The Biological and Molecular Action of Ozone and Its Derivatives: State-of-the-Art, Enhanced Scenarios, and Quality Insights.

The ultimate objective of this review is to encourage a multi-disciplinary and integrated methodological approach that, starting from the recognition of some current uncertainties, helps to deepen the molecular bases of ozone treatment effects on human and animal well-being and to optimize their performance in terms of reproducibility of results, quality, and safety. In fact, the common therapeutic treatments are normally documented by healthcare professionals' prescriptions. The same applies to medicinal gases (whose uses are based on their pharmacological effects) that are intended for patients for treatment, diagnostic, or preventive purposes and that have been produced and inspected in accordance with good manufacturing practices and pharmacopoeia monographs. On the contrary, it is the responsibility of healthcare professionals, who thoughtfully choose to use ozone as a medicinal product, to achieve the following objectives: (i) to understand the molecular basis of the mechanism of action; (ii) to adjust the treatment according to the clinical responses obtained in accordance with the principles of precision medicine and personalized therapy; (iii) to ensure all quality standards.

Comment on Barczyk et al. Potential Clinical Applications of Ozone Therapy in Dental Specialties-A Literature Review, Supported by Own Observations. Int. J. Environ. Res. Public Health 2023, 20, 2048.

A review from Barczyk et al. has just appeared online [...].

Topical Hyperbaric Oxygen Therapy Versus Local Ozone Therapy in Healing of Venous Leg Ulcers.

BACKGROUND: the treatment of venous leg ulcers still poses a difficult interdisciplinary medical problem. The aim of this study was to compare the therapeutic efficacy of local hyperbaric oxygen therapy with local ozone therapy in the treatment of venous leg ulcers. MATERIALS: this study included 114 patients; 60 males (52.63%) and 54 females (47.36%) of ages ranging between 39 and 88 years (mean age: 68.9 ± 9.8 years) with venous leg ulcers, who underwent topical hyperbaric oxygen therapy (group I) and local ozone therapy (group II). In each of the study groups, the patients underwent 30 therapeutic procedures lasting 30 min each. The progress in wound healing was evaluated by computerized planimetry, and the intensity of pain was assessed with the use of the Visual Analogue Scale (VAS). RESULTS: in both groups of treated patients, a statistically significant (p = 0.000001) reduction in the area of treated ulcers was achieved. In group I, the wound area decreased by an average of 69.67 ± 22.52%, from 7.55 ± 2.99 cm2 to 2.78 ± 2.43 cm2, and in group II, by an average of 41.33 ± 21.31%, from 7.36 ± 2.82 cm2 to 4.62 ± 2.76 cm2. In both groups of patients, a statistically significant (p = 0.000001) reduction in the intensity of pain ailments was observed: in group I, by an average of 0.55 ± 0.54 points, and in group II, by an average of 2.33 ± 0.82 points on the VAS scale. CONCLUSIONS: local hyperbaric oxygen therapy and local ozone therapy cause a statistically significant reduction in the surface area of venous leg ulcers as well as in the intensity of pain. Better results were observed after the application of local hyperbaric oxygen therapy procedures.

Approach to the management of COVID-19 patients: When home care can represent the best practice.

BACKGROUND: The pandemic that began around February 2020, caused by the viral pathogen SARS-CoV-2 (COVID-19), has still not completed its course at present in June 2022. OBJECTIVE: The open research to date highlights just how varied and complex the outcome of the contagion can be. METHOD: The clinical pictures observed following the contagion present variabilities that cannot be explained completely by the patient's age (which, with the new variants, is rapidly changing, increasingly affecting younger patients) nor by symptoms and concomitant pathologies (which are no longer proving to be decisive in recent cases) in relation to medium-to-long term sequelae. In particular, the functions of the vascular endothelium and vascular lesions at the pre-capillary level represent the source of tissue hypoxia and other damage, resulting in the clinical evolution of COVID-19. RESULTS: Keeping the patient at home with targeted therapeutic support, aimed at not worsening vascular endothelium damage with early and appropriate stimulation of endothelial cells, ameliorates the glycocalyx function and improves the prognosis and, in some circumstances, could be the best practice suitable for certain patients. CONCLUSION: Clinical information thus far collected may be of immense value in developing a better understanding of the present pandemic and future occurrences regarding patient safety, pharmaceutical care and therapy liability.

Neuroticism and Conscientiousness Moderate the Effect of Oral Medication Beliefs on Adherence of People with Mental Illness during the Pandemic.

BACKGROUND: After the declaration of the pandemic status in several countries, the continuity of face-to-face visits in psychiatric facilities has been delayed or even interrupted to reduce viral spread. Little is known about the personality factors associated with medication beliefs and adherence amongst individuals with mental illness during the COVID-19 pandemic. This brief report describes a preliminary naturalistic longitudinal study that explored whether the Big Five personality traits prospectively moderate the effects of medication beliefs on changes in adherence during the pandemic for a group of outpatients with psychosis or bipolar disorder. METHODS: Thirteen outpatients undergoing routine face-to-face follow-up assessments during the pandemic were included (41 observations overall) and completed the Revised Italian Version of the Ten-Item Personality Inventory, the Beliefs about Medicines Questionnaire, the Morisky Medication Adherence Scale-8-item and the Beck Depression Inventory-II. RESULTS: Participants had stronger concerns about their psychiatric medications rather than beliefs about their necessity, and adherence to medications was generally low. Participants who had more necessity beliefs than concerns had better adherence to medications. People scoring higher in Conscientiousness and Neuroticism traits and more concerned about the medication side effects had poorer adherence. CONCLUSIONS: These preliminary data suggest the importance of a careful assessment of the adherence to medications amongst people with psychosis/bipolar disorder during the pandemic. Interventions aimed to improve adherence might focus on patients' medication beliefs and their Conscientiousness and Neuroticism personality traits.

Evaluation of targeted oxidative stress induced by oxygen-ozone in vitro after ischemic induction.

Encephalic vascular accident, or stroke, is the most common pathology of the central nervous system in humans, the second leading cause of death and physical and cognitive disabilities, in developing countries. It presents as an ischemic (more common) or hemorrhagic form. Ozone therapy has been shown to be effective in neuromodulation, neuroprotection, and nerve regeneration. The present study aimed to evaluate the effect of targeted mild ozone after inducing cerebral ischemia in vitro. Neuroblastoma lineage cells (SH-SY5Y) and canine amniotic membrane stem cells were subjected to 24 hours of hypoxia in an incubator culture chamber. The cells were evaluated by MTT assay, colorimetric assay spectrophotometry, fluorescence microscopy, and flow cytometry. Treatment with low concentrations of ozone (2-10 µg/mL), indicated a possible neuroregenerative effect at low concentrations, correlated with lower levels of apoptosis and oxidative stress compared to cells not subjected to hypoxia. High concentrations of ozone (18-30 µg/mL) promoted an increase in rate of apoptosis and cell death. We developed a novel protocol that mimics ozone therapy for ischemic stroke, using ozonized culture medium after hypoxia induction. Although more studies are needed, we conclude that ozone has a dose-dependent hormetic effect and can reverse the effect of ischemia in vitro at low concentrations.

Ozone acting on human blood yields a hormetic dose-response relationship.

The aim of this paper is to analyze why ozone can be medically useful when it dissolves in blood or in other biological fluids. In reviewing a number of clinical studies performed in Peripheral Arterial Diseases (PAD) during the last decades, it has been possible to confirm the long-held view that the inverted U-shaped curve, typical of the hormesis concept, is suitable to represent the therapeutic activity exerted by the so-called ozonated autohemotherapy. The quantitative and qualitative aspects of human blood ozonation have been also critically reviewed in regard to the biological, therapeutic and safety of ozone. It is hoped that this gas, although toxic for the pulmonary system during prolonged inhalation, will be soon recognized as a useful agent in oxidative-stress related diseases, joining other medical gases recently thought to be of therapeutic importance. Finally, the elucidation of the mechanisms of action of ozone as well as the obtained results in PAD may encourage clinical scientists to evaluate ozone therapy in vascular diseases in comparison to the current therapies.

Ozonated sesame oil enhances cutaneous wound healing in SKH1 mice.

Ozone is well recognized as a bactericidal agent and its beneficial effect on wound healing could be a consequence of this property. Because ozone itself does not penetrate the cells but immediately reacts with polyunsaturated fatty acids, its effects should be the results of oxidative reaction. For this reason, ozonated oils could be a way to deliver ozone messengers to the skin. This paper evaluated the therapeutic effects of three different grades of ozonated sesame oil in acute cutaneous wounds made in the skin of SKH1 mice. Specifically, wound closure rate, histological parameters, and the level of key proteins such as vascular endothelial growth factors and cyclin D1 have been analyzed in relation to the peroxide level present in the ozonated oil. Treatment with moderately ozonated sesame oil--expressed as peroxide value about 1,500)--has a faster wound closure rate in the first 7 days than treatment with oil containing either lower or higher peroxide value, and even with controls. Moreover, under the same treatment, an earlier and higher response of cells involved in wound repair, a higher angiogenesis, as well as an enhanced vascular endothelial growth factors and cyclin D1 expression were observed. The present study shows the validity of ozonated sesame oil in cutaneous wound healing and emphasizes the importance of the ozonation grade.

The Relationship between Ozone and Human Blood in the Course of a Well-Controlled, Mild, and Transitory Oxidative Eustress.

In the last twenty years there has been a proliferation of articles on the therapeutic use of ozone. As it is well-known, the term ozone therapy is very broad. It ranges from either systemic or loco-regional administration of unstable gaseous oxygen/ozone mixtures to the topical application of stable ozonated derivatives. Anyway, in relation to the absence of specific receptors and the extreme reactivity with the biological liquids with which it comes into contact, gaseous ozone cannot be classified as either a drug or a pro-drug. When the gaseous ozone impacts a biological matrix, both reactive oxygen species (ROS) and lipid oxidation products (LOPs) are formed. They represent the effector molecules responsible for modulating the therapeutic activity in the body. Apart from the merits of the action mechanisms resulting from the use of ozone, this article seeks to validate the practice of ozone therapy as an adjuvant treatment in full compliance with the physiology of the whole organism.

Ozone and its derivatives in veterinary medicine: A careful appraisal.

The therapeutic use of ozone and its derivatives in the veterinary medicine it is still in an emergent stage. Gaseous ozone chemical instability makes necessary its extemporaneous preparation and the accordance about ozone treatments with the highest quality standards in publications is of paramount importance. Moreover, the numerous method of administration in different animal species, the prevalence of case reports, the deficiency of consistent evaluation of the outcomes, as well as the lack of standardization of the treatment operating procedures represents an open question for its spreading and official approval. The keywords "ozone", "ozonated", "ozonation" "ozonized", "ozonization", "oxygen-ozone therapy", "veterinary", "pets", "animal" were used to perform a literature review using PubMed, Cochrane, Google Scholar, Zotero databases with the temporal restriction for published manuscripts starting from 2010. All the researches were critically evaluated, regardless of the impact factor, if any, of the journals in which they were presented. The deepening of the mechanisms of action of this bio-oxidative therapy can open new horizons on its use. The distinctive condition to achieve such a scenario is an improved knowledge of the qualitative/quantitative characteristics of ozone and its derivatives. All with the aim of taking nothing away to the cited original research papers, but of improving the promising therapeutic implications of ozone therapy in veterinary medicine as a standardization stimulus about this therapeutic resource with multiple application specificities.

Are dialysis devices usable as ozone gas exchangers?

A study aimed to compare the efficiency of the ozone transfer of four hydrophilic dialysis filters, and one hydrophobic gas-exchange device (GED) has been performed. Obviously, the former should be specifically used only for dialysis. Unfortunately, some clinicians incautiously use them as GEDs. It has been shown that: (i) dialysis filters present a wide range of gas-exchange yield (from 0 up to 70%), often related to variability according to the treatment time; (ii) by scanning microscopy, it has been noticed that hollow fibers are somewhat altered by ozone; and (iii) because their constitutive materials may not be ozone-resistant, they may release toxic compounds harmful for the patients. On the contrary, the appropriate GED is ozone-transfer efficient, is ozone-resistant, and is suitable for blood autotransfusion and ozonation.

Effects of ozone blood treatment on the metabolite profile of human blood.

Metabonomic characterization of the effects caused by ozone and other stressors on normal human blood was performed. Samples of blood obtained from healthy subjects were treated ex vivo with increasing concentrations of ozone and/or with UV radiation and heat. (1)H-NMR analysis of plasma samples after treatments showed the quantitative variation of some metabolites and the formation of new metabolites normally absent. Both the increment of some metabolites like formate, acetoacetate, and acetate and the decrement of pyruvate were of particular interest. Moreover, the oxidation of ascorbic acid and the transformation of uric acid into allantoin after ozonation within the therapeutic concentration range were observed. In the ozonated spectra, 2 unidentified peaks appeared at 2.82 ppm and 8.08 ppm. They are related to the direct antioxidant activity of albumin in the presence of ozone and they could be considered as specific markers of the blood ozonation.

Ozone influences migration and proliferation of neural stem cells in vitro.

Ozone (O3) is a short-lived molecule which can be produced in a controlled reaction when oxygen is exposed to electric discharge. In the last few decades, many publications dealing both with animals and humans reported beneficial effects of ozone administration linked to its immunomodulatory and protective role against cellular damage. This is the first work which brings insight into how ozone influences cells of neural lineage in vitro and hypothesizes the potential molecular and novel electromagnetic mechanisms behind its action. By using neural stem cells, we show that ozone, especially in concentrations of around 11 µg/mL, significantly increases the speed of neural cell migration. With much lower effects, it also increases cell proliferation and cytokine production. Results of this study, at least partly, explain the observed beneficial effects of ozone in diseases of the nervous system tested on animal models and in human clinical trials. Therefore, here described effects of ozone on cellular level represent a firm basis for further investigation of possible applications of ozone in regeneration of the nervous system.

The ozone paradox: ozone is a strong oxidant as well as a medical drug.

After five decades characterized by empiricism and several pitfalls, some of the basic mechanisms of action of ozone in pulmonary toxicology and in medicine have been clarified. The present knowledge allows to understand the prolonged inhalation of ozone can be very deleterious first for the lungs and successively for the whole organism. On the other hand, a small ozone dose well calibrated against the potent antioxidant capacity of blood can trigger several useful biochemical mechanisms and reactivate the antioxidant system. In detail, firstly ex vivo and second during the infusion of ozonated blood into the donor, the ozone therapy approach involves blood cells and the endothelium, which by transferring the ozone messengers to billions of cells will generate a therapeutic effect. Thus, in spite of a common prejudice, single ozone doses can be therapeutically used in selected human diseases without any toxicity or side effects. Moreover, the versatility and amplitude of beneficial effect of ozone applications have become evident in orthopedics, cutaneous, and mucosal infections as well as in dentistry.

Physico-chemical characterization of sesame oil derivatives.

Ozone treatment of commercially available vegetable oils gives rise to the formation of chemical species that are responsible for the therapeutic properties of ozonated oil derivatives in dermatological diseases. In the last years, these products have been successfully used as a topical disinfectant in a number of serious skin affections. The medical application of empirically prepared ozonated oil has yielded striking improvements with unexpected and rapid healing, compelling us to begin a long-range study aiming first to define the main characteristics of the most common ozonated vegetable oils, about which there is usually no medical consensus because of the lack of standardization of their technological parameters. Sesame oil was selected because of its great amount of polyunsaturated acyl groups, as well as natural antioxidants. Moreover, we have determined the kinetics and optimal conditions of ozonation (e.g., ozone concentrations, time of exposure, temperature) for obtaining an ozonated oil characterized by well-established technological and physico-chemical properties, namely an accurate peroxide value determination. On the basis of the results, we have gained an understanding of the modifications of the vegetable oils during the ozonation process.