OZONE THERAPY: A PARADOX OR PANACEA IN VARIOUS AILMENTS

OZONE THERAPY: A PARADOX OR PANACEA IN VARIOUS AILMENTS

Prachi Pimple ^* and Gaurav Doshi

SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, V. M. Road, Vile Parle (W), Mumbai - 400056, Maharashtra, India.

ABSTRACT: Ozone gas (O₃), being an unstable molecule, attracts uncertainty as an alternative to medication, opening avenues for copious research. Ozone therapy (OT) shows its therapeutic efficacy by its reactions with biological components and the production of oxidative stress. It is found useful in various disease conditions like cancer, cardiovascular diseases, pulmonary diseases, wound healing, dental conditions, etc. The therapy on contrast also shows side effects depending on the type of treatment includes burns, coughing, cramping, headaches, nausea, vomiting or severe respiratory complications, and also sometimes flu-like symptoms. The investigation for the use of the OT as a technology is still under development to be used in several ways like ozonated water, injections, insufflations, oil, blow the gas into the body, use an ozone sauna, autohemotherapy. The therapy raises many questions to be used as a solution for diseases with self-contradiction due to the adverse effects occurring after the use of therapy or exposure to the ozone.

Oxidative stress, Reactive oxygen species, Inflammation, Radical, Antioxidant

INTRODUCTION: Ozone (O₃) is found to have some dangerous effects, but O₃ therapy (OT) is studied for years for its application in various segments and minimal plus preventable side effects. O₃ is a colorless, water-soluble unstable molecule explosive in nature. Over 150 years, medical O₃ is used as a disinfectant and ailment for several diseases, especially in wound healing. It is generated by the UV system, cold plasma system or corona discharge system. OT is known to restore oxygen metabolism, avoid stroke or shock damage, eradicate or inactivate pathogens, reduce pain and inflammation, and improve the immune system.

O₃ acts on bacteria by undergoing oxidation and disrupting the cell envelope, whereas cell growth is inhibited in fungi at certain stages, and in viruses, their reproductive cycle is disrupted and damages the capsid by the peroxidation effect. O₃ induces the production of prostacyclin and acts as a vasodilator. It is also effective as inflammation, asthma, chronic pulmonary obstructive disease (COPD), osteoarthritis, lumbar-herniated disc, etc. ¹

O₃ is effective against diabetic complications by affecting glycemic levels and increases immunity by producing cytokine. It also acts as a disinfectant against various microbes like Clostridium, Acineto-bacter baumannii, and Staphylococcus aureus ¹. It arises many reactions like peroxidation and free radical generation leading to changes in membrane permeability, the reaction of O₃ with unsaturated fatty acids forming lipid ozonation products causing inflammation or enzyme inactivation.

Lung alveoli are affected during photochemical smog by O₃ and NO₂ combination. On undergoing oxidation, it produces arachidonic acid peroxides causing platelet aggregation. So various mechanisms of actions involved are reaction with reactive oxygen species or polyunsaturated fatty acids and creating lipid ozonation products like hydro-peroxides, isoprostanes, 4-hydroxynonenal, etc. ^{1, 3, 5, 7}

Through stoichiometric calculations, O₃ auto-hemotrafusion was performed using oxygen-ozone (O₂-O₃) infusion. Similar techniques to administer O₃ therapy are ozonation, extracorporeal blood oxygenation, rectal insufflation, and direct injection through intradiscal, intramuscular or paravertebral at the target site of action. Though oral, vaginal, nasal, vesical, tubal and peritoneal cavities are advisable routes ³. Different methods of applying OT are autohemotherapy, topical ozone, rectal or bladder ozone, prolozone, and hocatt.

2. Clinical Effects of Ozone Therapy: The route of administration and concentration of administering ozone is the determining factor of the different effects produced by ozone therapy.

• Bactericidal, Fungicidal and Virucidal: Direct oxidative effect on the membrane of microorganism is achieved on the external application high concentration of ozone in the form of a gaseous mixture or ozonated solution. All types of bacteria, fungi, viruses, protozoa are sensitive to oxidation.
• Rectification and stimulation of metabolic processes in the hepatic and renal tissues safeguard neutralization and clearance of the harmful compounds from the organ; this contributes to the detoxification effect of ozone.
• Ozone also synchronizes metabolic reactions of inflamed tissues and settle down the pH.

3. Applications: An OT can benefit biological systems with pharmaceutical science intervention in numerous ways. It is used as an antibacterial against Actinomyces naeslundii, Streptococcus mutans and Lactobacilli casei for oral infection treatment ¹.

O₃ damages tumor cells and amplifies radio and chemotherapy in cancer treatment as a complementary therapy. O₃ therapy is beneficial in cancer treatment by modifying tumor hypoxia, loco-regional blood flow, hemoglobin dissociation curve, and 2,3-diphosphoglycerate level 2.

It is also useful in pain management as an analgesic and anti-inflammatory action.

3.1. Wound Healing: OT is used to treat burns by skin healing and reducing uncontrolled bacterial infections and inflammation by activating transforming growth factor-β. It is also proved that epithelial-mesenchymal transition is increased ozone, oil ultimately helps in fibroblasts. OT possesses the disinfectant property with radical scavenging by inactivating bacterial growth ^{13, 14}. Ozone therapy has been proposed as a treatment for chronic wounds, potentially acting by eliciting mild oxidative stress or disinfection.

3.2 Diabetes: Induction of oxidative stress is a major reason for diabetes pathogenesis, ultimately damaging tissue and producing free radicals. The mechanism involved includes xanthine oxidase pathway obstruction to inhibit ROS production and preconditioning oxidant systems. Insulin effects were found to be potentiated along with ozone therapy integration improves systematic blood pressure and antioxidant capacity resulting in a reduction of glucose and lipid oxidation maintain antioxidant therapy caused by diabetes induction.

People suffering from diabetes mellitus foot ulcers are treated by OT due to the activation of the antioxidant system and superoxide dismutase. However, OT is not yet reliable in the treatment of chronic wounds by intralesional injection. OT is used as a complementary treatment by topically using ozonated water and vegetable oils ^8-13.

3.3. Pulmonary Diseases: OT has a dilating effect on smooth muscle by nitric oxide radical, causing blood saturation eliminating hypoxia being useful in asthma and bronchitis treatment. Though, high dose induces gene transcription or inflammatory proteins and cytokine and downregulating to type I interferon protein signal and response to the viral protein ⁵. OT improves glucose penetration through cellular membranes by stimulating aerobic glycolysis and the pentose-phosphate pathway promoting hyperglycemia.

3.4. Dental: OT helps to control bleeding, cleansing wounds in soft tissues and bones, improves healing, acts as a disinfectant, especially for hypomineralized teeth therapy, tooth extraction, teeth whitening, gum recession, and root carries management. Ozonated water is sprayed or gargled to rinse the mouth to clean and disinfect the affected area. Tissue or organ regeneration occurs due to the activation of protein synthesis by ozone. O₃ water, oil or gas is applied to oral tissues to prevent dental infections. Though OT emerges as a noninvasive technique to treat dental caries, it may cause adverse effects and is contraindicated in pregnancy, myasthenia, hemorrhage, hyper-thyroidism, and other ozone allergies. The triple ozone treatment system is commercially available as O₃ water for oral infections ^{16, 17, 18}.

3.5. Cancer: OT is used as a non-conventional form and adjuvant therapy and not used as an alternative therapy to treat cancer as it damages tumor cells directly or stimulating oxidative stress, and affecting blood flow. Administration of systemic OT by autohemotransfusion showed a significant decrease in hypoxia and improved oxygenation. It is also proved as supportive therapy for fatigue and pain in cancer patients using O₂-O₃ therapy ^{2, 19, 20}.

3.6. Aging: Animal models show age-related controlled effects due to prophylactic OT by oxidative stress. OT enhances anti-aging by increasing blood oxygen levels causing an aerobic environment altering skin appearance and healing process. This improves circulation, oxygenated tissues, and sweats out toxins improving metabolism. The treatment is administered by rectal, intra-venous, or sauna with non-interference of the head to avoid respiratory effects. O₂-O₃ therapy is used thermostatically by quasi-total body exposure showing minimal effects acting as a mild stressor ^{3, 22}.

3.7. Orthopedic Diseases: OT was found an alternative for polyarthritis, painful joints, Morton’s disease, and osteoarthritis treatment by insufflation of the gaseous mixture by the increase of articular cartilage and matrix synthesis. It inhibits inflammation and ischemia, stimulating an analgesic effect. The Prolozone method is used for joint, muscle pain, sore, and damaged muscles by injecting to the inflamed area. OT is used in various orthopedic conditions like bone infections, rheumatoid arthritis, osteoarthritis, slipped disc, and osteoporosis. O₂-O₃ therapy shows the clinical application as an alternative in musculoskeletal disorders by inactivating viruses and bacteria, promoting tissue hyperoxygenation to treat joints, tendons, and muscles. However, its activity for plantar fasciitis, costochondritis, and myofascial syndrome treatment is under investigation due to its common side effects ^{7, 23, 24}.

3.8. Cardiovascular Diseases: OT activates the immune system and increases endothelial progenitor cells, growth factors, and antioxidant enzymes, ultimately reducing cardiovascular diseases being potential therapy in atherosclerosis and ischemic heart disease. O₂-O₃ therapy has shown the optimal effects of cardiovascular disorders by blocking pathological progress ^{5, 25, 26}.

3.9. Anti-inflammatory and Analgesic: OT is marked safe, economical, and effective in the treatment of pain and inflammation. Compounds like prostaglandins, arachidonic acid is oxidized in a double layer, activates hypoxia-inducible factor- 1α, inactivates pain mediators, maintaining inflammation, and acts as an analgesic. However, OT shows the tomato effect and non-patentable technology, which contradicts the treatment. O₂-O₃ therapy, combined with physiotherapy, was found effective in low back pain by paravertebral-intramuscular administration by maintaining cytokines and prostaglandins and increasing superoxide dismutase levels ^{25, 27, 28, 31}.

3.10. AIDS: OT is effective in viral diseases like HIV by injecting ozone-treated blood showing no clinical toxicity or hematologic effects. It also reports the inactivation of human retroviruses in body fluids. Though rectal OT is not approved for AIDS treatment as it possesses life-threatening illness due to oxidation stress transient and super dismutase expression ^{29, 30}.

3.11. Dermatology: OT is used in dermatology as ozone hydrotherapy or ozonated oil with unclear mechanism of action and effects like reducing exudate, epigenetic modifications, etc. O₂-O₃ therapy was found useful in different forms of scleroderma, acne, lesions, pigmentation, which could be a replacement to laser therapy ³².

3.12. Gynecology and Obstetrics: OT acts as an adjunct agent in female infertility, especially caused by fallopian tube obstruction; experimented on rats showed better potential when compared to traditional or interventional methods. It is effective in gynecological infections, protects ovarian tissue and endometrium, decreases pelvic adhesions and vaginitis by stimulating blood immunoglobulins, decreasing reactive oxygen species, increasing glutathione peroxidase, and super dismutase activity. The OT may show a positive effect on pelvic inflammatory diseases, tubal occlusion, oocyte loss, etc., though clinical trials need constant follow-up to procure the desired results and uncover the unknown effects. On rectal insufflation, OT administration to female Wistar rats showed no teratogenic or embryotoxic effects though controlled clinical trials are recommended, especially towards obstetrics and method of administration ^{35, 36, 37}. Ozone therapy is proved to be one of the quickest relieving, cost-effective treatments for heart disease like cardiovascular complexities, and fatigue. It has a high success rate in treating heart diseases compared to an invasive procedure such as heart by-pass surgery or angioplasty. This naturopathic course of therapy works by boosting oxygen circulation and the utilization of oxygen by cells in energy production. Oxygen plays a crucial role in energy generation by various human cells. Appropriate energy generation will lead to less or least pain or fatigue. Blood - ozone mixture leads to the maintenance of oxygen use and supply chain.

3.13. Others: The OT show improved oxygen delivery and blood circulation in ischemic tissues by an increase in antioxidative enzymes, increasing erythroblast leading to oxidative preconditioning. It affects vascular and hematological modulation by reduced nicotinamide adenine dinucleotide and cytochrome c oxidation. As OT activates nuclear transcription factor, it is effective in vascular disease and hypoxia. OT was found useful in treating fibromyalgia management by auto-hemotransfusion and rectal insufflations. OT is known to reduce blood pressure with progression prevention. It acts by regulating serum endothelin receptor level reduction in vascular tissue and heart as anti-vasoconstrictor effects being affective in hypertension condition. It strengthens the immune system, cleanses the liver, improves circulation problems, rheumatic illness, allergies, joint stiffness, etc. Autohemo OT was found effective in patients with neurological disorders like multiple sclerosis by changing brain metabolism, and circulation OT act as mono or adjuvant therapy in the treatment of SARS by inactivating fungi, bacteria, and viruses by oxidizing cytochrome C and producing prostacyclin. It reduces maximal transpulmonary pressure in the lungs, hence increasing the rate of respiration and reduction in tidal volume ^{1, 21, 3, 4, 5, 6, 33}.

4. Toxicity: Though O₃ possesses various benefits, its toxicity and clinical efficacy depend on the route and concentration of dose administration as lung inhalation is a major concern. O₃ therapy escalates airway resistance without altering lung characteristics, and due to its low antioxidant competencies, direct contact with eyes and lungs is avoided. The production of oxidative stress by OT results in inflammation and tissue injury. Many experiments also show evidence for the respiratory system and pulmonary organ damage by exposure or inhalation of OT. Some contradictions may involve bleeding organs, thrombocytopenia, or apoplectic shock. It may possess some teratogenic or embryotoxic effects; hence clinical trials are required before OT implementation in various diseases or disorders. Intravenous administration of OT showed neurotoxicity involving nausea, headache, confusion, and blurred vision ^{3, 4, 34}.

5. Different Methods of Applying Ozone Therapy:

• Autohemotherapy: Major clinical application that involves withdrawing 60-200 ml of blood along with the addition of ozone and finally reinfusing it.
• Limb Bagging: An application-based technique in which a plastic bag is placed over the affected limb area and thereby infusing ozone into the bag to cover the ulcer or rash.
• Prolozone: An injectable ozone technique that provides therapy for joint as well as muscular pains, repairs the damaged cartilage, tearing of tendons and ligaments.
• Insufflation: The technique directly delivers ozone to the rectum, vagina, or urinary bladder.
• Hocatt: It is termed as the ability to expose the entire body to the healing effects of ozone. Ozone is drawn toward negatively charged foreign cells such as bacteria, yeast, viruses, and parasites, which neutralizes them further enhances the killing of these active infections.

CONCLUSION: The OT raises many questions for several treatment options requiring preclinical and clinical studies. A protocol needs to be developed for dose variations and response relationships, providing compelling evidence. It releases growth factors and activates immune and neuroprotective systems proving wellness in some conditions. Some reports show the effects of OT as safe and consistent, but O₃ possesses hazardous effects, especially affecting an individual lung during smog leading to death from respiratory ailment. Some reported side effects include poor circulation, heart problems, blood vessel swelling, inactivation of enzymes, pulmonary embolism, etc. OT is still under research where new facts throw light as OT usage for a safe alternative to conventional medications. OT still lies under orthodox medicine will poor regulation due to non-patentable therapy or gas. It may break paths as an innovative therapy by controlled trials with demonstrated validity and toxicity for the suitable disease condition.

ACKNOWLEDGEMENT: We wish to acknowledge Ved Hemen Sanjay (Department of Pharmacology) for his help and support in the compilation of the article.

CONFLICTS OF INTEREST: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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    How to cite this article:

    Pimple P and Doshi G: Ozone therapy: a paradox or panacea in various ailments. Int J Pharm Sci & Res 2021; 12(2): 754-59. doi: 10.13040/IJPSR.0975-8232.12(2).754-59.

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