Modulation by Ozone Therapy of Oxidative Stress in Chemotherapy-Induced Peripheral Neuropathy: The Background for a Randomized Clinical Trial.

(1) Background: Chemotherapy-induced peripheral neuropathy (CIPN) decreases the quality of life of patients and can lead to a dose reduction and/or the interruption of chemotherapy treatment, limiting its effectiveness. Potential pathophysiological mechanisms involved in the pathogenesis of CIPN include chronic oxidative stress and subsequent increase in free radicals and proinflammatory cytokines. Approaches for the treatment of CIPN are highly limited in their number and efficacy, although several antioxidant-based therapies have been tried. On the other hand, ozone therapy can induce an adaptive antioxidant and anti-inflammatory response, which could be potentially useful in the management of CIPN. (2) Methods: The aims of this works are: (a) to summarize the potential mechanisms that could induce CIPN by the most relevant drugs (platinum, taxanes, vinca alkaloids, and bortezomib), with particular focus on the role of oxidative stress; (b) to summarize the current situation of prophylactic and treatment approaches; (c) to describe the action mechanisms of ozone therapy to modify oxidative stress and inflammation with its potential repercussions for CIPN; (d) to describe related experimental and clinical reports with ozone therapy in chemo-induced neurologic symptoms and CIPN; and (e) to show the main details about an ongoing focused clinical trial. (3) Results: A wide background relating to the mechanisms of action and a small number of experimental and clinical reports suggest that ozone therapy could be useful to prevent or improve CIPN. (4) Conclusions: Currently, there are no clinically relevant approaches for the prevention and treatment of stablished CIPN. The potential role of ozone therapy in this syndrome merits further research. Randomized controlled trials are ongoing.

Potential Cytoprotective Activity of Ozone Therapy in SARS-CoV-2/COVID-19.

(1) Background: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) in China at the end of 2019 has caused a large global outbreak. Systemic ozone therapy (OT) could be potentially useful in the clinical management of several complications secondary to SARS-CoV-2. The rationale and mechanism of action has already been proven clinically in other viral infections and has been shown in research studies to be highly effective at decreasing organ damage mediated by inflammation and oxidative stress. This review summarizes the OT studies that illustrate the possible cytoprotective mechanism of action of ozone and its physiological by-products in target organs affected by SARS-CoV-2. (2) Methods: This review encompasses a total of 74 peer-reviewed original articles. It is mainly focused on ozone as a modulator of the NF-κ B/Nrf2 pathways and IL-6/IL-1ß expression. (3) Results: In experimental models and the few existent clinical studies, homeostasis of the free radical and antioxidant balance by OT was associated with a modulation of NF-κ B/Nrf2 balance and IL-6 and IL-1ß expression. These molecular mechanisms support the cytoprotective effects of OT against tissue damage present in many inflammatory diseases, including viral infections. (4) Conclusions: The potential cytoprotective role of OT in the management of organ damage induced by COVID-19 merits further research. Controlled clinical trials are needed.

Modulation of Oxidative Stress by Ozone Therapy in the Prevention and Treatment of Chemotherapy-Induced Toxicity: Review and Prospects.

(1) Background: Cancer is one of the leading causes of mortality worldwide. Radiotherapy and chemotherapy attempt to kill tumor cells by different mechanisms mediated by an intracellular increase of free radicals. However, free radicals can also increase in healthy cells and lead to oxidative stress, resulting in further damage to healthy tissues. Approaches to prevent or treat many of these side effects are limited. Ozone therapy can induce a controlled oxidative stress able to stimulate an adaptive antioxidant response in healthy tissue. This review describes the studies using ozone therapy to prevent and/or treat chemotherapy-induced toxicity, and how its effect is linked to a modification of free radicals and antioxidants. (2) Methods: This review encompasses a total of 13 peer-reviewed original articles (most of them with assessment of oxidative stress parameters) and some related works. It is mainly focused on four drugs: Cisplatin, Methotrexate, Doxorubicin, and Bleomycin. (3) Results: In experimental models and the few existing clinical studies, modulation of free radicals and antioxidants by ozone therapy was associated with decreased chemotherapy-induced toxicity. (4) Conclusions: The potential role of ozone therapy in the management of chemotherapy-induced toxicity merits further research. Randomized controlled trials are ongoing.

Ozone Therapy as Adjuvant for Cancer Treatment: Is Further Research Warranted?

INTRODUCTION: This article provides an overview of the potential use of ozone as an adjuvant during cancer treatment. METHODS: We summarize the findings of the most relevant publications focused on this goal, and we include our related clinical experience. RESULTS: Over several decades, prestigious journals have published in vitro studies on the capacity of ozone to induce direct damage on tumor cells and, as well, to enhance the effects of radiotherapy and chemotherapy. Indirect effects have been demonstrated in animal models: immune modulation by ozone alone and sensitizing effect of radiotherapy by concurrent ozone administration. The effects of ozone in modifying hemoglobin dissociation curve, 2,3-diphosphoglycerate levels, locoregional blood flow, and tumor hypoxia provide additional support for potential beneficial effects during cancer treatment. Unfortunately, only a few clinical studies are available. Finally, we describe some works and our experience supporting the potential role of local ozone therapy in treating delayed healing after tumor resection, to avoid delays in commencing radiotherapy and chemotherapy. CONCLUSIONS: In vitro and animal studies, as well as isolated clinical reports, suggest the potential role of ozone as an adjuvant during radiotherapy and/or chemotherapy. However, further research, such as randomized clinical trials, is required to demonstrate its potential usefulness as an adjuvant therapeutic tool.

Ozone Therapy in the Management of Persistent Radiation-Induced Rectal Bleeding in Prostate Cancer Patients.

Introduction. Persistent radiation-induced proctitis and rectal bleeding are debilitating complications with limited therapeutic options. We present our experience with ozone therapy in the management of such refractory rectal bleeding. Methods. Patients (n = 12) previously irradiated for prostate cancer with persistent or severe rectal bleeding without response to conventional treatment were enrolled to receive ozone therapy via rectal insufflations and/or topical application of ozonized-oil. Ten (83%) patients had Grade 3 or Grade 4 toxicity. Median follow-up after ozone therapy was 104 months (range: 52-119). Results. Following ozone therapy, the median grade of toxicity improved from 3 to 1 (p < 0.001) and the number of endoscopy treatments from 37 to 4 (p = 0.032). Hemoglobin levels changed from 11.1 (7-14) g/dL to 13 (10-15) g/dL, before and after ozone therapy, respectively (p = 0.008). Ozone therapy was well tolerated and no adverse effects were noted, except soft and temporary flatulence for some hours after each session. Conclusions. Ozone therapy was effective in radiation-induced rectal bleeding in prostate cancer patients without serious adverse events. It proved useful in the management of rectal bleeding and merits further evaluation.

Los retos de la ozonoterapia y el acceso a sus fuentes de información / Challenges of ozone therapy and access to information sources

La ozonoterapia es hoy una práctica médica generalizada en Cuba. Una sólida investigación básica y clínica sustenta la aplicación de este proceder. No obstante, a nivel mundial los comentarios que frecuentemente se escuchan sobre el uso de la ozonoterapia entre los profesionales la desconocen, la tienden a clasificar como una terapia fraudulenta y en ocasiones peligrosa. Estos comentarios son tan carentes de argumento que si no fueran reslizados por profesionales podría decirse que son habladurías de comadres.1 Tal es así que se ha escuchado recientemente a un profesional que intervenía públicamente, decir que tenía dudas sobre la existencia propia de la molécula del ozono. Es sorprendente, además, ver como los grandes medios de los EE. UU. han lanzado como eslogan La ozonoterapia, un fraude médico. Pero los propios medios de ese país se han encargado de desmentir ese eslogan y profundizar en las raíces del problema. El documental Ozone, A Medical Breakthrough? del realizador Geoff Rogers, muestra como detrás de esta campaña están los círculos de poder de la gran industria farmacéutica que tendría grandes pérdidas económicas si la ozonoterapia fuera introducida masivamente. No es menos cierto que el ozono a altas dosis y en dependencia de la vía por donde sea administrado, origina efectos tóxicos. En particular, la vía inhalatoria es muy dañina. El ozono producido por las máquinas industriales, las fotocopiadoras y los ordenadores son causa frecuente de dolores de cabeza y otros disturbios.2 El ozono generado durante las tormentas eléctricas y arrastrado a las capas inferiores de la atmósfera por fuertes vientos, está relacionado con el incremento en la frecuencia de ingresos a los hospitales por trastornos respiratorios. El hecho es que al menos por sus efectos tóxicos, el ozono ha ganado fama y ha sido motivo de múltiples investigaciones para...(AU)

Effects of ozone therapy on haemostatic and oxidative stress index in coronary artery disease.

Coronary artery disease (CAD) is the most common cause of sudden death, and death of people over 20 years of age. Because ozone therapy can activate the antioxidant system and improve blood circulation and oxygen delivery to tissue, the aim of this study was to investigate the therapeutic efficacy of ozone in patients with CAD, treated with antithrombotic therapy, Aspirin and policosanol. A randomized controlled clinical trial was performed with 53 patients divided into two groups: one (n=27) treated with antithrombotic therapy and other (n=26) treated with antithrombotic therapy plus rectal insufflation of O(3). A parallel group (n=50) age and gender matched was used as reference for the experimental variables. The efficacy of the treatments was evaluated by comparing hemostatic indexes and biochemical markers of oxidative stress in both groups after 20 day of treatment. Ozone treatment significantly (P<0.001) improved prothrombin time when compared to the antithrombotic therapy only group, without modifying bleeding time. Combination antithrombotic therapy+O(3) improved the antioxidant status of patients reducing biomarkers of protein and lipid oxidation, enhancing total antioxidant status and modulating the level of superoxide dismutase and catalase with a 57% and 32% reduction in superoxide dismutase and catalase activities respectively, moving the redox environment to a status of low production of O(2)(•-) with an increase in H(2)O(2) detoxification. No side effects were observed. These results show that medical ozone treatment could be a complementary therapy in the treatment of CAD and its complications.

Efecto protector de los polifenoles de Rhizophora mangle L sobre el daño oxidativo a proteínas y ADN / Protective effect of polyphenols from Rhizophora mangle L on oxidative damage to proteins and DNA

Al extracto acuoso de la corteza de Rhizophora mangle L se le ha demostrado un amplio espectro de usos medicinales: en el tratamiento de la mastitis bovina, la curación de heridas,las infecciones uterinas y las úlceras gastroduodenales; debido a sus propiedades antiséptica, cicatrizante, antiinflamatoria y antioxidante. Sin embargo, no se han completado los estudios de la actividad antioxidante a todos los niveles de complejidad para dilucidar los mecanismos de acción involucrados en este efecto farmacológico. Objetivo: determinar si el extracto acuoso de R. mangle y su fracción polifenólica protegen a las principales biomoléculas del daño oxidativo. La evaluación de la actividad antioxidante del extracto de R mangle y su fracción polifenólica sobre las principales biomoléculas se determinó mediante ensayo de daño oxidativo a la albúmina de suero bovino expuesta a los radicales hidroxilo generados en el sistema Fenton y ensayo de degradación oxidativa del ADN inducido por el sistema bleomicina-Fe3+.El extracto de R. mangle y su fracción polifenólica, a la máxima concentración ensayada, disminuyeron la oxidación de los grupos sulfidrilos en 87,3 y 89,1 por ciento; e inhibieron la degradación del ADN en 98,4 y 91,9 por ciento, respectivamente. El análisis de regresión mostró que ambos efectos fueron dependientes de la concentración de taninos en el extracto y su fracción. La comparación de las líneas de regresión reveló que el extracto y su fracción resultaron igualmente eficaces en proteger a la albúmina de suero bovino de la oxidación por los radicales hidroxilos, sin embargo, el extracto fue más eficaz en proteger al ADN de la degradación oxidativa que su fracción. El extracto acuoso de R. mangle mostró un efecto protector a las principales biomoléculas del daño oxidativo, evidenciado por la inhibición de la pérdida de grupos sulfidrilos en la albúmina de suero bovino y la disminución de la degradación del ADN... (AU)

The aqueous extract from Rhizophora mangle (L) bark has demonstrated a broad spectrum of medicinal uses; for example, in treating bovine mastitis, wound healing, uterine infections and gastroduodenal ulcers, due to its antiseptic, healing, anti-inflammatory and antioxidant properties. However, the antioxidant activity in its whole complexity has not been fully studied in order to elucidate the mechanisms of action involved in this pharmacological effect. Objective: to determine if R. mangle bark aqueous extract and its polyphenolic fraction protect the main biomolecules from oxidative damage. The antioxidant activity of R. mangle extract and its polyphenolic fraction on the main biomolecules was determined by the following methods: oxidative damage trial on bovine serum albumin exposed to hydroxyl radicals generated in the Fenton system and the bleomycin-Fe3+ system-induced DNA oxidative degradation trial. Results: the R. mangle bark extract and its polyphenolic fraction, at the highest tested concentration, reduced the sulfhydryl group oxidation by 87,3 percent and 89,1 percent and they also inhibited the DNA degradation by 98.4 percent and 91.9 percent respectively. The regression analysis demonstrated that both effects depended on tannin concentration in the extract and its fraction. The comparison of regression lines revealed that the extract and its fraction were equally effective in protecting bovine serum albumin from oxidation by hydroxyl radicals; however, the extract was more effective when protecting DNA from oxidative degradation than its fraction. The R mangle aqueous extract showed a protective effect on the main biomolecules from the oxidative damage, evidenced by inhibiting loss of sulfhydryl group in bovine serum albumin and decreasing the DNA degradation. At the same time, it was shown that polyphenolic compounds present in the extract were the main responsible for the antioxidant effects observed in this study(AU)

Efecto protector de los polifenoles de Rhizophora mangle L sobre el daño oxidativo a proteínas y ADN / Protective effect of polyphenols from Rhizophora mangle L on oxidative damage to proteins and DNA

Al extracto acuoso de la corteza de Rhizophora mangle L se le ha demostrado un amplio espectro de usos medicinales: en el tratamiento de la mastitis bovina, la curación de heridas,las infecciones uterinas y las úlceras gastroduodenales; debido a sus propiedades antiséptica, cicatrizante, antiinflamatoria y antioxidante. Sin embargo, no se han completado los estudios de la actividad antioxidante a todos los niveles de complejidad para dilucidar los mecanismos de acción involucrados en este efecto farmacológico. Objetivo: determinar si el extracto acuoso de R. mangle y su fracción polifenólica protegen a las principales biomoléculas del daño oxidativo. La evaluación de la actividad antioxidante del extracto de R mangle y su fracción polifenólica sobre las principales biomoléculas se determinó mediante ensayo de daño oxidativo a la albúmina de suero bovino expuesta a los radicales hidroxilo generados en el sistema Fenton y ensayo de degradación oxidativa del ADN inducido por el sistema bleomicina-Fe3+.El extracto de R. mangle y su fracción polifenólica, a la máxima concentración ensayada, disminuyeron la oxidación de los grupos sulfidrilos en 87,3 y 89,1 por ciento; e inhibieron la degradación del ADN en 98,4 y 91,9 por ciento, respectivamente. El análisis de regresión mostró que ambos efectos fueron dependientes de la concentración de taninos en el extracto y su fracción. La comparación de las líneas de regresión reveló que el extracto y su fracción resultaron igualmente eficaces en proteger a la albúmina de suero bovino de la oxidación por los radicales hidroxilos, sin embargo, el extracto fue más eficaz en proteger al ADN de la degradación oxidativa que su fracción. El extracto acuoso de R. mangle mostró un efecto protector a las principales biomoléculas del daño oxidativo, evidenciado por la inhibición de la pérdida de grupos sulfidrilos en la albúmina de suero bovino y la disminución de la degradación del ADN...

The aqueous extract from Rhizophora mangle (L) bark has demonstrated a broad spectrum of medicinal uses; for example, in treating bovine mastitis, wound healing, uterine infections and gastroduodenal ulcers, due to its antiseptic, healing, anti-inflammatory and antioxidant properties. However, the antioxidant activity in its whole complexity has not been fully studied in order to elucidate the mechanisms of action involved in this pharmacological effect. Objective: to determine if R. mangle bark aqueous extract and its polyphenolic fraction protect the main biomolecules from oxidative damage. The antioxidant activity of R. mangle extract and its polyphenolic fraction on the main biomolecules was determined by the following methods: oxidative damage trial on bovine serum albumin exposed to hydroxyl radicals generated in the Fenton system and the bleomycin-Fe3+ system-induced DNA oxidative degradation trial. Results: the R. mangle bark extract and its polyphenolic fraction, at the highest tested concentration, reduced the sulfhydryl group oxidation by 87,3 percent and 89,1 percent and they also inhibited the DNA degradation by 98.4 percent and 91.9 percent respectively. The regression analysis demonstrated that both effects depended on tannin concentration in the extract and its fraction. The comparison of regression lines revealed that the extract and its fraction were equally effective in protecting bovine serum albumin from oxidation by hydroxyl radicals; however, the extract was more effective when protecting DNA from oxidative degradation than its fraction. The R mangle aqueous extract showed a protective effect on the main biomolecules from the oxidative damage, evidenced by inhibiting loss of sulfhydryl group in bovine serum albumin and decreasing the DNA degradation. At the same time, it was shown that polyphenolic compounds present in the extract were the main responsible for the antioxidant effects observed in this study

Efectos antioxidantes de una mezcla de principios activos de origen natural con actividad potencial en el tratamiento del vitiligo / Antioxidant effect of a mixture of natural origin with potential use in vitiligo

Se ha propuesto que el estrés oxidativo estaría involucrado en la patogénesis de la degeneración del melanocito en el vitiligo, donde se ha demostrado un desequilibrio tisular del sistema óxido-reducción. Estos hallazgos han promovido la utilización de nuevos tratamientos que contribuyan al equilibrio de antioxidantes en la epidermis afectada. Una nueva formulación de origen vegetal que contiene extractos de Pimenta racemosa, Cucumis melo y Citrus aurantifolia fue estudiada en un ensayo clínico experimental, aleatorizado y a doble ciego en pacientes con vitiligo vulgar estable con resultados satisfactorios. En el presente trabajo se evaluó la mezcla de principios activos en modelos experimentales in vitro, básicamente sus efectos antioxidantes sobre los fosfolípidos de membrana y sobre mediadores redox de interés en la fisiopatología del vitiligo. El extracto ensayado posee efectos inhibitorios de la peroxidación lipídica espontánea de fosfolípidos. Presenta actividad catalítica frente al H2O2 y actividad secuestradora de radicales libres, particularmente del radical hidroxilo, uniéndose al hierro, de forma que impide la formación de este radical. Adicionalmente, posee efectos fotoprotectores. Dados estos resultados, parece probable que el efecto observado en la clínica para esta combinación de principios activos naturales esté mediado por la mejora del sistema redox del entorno del melanocito.

Oxidative stress has been proposed as a part of the pathological mechanisms of melanocyte degradation invitiligo. It has been demonstrated a redox disruption inaffected areas. New therapeutically approach based onthese facts has been proposed recently. A novel combination of natural extracts (Pimenta racemosa, Cucumis melo, and Citrus aurantifolia) has been successfully tested in a double blind clinical assay in vitiligo. In the present manuscript it has been tested this mixture in in vitro assays, basically in the inhibition of phospholipids oxidation and related assays on redox mediator, involving in vitiligo physiopathology. The sample showed an antioxidant effect when assayed on spontaneous lipid peroxidation test in phospholipids. Inaddition the extract acted as a scavenger of H2O2, and free radicals, in particular hydroxyl radical by a mechanisms involving iron quenching. A photo protective effect of the sample has been also demonstrated. Insummary, our results shown that the modification of melanocyte redox environment may explain, at least inpart, the favorable clinical effects of this natural combination in vitiligo.

Therapeutic efficacy of ozone in patients with diabetic foot.

Oxidative stress is suggested to have an important role in the development of complications in diabetes. Because ozone therapy can activate the antioxidant system, influencing the level of glycemia and some markers of endothelial cell damage, the aim of this study was to investigate the therapeutic efficacy of ozone in the treatment of patients with type 2 diabetes and diabetic feet and to compare ozone with antibiotic therapy. A randomized controlled clinical trial was performed with 101 patients divided into two groups: one (n = 52) treated with ozone (local and rectal insufflation of the gas) and the other (n = 49) treated with topical and systemic antibiotics. The efficacy of the treatments was evaluated by comparing the glycemic index, the area and perimeter of the lesions and biochemical markers of oxidative stress and endothelial damage in both groups after 20 days of treatment. Ozone treatment improved glycemic control, prevented oxidative stress, normalized levels of organic peroxides, and activated superoxide dismutase. The pharmacodynamic effect of ozone in the treatment of patients with neuroinfectious diabetic foot can be ascribed to the possibility of it being a superoxide scavenger. Superoxide is considered a link between the four metabolic routes associated with diabetes pathology and its complications. Furthermore, the healing of the lesions improved, resulting in fewer amputations than in control group. There were no side effects. These results show that medical ozone treatment could be an alternative therapy in the treatment of diabetes and its complications.

Protective effect of gossypitrin on carbon tetrachloride-induced in vivo hepatotoxicity.

Carbon tetrachloride (CCl4) is a known environmental biohazard, which induces lipid peroxidation (LPO) and oxidative damage in rat liver. In this study, the hepatoprotective effect of Gossypitrin, a flavonoid extracted from Hibiscus elatus S.W, was investigated against the CCl4-induced in vivo hepatotoxicity. The levels of malondialdehyde (MDA) were assayed as an index of LPO and the levels of catalase (CAT) activity as a biomarker of oxidative damage. Leakage of aspartate aminotransferase (ALT) and lactate dehydrogenase (LDH), liver weight/body weight ratio as well as morphological parameters were used as signs of hepatotoxicity. CCl4 (1 ml/kg), intraperitoneally injected into rats, caused increased MDA production and CAT activity, and also a significant ALT and LDH leakage as compared to levels of these constituents in the control group. Changes in morphology, including steatosis, cells forming balloon cells and necrosis were evaluated in the hepatotoxin-induced damage. Treatment of rats with Gossypitrin (3.98, 5.97 and 8.95 mg/kg) 2 h before and 2 h after CCl4 injection, protected hepatocytes against cell injury induced by CCl4 and its efficacy as an antioxidant was similar to vitamin E (used as a reference antioxidant). These results are consistent with the conclusion that the toxicity of CCl4 is due to LPO and the generation of reactive oxygen species (ROS), and that Gossypitrin's protective effects relate to its direct radical scavenging ability and other antioxidative processes induced by its structure.