interviews. Statistical analysis was performed by means of the χ2 test.

View this table:

Modified MacNab method for assessing clinical outcome after oxygen-ozone therapy


Treatment was a success in 211 patients (70.3%) in group A and 235 patients (78.3%) in group B. In the remaining 89 patients (29.7%) in group A and 65 patients (21.7%) in group B, treatment was deemed a failure. The difference in outcome in the two groups was statistically significant at χ2 test (P < .05).

Among the group A patients whose treatment was a success, outcome was excellent in 151 patients (50.3%) and good in 60 (20%). Among the patients in group A whose treatment was a failure, this was poor in 75 (25%) and poor with recourse to surgery in 14 (4.7%) (Fig 3). Among the patients in group B whose treatment was a success, outcome was excellent in 160 cases (53.3%) and good in 75 (25%). Among the patients in group B whose treatment was a failure, this was poor in 50 (16.7%) and poor with recourse to surgery in 15 (5%) (Fig 3).

FIG 3.

Therapeutic outcome 6 months after oxygen-ozone therapy. Light gray bars indicate group A (n=300); dark gray bars, group B (n=300). Numbers at top of bars are percentages.

Complications occurred in two group B patients, who presented with episodes of impaired sensitivity in the lower limb ipsilateral to the treatment; the episode resolved spontaneously within 2 hours.


The appropriate treatment of lumbar sciatica and disk herniation is a challenge, particularly because the concept of a disk hernia represents only a simplification of the problem. So many largely unknown or poorly understood factors are involved in the pathophysiology of this disease that the right treatment is very difficult to pinpoint; this is the main reason so many treatments are continuously proposed. In addition, many specialists are convinced that conservative treatment offers the same level of results, if checked at a late follow-up, with surgery being undertaken less frequently. In this setting, attention has focused on minimally invasive treatments. Our study addressed the use of an oxygen-ozone mixture, the least invasive technique currently available.

Oxygen-ozone therapy exploits the chemical properties of ozone, an unstable allotropic form of oxygen with the symbol O3 and a molecular weight of 48 kDa. Many biologic effects have been attributed to ozone: increased glycolysis (28); effects on red blood cells (2930); effects on rheology (31); bactericidal, fungicide, and virustatic (28); immunomodulating action (2932); and analgesic and antiinflammatory effects (1518). This broad spectrum of action explains the many indications for medical ozone administration (14).

The dose of ozone administered is crucial (33) and must not exceed the capacity of antioxidant enzymes (superoxide dismutase and catalase)and glutathione to prevent accumulation of the superoxide anion (O2-) and hydrogen peroxide (H2O2) (3436), which can cause cell membrane degradation (3337). Free radicals are mainly formed by ozone in a medium with a pH higher than 8, whereas at a pH less than 7.5 the ozonolysis mechanism prevails, mainly leading to the formation of peroxides (3538).

In oxygen-ozone therapy, ozone is administered in the form of an oxygen-ozone gas mixture, medical ozone, at nontoxic concentrations varying from 1 to 40 μg of ozone per milliliter of oxygen (14). Empirical studies performed in vivo on rabbits and in vitro on resected human disk specimens have demonstrated that for intradiscal administration the optimal concentration of ozone per milliliter of oxygen is 27 μg. At this concentration, ozone has a direct effect on the proteoglycans composing the disk’s nucleus pulposus, resulting in its release of water molecules and subsequent cell degeneration of the matrix, which is replaced by fibrous tissues in the space of 5 weeks and the formation of new blood cells. Together, these events result in a reduction in disk volume (15).

In our series, these effects were confirmed in five histologic disk specimens removed during surgical microdiskectomy from patients who had received intradiscal injections of medical ozone at a concentration of 27 μg/mL. The specific feature of oxygen-ozone therapy noted in these specimens was dehydration of the fibrillary matrix of the nucleus pulposus, revealing collagen fibers and signs of regression (vacuole formation and fragmentation)—a sort of disk “mummification.” The other findings such as chondrocyte hyperplasia at the lesion margin, proliferating and large, and signs of new blood cell formation accompanied by mainly lymphocyte inflammatory tissue are commonly encountered at histopathologic examination of a herniated disk not treated with medical ozone (39) (Fig 4). A reduction in herniated disk volume is one of the therapeutic motives for intradiscal administration of medical ozone, as a reduction in disk size may reduce nerve root compression (17). Disk shrinkage may also help to reduce venous stasis caused by disk compression of vessels, thereby improving local microcirculation and increasing the supply of oxygen. This effect has a positive effect on pain as the nerve roots are sensitive to hypoxia. Another reason for using medical ozone to treat disk herniation is its analgesic and antiinflammatory effects (1518), which may counteract disk-induced pain (4041). This action is correlated to inhibited synthesis of proinflammatory prostaglandins or release of bradykinin or release of algogenic compounds; increased release of antagonists or soluble receptors able to neutralize proinflammatory cytokines like interleukin (IL)-1, IL-2, IL-8, IL-12, IL-15, interferon-α, and tumor necrosis factor-α; and increased release of immunosuppressor cytokines like transforming growth factor-β1 and IL-10 (1518).

FIG 4.

A, Low-magnification photomicrograph of histologic specimen of the intervertebral disk shows chronic inflammatory infiltrate (hematoxylin & eosin stain; original magnification, × 4).

B, Higher magnification photomicrograph of histologic disk specimen discloses the lymphocytic nature of the infiltrate (hematoxylin & eosin stain; original magnification, × 10).

In the wake of literature reports on the efficacy of periganglionic administration of steroids to treat disk-induced pain (1922), this study combined intradiscal injection of medical ozone with subsequent periganglionic injection of a corticosteroid and anesthetic mixture (group B) and compared the outcome to findings in patients receiving intradiscal ozone injection alone (group A). The mechanisms underlying the periganglionic administration of steroids are correlated to both the substance administered and the strategic role of the spinal ganglion in causing and transmitting pain (144244). Therapeutic outcome evaluated 6 months after treatment was a success in 70.3% of group A patients and 78.3% of group B patients, whereas the failure rate was 29.7% in group A and 21.7% in group B. Group B therefore presented a cumulative effect of corticosteroid and ozone effects that enhanced the therapeutic success rate. The combined intradiscal and periganglionic injection of medical ozone and periganglionic injection of a corticosteroid is thought to affect both the mechanical and inflammatory components of pain caused by disk herniation, enhancing the effect of periganglionic injection of steroids alone (1922).

In our group B patients, anesthetic administration may have led to early improvement in pain, as most patients with an excellent or good outcome had a clinical course as follows: 1) immediate total or partial remission of pain, 2) stability or mild worsening of pain in the subsequent 2 weeks, and 3) a second improvement phase in the space of 6–8 weeks. The initial phase of immediate pain relief was much less evident in group A patients in whom symptoms improved gradually.

Comparison of our results with those of other percutaneous treatments for disk herniation indicates that the outcome in our series was satisfactory. In particular, our success rates are similar to those of enzymatic chemonucleolysis (574546). This is important as these two procedures are similar, although oxygen-ozone therapy is less invasive for the following reasons: the needle used is narrower and hence less traumatic; there are no allergic or anaphylactic reactions (0.5% and 0.05%, respectively) and hence premedication is not required; discomfort after treatment and recommended bed rest are 2–3 days compared with the 1–2 weeks advised after enzymatic chemonucleolysis; and treatment can be repeated. Also, ozone has a well known antiseptic activity, reducing the risk of infectious complications (25).

The patients in our series who failed to benefit from oxygen-ozone therapy subsequently underwent surgery. In all cases, the previous oxygen-ozone treatment had no negative effect on the surgical procedure. The complications we encountered in two of our group B patients are thought to have been caused by the periganglionic injection of anesthetic.


Our study provides evidence that the combined intradiscal and periganglionic injection of medical ozone and periganglionic injection of steroids has a cumulative effect that enhances the overall outcome of treatment. For this reason, oxygen-ozone therapy is an option to treat lumbar disk herniation that has failed to respond to conservative management, before recourse to surgery or when surgery is not possible.


  • Received July 9, 2002.
  • Accepted after revision October 23, 2002.

Articles citing this article

1/ Ozone is AntiAging (some of those AntiAging effects can be attributed to the following list of actions…)

2/ Ozone Increases Oxygenation of your Cells (it has been proven that cancer and disease grow in poorly oxygenated tissues in your body).
3/ Ozone Modulcates your Immune System (for those with a weakened immune system, Ozone will boost the immune system. For those with Auto-Immune Disorders, Ozone will modulate the immune system to help to stop it from attacking healthy human cells.)
4/ Ozone Increases Energy Production in your Cells (your cells need energy to be healthy; low energy levels mean that you and your cells will not be healthy and will age)
5/ Ozone Increases the Activity of your “Anti-Oxidant Enzyme Systems”. This means ozone will reduce the oxidation levels of your body.
6/ Ozone Reduces the level of acidity of your body (never mind the Alkaline Water…use Ozone!)
7/ Ozone kills Bacteria, Viruses (and virtually all other disease causing organisms) on contact
8/ Ozone Kills Cancer cells on contact

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