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Ozone Therapy References

Please find this comprehensive list of studies on therapeutic uses of Ozone:

Safety

Note: many RCT also include side effects experience. In general there are minimal (if any at all) side effects from the treatment.

1) Martínez-Sánchez G, Delgado-Roche L, Díaz-Batista A, Pérez-Davison G, Re L.Effects of ozone therapy on haemostatic and oxidative stress index in coronary artery disease. Eur J Pharmacol. 2012 Sep 15;691(1-3):156-62.

• Improved prothrombin time, antioxidant status (reduced biomarkers protein/lipid oxidation), decs SOD and catalase activity. No S/E.

2) Bo W, Longyi C, Jian T, Guangfu H, Hailong F, Weidong L, Haibin T. A pyogenic discitis at c3-c4 with associated ventral epidural abscess involving c1-c4 after intradiscal oxygen-ozone chemonucleolysis: a case report. Spine (Phila Pa 1976). 2009 Apr 15;34(8):E298-304.

• Case: O2-O3 therapy injections at discs btw C3-C4, C4-C5, and C6-C7. 5 days later went to emerge.

3) Biedunkiewicz B, Lizakowski S, Tylicki L, Skiboeska A, Nieweglowski T, Chamienia A, Debska-Slizien A, Rutkowski B. Blood coagulation unaffected by ozonated autohemotherapy in patients on maintenance hemodialysis. Arch Med Res. 2006 Nov;37(8):1034-7.

• O(3)-AHT with ozone concentration of 50 microg/mL and citrate as an anticoagulant does not influence blood coagulation parameters in hemodialyzed patients with PAOD.

Uses

Systemic Ozone - Major Autohemotherapy (MAH)

1) Re L, Martínez-sánchez G, Bordicchia M, et al. Is ozone pre-conditioning effect linked to Nrf2/EpRE activation pathway in vivo? A preliminary result. Eur J Pharmacol. 2014;742:158-62.

• MAH: after 3 Tx showed activation of the Nrf2 pathway by a low dose of ozone and the promotion of the feedback mechanism that induces the synthesis of proteins which collectively favors cell survival.

2) Clavo B, Santana-Rodriguez N, Gutierrez D, et al. Long-term improvement in refractory headache following ozone J Altern Complement Med. 2013;19(5):453- 458.

• MAH Trial: Decreased refractory HA in 5 patients

3) Sönmez O, Külahlı I, Vural A, Sahin MI, Aydın M. The evaluation of ozone and betahistine in the treatment of tinnitus. Eur Arch Otorhinolaryngol. 2013; 270(7):1999-2006.

• MAH: 10 Tx for tinnitus was ineffective compared to control after 3 and 6 months

4) Borrelli E, Diadori A, Zalaffi A, Bocci V. Effects of major ozonated autohemotherapy in the treatment of dry age related macular degeneration: a randomized controlled clinical study. Int J Ophthalmol. 2012;5(6):708-713.

• MAH: Clinical trial with dry age related macular degeneration patients, showed improvement in degeneration scores compared to control group decreasing scores after 6 months and 12 months with 2-3 Tx/ month.

5) Ciborowski M, Lipska A, Godzien J, et al. Combination of LC-MS- and GC-MSbased metabolomics to study the effect of ozonated autohemotherapy on human blood. J Proteome Res. 2012;11(12):6231-6241.

• MAH Safety Risk: Ozonated blood in PVC bags stimulates leaching (No full text, “blood stored in PVC bags”, unsure how long the blood was stored before analysis by LC-MS and GC-MS). PVC is known to be an ozone resistant material, but ozonation of blood in PVC bags stimulates leaching of plasticizers into the blood

6) Zaky S, Kamel SE, Hassan MS, et al. Preliminary results of ozone therapy as a possible treatment for patients with chronic hepatitis C. J Altern Complement Med. 2011;17(3):259-263.

• MAH + minor AH + Rectal insufflation: Clinical trial HVC patients, improved Sx, ALT+AST vs controls and increased negative HVC RNA titers (by PCR) after 30-60 Tx

7) Biedunkiewicz B, Lizakowski S, Tylicki L, et al. Blood coagulation unaffected by ozonated autohemotherapy in patients on maintenance hemodialysis. Arch Med Res. 2006;37(8):1034-7.

• MAH using citrate dextrose anticoagulant ineffective at influencing blood coagulation parameters in hemodialyzed patients with PAOD.

8) Larini A, Bocci V. Effects of ozone on isolated peripheral blood mononuclear cells. Toxicol In Vitro. 2005;19(1):55-61.

• MAH in vitro: Overall cytokines decreased at 40 gamma+. Ozone reduced IL-4 Expression, no change to IL-6. Low [O3] slightly stimulated TNF-a and IFN-y while higher [ ] inhibit them.

9) Giunta R, Coppola A, Luongo C, et al. Ozonized autohemotransfusion improves hemorheological parameters and oxygen delivery to tissues in patients with peripheral occlusive arterial disease. Ann Hematol. 2001;80(12):745-748.

• MAH: Clinical trial for POAD patients, oxidation markers showed MAH may be useful to improve both the poor rheological properties of the blood and the oxygen delivery to tissues in patients suffering from POAD

10) Bocci V, Valacchi G, Corradeschi F, et al. Studies on the biological effects of ozone: 7. Generation of reactive oxygen species (ROS) after exposure of human blood to ozone. J Biol Regul Homeost Agents. 1998;12(3):67-75.

• MAH: 100 gamma O3 per g blood induces cytokines TNF-alpha, IFNgamma and IL-2, one limitation is in heparinized blood 03 at [ ] of 40+ gamma can cause platelet aggregation

10a) References for Simonetti MAH protocol: PMIDs 27734309, 25280029, 24111149

11) Molinari, F., et al. “Ozone Autohemotherapy Induces Long-Term Cerebral Metabolic Changes in Multiple Sclerosis Patients.” International Journal of Immunopathology and Pharmacology, vol. 27, no. 3, 2014, pp. 379–389., doi:10.1177/039463201402700308.

● MAH: Controlled Trial of 54 subjects

● Near-infrared spectroscopy (NIRS) to monitor cerebral metabolism and transcranial Doppler (TCD) to measure blood flow velocity

● The concentration of oxygenated haemoglobin 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 significant changes were observed on the blood flow velocity

● 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

12) Akbudak, Ismail Hakki, et al. “Investigation of the Effects of Major Ozone Autohemotherapy Application on Erythrocyte Deformability and Aggregation.” Clinical Hemorheology and Microcirculation, 2018, pp. 1–8., doi:10.3233/ch180417.

● Compared with the Control value, there was a significant increase in TOS, TAS for the doses of 10 and 50μg/ml. The increase in TAS was found to be more significant at 10μg/ml dose

● Ozone at 10 and 50μg/ml doses did not alter erythrocyte aggregation

● 50μg/ml ozone increased red blood cell (RBC) deformability measured at 0.53 Pa

● The most obvious increase in OSI value was observed at 50μg/ml.

IV Ozonated Saline

1) Gadzhiev ND, Sushkov SV, Klimova EM, Kordon TI. [Comparative estimation of efficacy of the immunecorrecting combined three- level cytokino- and ozonotherapy in complex treatment of extended peritonitis]. Klin Khir. 2013;(5):10-3.

• O3 Saline IV: Clinical Trial Peritonitis patients , improved immunomodulation in combo with basic Tx

2) Belianin II, Shmelev EI. [Ozone therapy for protracted pneumonias]. Probl Tuberk Bolezn Legk. 2009;(3):28-33.

• O3 Saline IV: 6 Tx over 3 weeks (400 mL) produced sputum negative reaction against Chlamydia and Mycoplasma 2-3 weeks earlier in combo with antibiotics compared to control antibiotic pneumonia patients, as well as improved Sx.

3) Fedorov AA, Gromov AS, Sapronenok SV, Kurochkin VIu, Zhernakova ZM. [Ozone therapy in gastroduodenal pathology associated with Helicobacter pylori]. Vopr Kurortol Fizioter Lech Fiz Kult. 2006;(6):34-7.

• O3 Saline IV: IV as well as oral intake of ozonized low-mineral water, and combination of the two treatments proved effective in relation to regress of clinical symptoms, regeneration processes, eradication of Helicobacter pylori, but the combined regimen was the best.

Rectal Ozone Insufflation

1) Sahin H1, Simsek T1, Turkon H2, Kalkan Y3, Ozkul F4, Ozkan MT5, Erbas M6, Altinisik U1, Demiraran Y7.The acute effects of preoperative ozone therapy on surgical wound healing. Acta Cir Bras. 2016 Jul;31(7):472-8.

• Intestinal Insufflation: Rabbit model surgical wound treated with ozone significantly better vs. controls. Measures at 72 hours post. tx: signif lower TNF-alfa, IL-6 levels increase angiogenesis, decs inflammatory cells, epidermal and dermal regeneration, better collagen deposition, increased keratinisation in stratum corneum

2) Aslaner A1, Çakır T1, Tekeli SÖ2, Avcı S3, Doğan U1, Tekeli F2, Soylu H3, Akyüz C4, Koç S5, Üstünel İ3, Yılmaz N. Medical ozone treatment ameliorates the acute distal colitis in rat. Acta Cir Bras. 2016 Apr;31(4):256-63.

• Intestinal Insufflation: animal model, rats. acute distal colitis - treated 3 weeks O3 rectally and intraperitoneally O3 vs. controlled showed improved healing: increase in tissue MDA, MPO activity, TNF-α and IL1β, difference at immunostaining densities of histopathological examination

3) León Fernández OS1, Viebahn-Haensler R2, Cabreja GL3, Espinosa IS3, Matos YH4, Roche LD5, Santos BT4, Oru GT4, Polo Vega JC4.Medical ozone increases methotrexate clinical response and improves cellular redox balance in patients with rheumatoid arthritis. Eur J Pharmacol. 2016 Oct 15;789:313-8.

• Intestinal Insufflation

4) Aslaner A1, Çakır T1, Çelik B2, Doğan U1, Mayir B1, Akyüz C3, Polat C4, Baştürk A5, Soyer V6, Koç S6, Şehirli AÖ7. Does intraperitoneal medical ozone preconditioning and treatment ameliorate the methotrexate induced nephrotoxicity in rats? Int J Clin Exp Med. 2015 Aug 15;8(8):13811-7. eCollection 2015.

• Intestinal Insufflation: O3 25mcg/mL (5mL) intraperitoneally daily. Significant amelioration of nephrotoxicity MOA: via activating antioxidant enzymes.

5) Clavo B1, Santana-Rodriguez N2, Llontop P3, Gutierrez D4, Ceballos D5, Méndez C3, Rovira G6, Suarez G4, Rey-Baltar D4, Garcia-Cabrera L7, MartínezSánchez G8, Fiuza D3. Ozone Therapy in the Management of Persistent Radiation-Induced Rectal Bleeding in Prostate Cancer Patients. Evid Based Complement Alternat Med. 2015; 2015:480369

• Intestinal Insufflation: Radiation-induced proctitis and rectal bleeding from radiation rectal insufflation vs. topical oil. (further results not in abstract) O3 effective and safe.

6) Hidalgo-Tallón J1, Menéndez-Cepero S, Vilchez JS, Rodríguez-López CM, Calandre EP. Ozone therapy as add-on treatment in fibromyalgia management by rectal insufflation: an open-label pilot study. J Altern Complement Med. 2013 Mar;19(3):238-42

• Intestinal Insufflation: 24 sessions. 5 days / week for 2 weeks, then 2x/week weeks 3-6, weekly weeks 7-12 of O3 8mg (200mL @ 40 mcg/mL) rectal insufflation improvements in first 4 weeks Fibro impact questionnaire, PSQI, SF-12, BDI reported S/E transient abd distension.

7) Martínez-Sánchez G, Delgado-Roche L, Díaz-Batista A, et al. Effects of ozone therapy on haemostatic and oxidative stress index in coronary artery disease. Eur J Pharmacol. 2012; 691(1-3):156-162.

• Intestinal Insufflation: Improved the antioxidant status of CAD patients reducing biomarkers of protein and lipid oxidation. Medical ozone treatment could be a complementary therapy in the treatment of CAD and its complications.

Injections - SubQ, IM, Periapical, Intraairticular

1) Lu L., Pan C, Chen L, Hu L, Wang C, Han Y, Yang Y, Cheng Z, Liu WT. AMPK activation by peri-sciatic nerve administration of ozone attenuates CCI-induced neuropathic pain in rats. J Mol Cell Biol. 2016 Oct 15.

• IM injection: Rat model. Peri-sciatic nerve O3 injection decreased pain and thermal hyperplasia.

2) Giombini A., Menotti F., Di Cesare A., Giovannangeli F., Rizzo M., Moffa S., Martinelli F.Comparison between intrarticular injection of hyaluronic acid, oxygen ozone, and the combination of both in the treatment of knee osteoarthrosis. J Biol Regul Homeost Agents. 2016 Apr-Jun;30(2):621-5

• Knee O3 + hyaluronic acid injections improved VAS pain scale and KOOS questionnaire vs. hyaluronic acid alone

3) Karatieieva S., Yurkiv O., Semenenko S., Kozlovskaya I., Yakobchuk S. Evaluation of the use of ozone therapy in treatment of inflammatory processes in diabetes mellitus in an experiment. Georgian Med News. 2016 Oct;(259):58- 61.

• Unsure of method O3 used (full access needed)

• Rat model with diabetes and subcutaneous abscess.

• O3 tx did NOT show protective properties (their measures are unclear) - azoalbumin lysis, total non-enzymatic fibrinolytic activity, proteinase activity.

4) Chen H, Yu B, Lu C, Lin Q. The effect of intra-articular injection of different concentrations of ozone on the level of TNF-α, TNF-R1, and TNF-R2 in rats with rheumatoid arthritis.Rheumatol Int. 2013;33(5):1223-1227.

• Intra-articular for RA

• Outcomes: decs joint cytokines TNF alpha, R2, incs TNF R1, Decs thickness

5) Zhang Y, Ma Y, Jiang J, et al. Treatment of the lumbar disc herniation with intradiscal and intraforaminal injection of oxygen-ozone. J Back Musculoskelet Rehabil. 2013;26(3):317-322

• Intraforaminal injections for herniated disc.

• Pain rating VAS and JOA score: No diff btw O2+O3 vs O3+steroid

6) Daif ET. Role of intra-articular ozone gas injection in the management of internal derangement of the temporomandibular joint. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113(6):e10-e14.

• Intra-TMJ injection: 2mL O2+O3 (10 microg/mL) 2x/wk for 3 weeks. Outcome: completely recovered or improved 50% vs. NSAID + muscle relaxants.

7) Magalhaes FN, Dotta L, Sasse A, et al. Ozone therapy as a treatment for low back pain secondary to herniated disc: a systematic review and meta-analysis of randomized controlled trials. Pain 2012;15(2):E115-E129.

• Percutaneous, intradiscal O3 decs pain for chronic LBP

8) Melchionda D, Milillo P, Manente G, et al. Treatment of radiculopathies: a study of efficacy and tollerability of paravertebral oxygen-ozone injections compared with pharmacological anti-inflammatory treatment. J Biol Regul Homeost Agents. 2012;26(3):467-474.

• Paravetebral injections. Measures: MRI, EMG, pain VAS, ODI. Decreased pain after 1 week O3 inject. 80% of px had no pain @6 months.

9) Rahimi-Movaghar V, Eslami V. The major efficient mechanisms of ozone therapy are obtained in intradiscal procedures. Pain 2012;15(6):E1007-E1008.

• RCT Meta analysis. Tx for low back pain and herniated disc. Ozone effects: anti-inflammatory decreases arachidonic acid, increase oxygenation to the area, oxidization breaks down glycosaminoglycan chains decs. amount of water in pulpous thus decreasing size of herniation, stimulates fibroblastic activity and increases collages deposition.

10) Rodríguez ZZ, Guanche D, Alvarez RG, Martinez Y, Alonso Y, Schulz S. Effects of ozone oxidative preconditioning on different hepatic biomarkers of oxidative stress in endotoxic shock in mice. Toxicol Mech Methods. 2011 Mar;21(3):236- 40.

• Intraperitoneal injections: Restore the redox balance induced by endotoxemia. SOD, glutathione peroxidase, GST analyzed and better w preconditioning of O3.

11) Alberto P.O. Ozone the one and only drug. Acta Neurochir Suppl. 2011;108:143-146.

• Fluoroscopic (x-ray) control intradiscal and periganglionic

12) Guanche D, Hernandez F, Zamora Z, Alonso Y. Effect of ozone pre-conditioning on redox activity in a rat model of septic shock. Toxicol Mech Methods. 2010 Oct;20(8):466-71.

• Animal Model Intraparatoneal injections: O3 protected liver and lung for oxidative stress in septic shock. Decs levels of pro-inflammatory markers in Lung and Liver.

13) Fuccioa C., Luongob C., Capodannob C., Giordanoa C., Scafuroa M.A., Siniscalcoa D., Lettierib B., Rossia F., Maionea S., Berrinoa L. A single subcutaneous injection of ozone prevents allodynia and decreases the overexpression of pro-inflammatory caspases in the orbito-frontal cortex of neuropathic mice. European Journal of Pharmacology 2009; 603(1-3): 42-49.

• Subcutaneous injections: Decs pain and inflammation.

14) Fuccio C, Luongo C, Capodanno P, et al. A single subcutaneous injection of ozone prevents allodynia and decreases the over-expression of proinflammatory caspases in the orbito-frontal cortex of neuropathic mice. Eur J Pharmacol. 2008;603:42–49.

• Subcutaneous injections

15) Bonetti M, Fontana A, Cotticelli B, et al. Intraforaminal O(2)-O(3) versus periradicular steroidal infiltrations in lower back pain: randomized controlled study. Am J Neuroradiol. 2005;26(5):996-1000.

• CT-guided intraforaminal infiltration of an O(2)-O(3) gas mixture vs. periradicular infiltration of steroids. Better pain reduction for O3 in px with disc dz and fewer px with poor outcome without disc dz.

16) Rowen, Robertjay. “Ozone Therapy in Conjunction with Oral Antibiotics as a Successful Primary and Sole Treatment for Chronic Septic Prosthetic Joint: Review and Case Report.” Medical Gas Research, vol. 8, no. 2, 2018, p. 67., doi:10.4103/2045-9912.235139.

● Case Study: Septic hip responding to intra-articular ozone injection

17) Niu, Tong, et al. “Therapeutic Effect of Medical Ozone on Lumbar Disc Herniation.” Medical Science Monitor, vol. 24, 2018, pp. 1962–1969., doi:10.12659/msm.903243.

● A total of 80 patients were included and were grouped into a control group, a low medical ozone (20 μg/ml) group, a medium medical ozone (40 μg/ml) group, and a high medical ozone (60 μg/ml) group.

● The CT scan and enzyme-linked immunosorbent assay (ELISA) were used to detect IL-6 level, SOD activity, IgM, and IgG levels upon admission and at 6 and 12 months after follow-up

● CONCLUSIONS Low concentrations of medical ozone (20 μg/ml and 40 μg/ml) reduced the serum IL-6, IgG, and IgM expression, presenting as analgesic and anti-inflammatory effects, while high concentrations of medical ozone (60 μg/ml) increased the serum IL-6, IgG, IgM expression, presenting as pain and pro-inflammatory effects. The medical ozone concentration of 40 μg/ml showed the optimal treatment efficacy.

18) Li, Qingsong, et al. “Intra-Articular Oxygen-Ozone versus Hyaluronic Acid in Knee Osteoarthritis: A Meta-Analysis of Randomized Controlled Trials.” International Journal of Surgery, vol. 58, 2018, pp. 3–10., doi:10.1016/j.ijsu.2018.08.007.

● A total of four RCTs including 289 patients were included.

● The present meta-analysis indicated that there was a significant difference between groups regarding the visual analog scale (VAS) and WOMAC stiffness and function.

● The improvements in WOMAC pain were similar. No significant difference in adverse events occurrence was observed.

19)Wang, Xiangjiang, et al. “Effectiveness of Intra‑Articular Ozone Injections on Outcomes of Post‑Arthroscopic Surgery for Knee Osteoarthritis.” Experimental and Therapeutic Medicine, 2018, doi:10.3892/etm.2018.6101.

● The present study retrospectively evaluated 80 patients with symptomatic knee OA (Kellgren-Lawrence grade II or III), who either did or did not receive 20 ml of 20 µg/ml ozone as an intra-articular injection after arthroscopic surgery.

● The minimum follow-up period was 12 months. The outcomes evaluated for knee OA were pain on the Visual Analogue Scale (VAS), Lequesne Index, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Clinical Global Impression (CGI).

● The VAS score in the ozone group was significantly better than that in the control group at all post-operative follow-up time-points (P<0.05). The ozone group also exhibited a significantly greater improvement in Lequesne Index scores (P<0.05). In the ozone group, the score on the WOMAC-pain, WOMAC-stiffness and WOMAC-function subscales, as well as the total WOMAC score decreased significantly (P<0.05)

● The present study suggests that intra-articular ozone injections after arthroscopic surgery may effectively improve the outcomes of arthroscopic surgery in terms of pain relief, functional improvement and quality of life in patients with knee OA of Kellgren-Lawrence grade II or III.

Miscellaneous Ozone Applications

1) Zhou Y.T., Zhao X.D., Jiang J.W., Li X.S., Wu Z.H. Ozone Gas Bath Combined with Endovenous Laser Therapy for Lower Limb Venous Ulcers: A Randomized Clinical Trial. J Invest Surg. 2016 Oct;29(5):254-9.

• RCT: Endovenous laser therapy vs. ozone gas bath on limb first then EVLT. Follow up 12 months improved healing of venous ulcer, lower recurrence ratio for O3+EVLT

2) Kist S, Kollmuss M, Jung J, Schubert S, Hickel R, Huth KC. Comparison of ozone gas and sodium hypochlorite/chlorhexidine two-visit disinfection protocols in treating apical periodontitis: a randomized controlled clinical trial. Clin Oral Investig. 2016 May 12

• Single blinded RCT. O3 gas (32 g m-3) topical application vs. NaOCl (3%) with standard dressing. No significant differences found.

3) Bayrak O., Erturhan S., Seckiner I., Erbagci A., Ustun A., & Karakok M. Chemical cystitis developed in experimental animals model: Topical effect of intravesical ozone application to bladder. Urol Ann. 2014 Apr-Jun; 6(2): 122–126.

• Rabbit models. Cystitis, ozone admin intravesical 2x/week showed basal membrane and mucosal integrity were maintained, inflammatory cells were suppressed. Control group showed mucosal integrity was spoiled and accumulation of inflammatory cells

4) Neimark AI, Nepomnyashchikh LM, Lushnikova EL, Bakarev MA, Abdullaev NA, Sizov KA. Microcirculation and structural reorganization of the bladder mucosa in chronic cystitis under conditions of ozone therapy. Bull Exp Biol Med. 2014 Jan;156(3):399-405.

• O3 tx improves microcirculation in bladdar mucosa

5) Rahimi S., Janani M., Lotfi M., Shahi S., Aghbali A., Pakdel MV., Milani AS., Ghasemi N. A Review of Antibacterial Agents in Endodontic Treatment. Iranian Journal

• Ozone typically used for antimicrobial properties

6) Magalhães FN1, Soares SC, Torres JM, Ungaretti A, Cacciacarro MF, Teixeira MJ, Fonoff ET. Effects of ozone applied by spinal endoscopy in patients with chronic pain related to failed back surgery syndrome: a pilot study. Neuropsychiatr Dis Treat. 2013;9:1759-66

• Ozone gas in the lumbar epidural space via spinal-sacral endoscopy. Overall at 6 months px had 44% decs lumbar pain, 61% decs leg pain , 44% improvement on ODI

7) Clavo B, Ceballos D, Gutierrez D, et al. Long-term control of refractory hemorrhagic radiation proctitis with ozone therapy. J Pain Symptom Manage. 2013;46(1):106-112.

• Persistent/severe hemorrhagic radiation - Hx prostate/uterine cancer. Rectal insufflation + topical ozonated oil. Significant improvement with O3 tx. follow up 3-56 months (average 40 months).

8) Bertolotti, A., Izzo, A., Grigolato, P.G., Letizia labichella, M. . The use of ozone therapy in Buruli ulcer had an excellent outcome. BMJ Case Rep. 2013; Published online 2013 Jan 31.

• Ozone 4x/week limb bagged with 30 mcg/mL + sterile topical application. Significant improvement after 2 weeks. 6 month follow up - healed.

9) Halbauer K, Prskalo K, Janković B, et al. Efficacy of ozone on microorganisms in the tooth root canal. Coll Antropol. 2013;37(1):101-107.

• Topical: post root canal 40s exposure to ozone. Significant decs bacteria Streptococcus and Propionibacterium acnes

10) Zaki BM, Abbas E.,Osman N., Elshahat A., Hussein A., Shadia El Rafei S. Evaluation of the Effect of Ozonized Water on Periodontium of Diabetic Rats. Der Pharmacia Sinica, 2012, 3 (1):31-40.

• Topical O3 to gingivitis & periodontitis. Outcome: No difference in cementum thickness. Increased bone cells with decreased bone cells with prolonged O3 exposure. Prolonged use shows structural change

11) Dähnhardt JE, Gygax M, Martignoni B, et al. Treating sensitive cervical areas with ozone. A prospective controlled clinical trial. Am J Dent. 2008;21(2):74-76.

• Tx hypersensitive teeth with gas O3 60seconds decs pain immediately 55%. No difference in pain O3 vs. control over time 0-22 weeks

12) Chang JD, Lu HS, Chang YF, Wang D. Ameliorative effect of ozone on cytokine production in mice injected with human rheumatoid arthritis synovial fibroblast cells.Rheumatol Int. 2005;26(2):142-151.

• Immunemodulator, cellular metabolic activator, AI, 3% , 5% ozone applied externally.

13) Valacchi G1, Fortino V, Bocci V. The dual action of ozone on the skin.Br J Dermatol. 2005 Dec;153(6):1096-100.

• Sauna and oil topically prove to improve chronic wounds

14) Muminov, AI, Khushvakova NZh. Ozone therapy in patients with chronic purulent frontal sinusitis. Vests Otorinolaringol. 2002; 46(6).

• Irrigation of sinuses with O2-O3 mixture. 5-7x. 89% tx group recovered faster (article in Russian)

15) Petrov GM, Kudriavtsev BP, Akulich, II. The efficacy of using ozone preparations in the combined treatment of paranasal sinusitis. Von Med Zh. 1996; 317(12):26-8,80.

• irrigation of the paranasal sinuses with ozone-oxygen mixture. 89% recovered quicker (article in Russian)

16) Amin, Laila E. “Biological Assessment of Ozone Therapy on Experimental Oral Candidiasis in Immunosuppressed Rats.” Biochemistry and Biophysics Reports, vol. 15, 2018, pp. 57–60., doi:10.1016/j.bbrep.2018.06.007.

● Animal study

● 60 rats immunosuppressed by dexamethasone and then divided into 4 groups

● Inoculated with candida albicans on the tongue

● Histological examination revealed that treatment with ozone therapy lead to gradual decrease in lingual papillary atrophy and invasion of candida yeast. Immunohistochemical study showed significant decrease in CD3 counting

17) Isler, Sila Cagri, et al. “The Effects of Ozone Therapy as an Adjunct to the Surgical Treatment of Peri-Implantitis.” Journal of Periodontal & Implant Science, vol. 48, no. 3, 2018, p. 136., doi:10.5051/jpis.2018.48.3.136.

● A total of 41 patients (22 males, 19 females; mean age, 53.55±8.98 years) with moderate or advanced peri-implantitis

● Ozone group vs. control (saline

● At the 12-month follow-up, the plaque and gingival index values were significantly better in the ozone group (P<0.05)

18) Rowen, Robert Jay. “Remission of Aggressive Autoimmune Disease (Dermatomyositis) with Removal of Infective Jaw Pathology and Ozone Therapy: Review and Case Report.” Autoimmunity Highlights, vol. 9, no. 1, 2018, doi:10.1007/s13317-018-0107-z.

● Case report of 48 year old male

19) Menéndez, S., et al. “Efficacy of Ozonized Sunflower Oil in the Treatment of Tinea Pedis.” Mycoses, vol. 45, no. 7-8, 2002, pp. 329–332., doi:10.1046/j.1439- 0507.2002.00780.x.

● in a controlled randomized phase III assay, comparing topical Oleozon with ketoconazole cream 2% (Nizoral) in 200 patients (100 in each group)

● The treatment administered was twice per day for a period of 6 weeks. The efficacy was evaluated clinically (disappearance of all lesions, with or without negative mycological results) and mycologically (negative culture results). A complete clinical and mycological cure was obtained in 75 and 81% for Oleozon and ketoconazole, respectively, with no significant differences between both groups. No side-effects or bacterial superinfections were observed

20) Fitzpatrick, Erin, et al. “Ozone Therapy for the Treatment of Chronic Wounds: A Systematic Review.” International Wound Journal, vol. 15, no. 4, 2018, pp. 633– 644., doi:10.1111/iwj.12907.

● Nine studies (n = 453 patients) matched the inclusion criteria

● Results consistently favour the application of ozone as a treatment for chronic wounds; however, there is no conclusive evidence of ozone therapy as superior compared with standard treatments. Compared with standard care, ozone therapy as an advanced wound care treatment may improve the proportion of chronic wounds healed in a shorter amount of time, but further research is required