Dos terapias conocidas podrían ser efectivas como adyuvantes en el paciente crítico infectado por COVID-19 / Two known therapies could be useful as adjuvant therapy in critical patients infected by COVID-19

La neumonía causada por coronavirus, que se originó en Wuhan, China, a finales de 2019, se ha extendido por todo el mundo convirtiéndose en una pandemia. Desafortunadamente, a día de hoy no existe ninguna vacuna específica para el virus COVID-19, y el tratamiento está siendo de soporte con añadido de antivirales y otros fármacos, sin que hasta la fecha se haya evidenciado un beneficio claro. Muchos de estos pacientes se deterioran rápidamente y requieren ser intubados y ventilados mecánicamente, lo que está provocando el colapso del sistema sanitario en muchos países debido a la falta de ventiladores y de camas de críticos. En este documento revisamos dos terapias adyuvantes sencillas de aplicar, sin efectos deletéreos y de un coste bajo que podrían ser de utilidad para el tratamiento de la infección por coronavirus agudo severo asociado al síndrome respiratorio agudo (SARS-CoV-2). La vitamina C, un potente antioxidante, se ha convertido en una terapia relevante debido a sus beneficios potenciales cuando se administra por vía intravenosa. El efecto potencial de la vitamina C en la reducción de la inflamación en los pulmones podría desempeñar un papel clave en la lesión pulmonar causada por la infección por coronavirus. Otra posible terapia eficaz es el ozono. Pese a la controversia que siempre le ha acompañado, se ha estudiado y utilizado ampliamente durante muchos años y su eficacia se ha demostrado en múltiples estudios. Sin embargo, nuestro objetivo no es hacer una revisión exhaustiva de dichas terapias sino difundir sus efectos beneficiosos. Obviamente, los ensayos clínicos son necesarios, pero dado el potencial beneficio de estas terapias, recomendamos incorporarlas al arsenal terapéutico para el tratamiento del SARS-CoV-2

Pneumonia caused by coronavirus, which originated in Wuhan, China, in late 2019, has been spread around the world already becoming a pandemic. Unfortunately, there is not yet a specific vaccine or effective antiviral drug for treating COVID-19. Many of these patients deteriorate rapidly and require intubation and are mechanically ventilated, which is causing the collapse of the health system in many countries due to lack of ventilators and intensive care beds. In this document we review two simple adjuvant therapies to administer, without side effects, and low cost that could be useful for the treatment of acute severe coronavirus infection associated with acute respiratory syndrome (SARS-CoV-2). Vitamin C, a potent antioxidant, has emerged as a relevant therapy due to its potential benefits when administered intravenous. The potential effect of vitamin C in reducing inflammation in the lungs could play a key role in lung injury caused by coronavirus infection. Another potential effective therapy is ozone: it has been extensively studied and used for many years and its effectiveness has been demonstrated so far in multiples studies. Nevertheless, our goal is not to make an exhaustive review of these therapies but spread the beneficial effects themselves. Obviously clinical trials are necessaries, but due to the potential benefit of these two therapies we highly recommended to add to the therapeutic arsenal

El paradigma del ozono en el tratamiento del dolor / The ozone paradigm in pain treatment

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Ozone against Pseudomonas aeruginosa biofilms in contact lenses storage cases.

Pseudomonas aeruginosa is associated with ocular infections such as keratitis. Multipurpose contact lens solutions can be used for washing, disinfection and storage of contact lenses, however, P. aeruginosa biofilm disinfection by this method is unsatisfactory. The present study aimed to investigate the effectiveness of ozonated water in reducing P. aeruginosa colony count. Lenses kept in storage cases were contaminated with P. aeruginosa and disinfected using ozonized water, chlorhexidine, ultrasound and multipurpose solutions. The multipurpose solutions and ultrasound methods reduced colony count from 1.17 to 1.63 log10 CFU/cm2 (92.93% to 97.31%), respectively, of P. aeruginosa biofilm cell viability when compared to the positive control. Both, ozonated water and chlorhexidine showed 7.42 log reduction in the number of viable cells of P. aeruginosa biofilm. As compared to chlorhexidine, ozonized water did not depose any known toxic residues, so that we recommend it as an alternative disinfectant solution for contact lenses storage cases.

Aging Exacerbates Neuroinflammatory Outcomes Induced by Acute Ozone Exposure.

The role of environmental stressors, particularly exposure to air pollution, in the development of neurodegenerative disease remains underappreciated. We examined the neurological effects of acute ozone (O3) exposure in aged mice, where increased blood-brain barrier (BBB) permeability may confer vulnerability to neuroinflammatory outcomes. C57BL/6 male mice, aged 8-10 weeks or 12-18 months were exposed to either filtered air or 1.0 ppm O3 for 4 h; animals received a single IP injection of sodium fluorescein (FSCN) 20 h postexposure. One-hour post-FSCN injection, animals were transcardially perfused for immunohistochemical analysis of BBB permeability. ß-amyloid protein expression was assessed via ELISA. Flow cytometric characterization of infiltrating immune cells, including neutrophils, macrophages, and microglia populations was performed 20 h post-O3 exposure. Flow cytometry analysis of brains revealed increased microglia "activation" and presentation of CD11b, F4/80, and MHCII in aged animals relative to younger ones; these age-induced differences were potentiated by acute O3 exposure. Cortical and limbic regions in aged brains had increased reactive microgliosis and ß-amyloid protein expression after O3 insult. The aged cerebellum was particularly vulnerable to acute O3 exposure with increased populations of infiltrating neutrophils, peripheral macrophages/monocytes, and Ly6C+ inflammatory monocytes after insult, which were not significantly increased in the young cerebellum. O3 exposure increased the penetration of FSCN beyond the BBB, the infiltration of peripheral immune cells, and reactive gliosis of microglia. Thus, the aged BBB is vulnerable to insult and becomes highly penetrable in response to O3 exposure, leading to greater neuroinflammatory outcomes.

Ozonoterapia en medicina del dolor. Revisión / No disponible

Cada vez se emplea mas el ozono medico en el tratamiento del dolor. Tanto es asi que recientemente el Ministerio de Sanidad espanol ha incluido la ozonoterapia en la cartera de servicios de las unidades de dolor. La efectividad, seguridad y buena tolerabilidad del ozono, tanto infiltrado como administrado por via sistemica, justifican la extension de su uso en los ultimos anos. Debido al escaso conocimiento que en general hay acerca del tema, pretendemos, con esta revision, poner al dia los conocimientos actuales en torno a la ozonoterapia en medicina del dolor (AU)

Increasingly more medical ozone is used in the treatment of pain. So much so that recently the Spanish Ministry of Health has included ozone therapy in the portfolio of pain units. The effectiveness, safety and good tolerability of ozone, infiltrated as well as administered systemically, justify the extent of its use in recent years. Because little is known in general on this subject, the aim of this revision is to update current knowledge about ozone therapy in pain medicine (AU)

[The study of dynamics of clinical and molecular phenotypes in the generalized form of myasthenia with optimized and combined treatment].

The aim of the study was the research of clinical and molecular phenotypes in the generalized form of myasthenia with optimized treantment, which includes the application of basic mode of the treatment and meglumine sodium succinate, and also the combined mode of the treatment, which includes the mode of the treatment and meglumine sodium succinate and ozonotherapy. The most epressed improvement of indicators of the clinical and neurologic status (the eliminaton of motoring breakdown, eye movement disrders, the weaknesses of mimic, respiratory and chewing muscles, bulbar syndrome, the doubling in eye and ptosis, pharyngeal violations and increase in volume of movement of eyes) was observed in the group of patients receiving the combined therapy. The reduction of the epressiveness of the defeat of the neuromotor device and the decrement of the amplitude of the various degree of M-answer in patients with myasthenla is revealed in the application of the combined therapy in the comparison with the application of the basic and optimized therapy. For the first time we have investigaed the dynamics of the intensity of the expression of specfic peptides and proteins in blood serum in patients with the application of basic therapy, reamberin and ozonotherapy, which have allowed to open the new mechanisms of the efficiency ofthe combined therapy of the disease.

The potential role of ozone in ameliorating the age-related biochemical changes in male rat cerebral cortex.

Controlled ozone (O(3)) administration is known to promote oxidative preconditioning and, thus, may reverse chronic oxidative stress that accompanies aging. Therefore, the present work was undertaken to study the potential role of O(3) in ameliorating certain age-related biochemical changes represented by impaired activities of inner mitochondrial membrane enzymes, compromised energy production and increased oxidative burden in male rat cerebral cortex. Prophylactic administration of O(3)-O(2) mixture to 3 month-old rats, at an intrarectal dose of 0.6 mg O(3) kg(-1) body weight twice/week for 3 months then once/week until the age of 15 months, normalized reduced glutathione content, adenosine triphosphate/adenosine diphosphate ratio, mitochondrial superoxide dismutase (SOD) and complex IV (cytochrome-c oxidase) activities, improved glutathione redox index (GSHRI), complex I (NADH-ubiquinone oxidoreductase) and mitochondrial nitric oxide synthase (mtNOS) activities, and attenuated the rise in malondialdehyde (MDA) and mitochondrial protein carbonyl levels. On the other hand, therapeutic administration of the same dose of O(3)-O(2) mixture to 14 month-old rats three times/week for 1 month, reduced mitochondrial protein carbonyl level only. Other favorable effects, including normalization of Na,K-adenosine triphosphatase (Na,K-ATPase) activity and reduction in lipofuscin level in the prophylactic group, as well as improvement in mitochondrial SOD and complex I activities with a decrease in total MDA level in the therapeutic group, were comparable to the effects observed in the corresponding O(2)-treated control groups. In conclusion, the present study revealed that prophylactic administration of O(3)-O(2) mixture provided better amelioration of age-related cerebrocortical alterations by combining the advantages of both O(3) and O(2) therapies.

Evolution of algal toxicity during (photo)oxidative degradation of diuron.

In the aquatic environment and in engineered water treatment systems, organic contaminants can undergo oxidative and photochemical transformations. For an overall risk assessment, the toxicity of the resulting transformation products has to be investigated. In this study, the toxicity of degradation products of diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) formed during its degradation by four (photo)oxidative processes (direct phototransformation, triplet-induced photosensitized oxidation, oxidation by hydroxyl radicals and ozone) was investigated in buffered aqueous solution. The toxicity was evaluated using the combined algae test with Pseudokirchneriella subcapitata that determines both, specific inhibition of photosynthesis and inhibition of the growth rate. The comparison between evolution of toxicity and degradation kinetics indicated that the toxicity during all studied processes was caused predominantly by diuron whereas the formation of degradation products did not contribute to the mixture toxicity. This implies that, if any more toxic transformation products than diuron were formed, their concentration was not sufficiently high to affect the mixture toxicity, which was dominated by the parent compound diuron. On this account, no further studies on identification of degradation products and their toxicity are needed. This study presents an example of a systematic and simple first tier method to assess the toxicity of degradation products.

Intra-peritoneal application of catechins and EGCG as in vivo inhibitors of ozone-induced oxidative stress.

Oxidative stress is considered as a prominent feature of many acute and chronic diseases as well as of the normal aging process. We examined the effects of intra-peritoneal administration of catechins and EGCG as in vivo inhibitors of oxidative stress induced by ozone administration in two groups of Wistar rats. The first group was treated by intra-peritoneal administration of catechins and EGCG after the administration of ozone and the second group was pretreated by intra-peritoneal administration of catechins and EGCG prior to ozone administration. We determined in blood the activity of the enzymes superoxide dismutase and glutathione peroxidase, total antioxidant capacity, levels of copper and zinc and in urine malonaldehyde contents. Ozone administration resulted in significant reduction of glutathione peroxidase activity, plasma zinc levels and plasma and Red Blood Cells antioxidant capacity. Catechins and EGCG upregulate superoxide dismutase activity and maintain plasma and Red Blood Cells antioxidant capacity. Malonaldehyde levels at the end of the study were significantly increased only in the first group. Our data demonstrate that treatment with catechins and EGCG cannot reverse or prevent the effects of oxidative stress although some modulation occurs.

Effects of L-Canavanine and ozone on vascular reactivity in septicemic rats

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Septicemia leads to oxidative stress with overproduction of reactive-oxygen species (ROS) and consumption of endogenous antioxidant enzymes. We tested a twofold hypothesis: (1) does oxidative stress (OxS) induced by sepsis acting alone or in concert with augmented inflammatory processes contributes to sepsis-related vascular dysfunction, and, (2) whether ozone (O3) and L-canavanine (CAV) mitigate the negative impact of the aforementioned phenomena. We investigated the relative impact of treatment with CAV and/or O3 on vascular OxS associated vascular functional changes in septicemic rats. For this study, 60 male Sprague–Dawley rats were used and divided into six experimental groups (n = 10): control group (C), sham-operated (Sham), septicemic rats (S), S rats treated with CAV (100 mg/kg. i.p; S + CAV), S rats treated with (..) (AU)

Combining sap flow and eddy covariance approaches to derive stomatal and non-stomatal O3 fluxes in a forest stand.

Stomatal O3 fluxes to a mixed beech/spruce stand (Fagus sylvatica/Picea abies) in Central Europe were determined using two different approaches. The sap flow technique yielded the tree-level transpiration, whereas the eddy covariance method provided the stand-level evapotranspiration. Both data were then converted into stomatal ozone fluxes, exemplifying this novel concept for July 2007. Sap flow-based stomatal O3 flux was 33% of the total O3 flux, whereas derivation from evapotranspiration rates in combination with the Penman-Monteith algorithm amounted to 47%. In addition to this proportional difference, the sap flow-based assessment yielded lower levels of stomatal O3 flux and reflected stomatal regulation rather than O3 exposure, paralleling the daily courses of canopy conductance for water vapor and eddy covariance-based total stand-level O3 flux. The demonstrated combination of sap flow and eddy covariance approaches supports the development of O3 risk assessment in forests from O3 exposure towards flux-based concepts.

Stomatal uptake of O3 in aspen and aspen-birch forests under free-air CO2 and O3 enrichment.

Rising atmospheric carbon dioxide (CO2) may alleviate the toxicological impacts of concurrently rising tropospheric ozone (O3) during the present century if higher CO2 is accompanied by lower stomatal conductance (gs), as assumed by many models. We investigated how elevated concentrations of CO2 and O3, alone and in combination, affected the accumulated stomatal flux of O3 (AFst) by canopies and sun leaves in closed aspen and aspen-birch forests in the free-air CO2-O3 enrichment experiment near Rhinelander, Wisconsin. Stomatal conductance for O3 was derived from sap flux data and AFst was estimated either neglecting or accounting for the potential influence of non-stomatal leaf surface O3 deposition. Leaf-level AFst (AFst(l)) was not reduced by elevated CO2. Instead, there was a significant CO2 x O(3) interaction on AFst(l), as a consequence of lower values of gs in control plots and the combination treatment than in the two single-gas treatments. In addition, aspen leaves had higher AFst(l) than birch leaves, and estimates of AFst(l) were not very sensitive to non-stomatal leaf surface O3 deposition. Our results suggest that model projections of large CO2-induced reductions in gs alleviating the adverse effect of rising tropospheric O3 may not be reasonable for northern hardwood forests.

Moving toward effective ozone flux assessment.

We present a comment about "Ozone risk assessment for plants: central role of metabolism-dependent changes in reducing power" by Dizengremel, Le Thiec, Bagard, and Jolivet. As tools for summarizing plant O(3) sensitivity in simple indices, Dizengremel et al. suggest: reducing power, as antioxidant regeneration through the Halliwell/Asada cycle requires NADPH from the photosynthetic light reaction; Rubisco/PEPc ratio, as an index of the energy balance between anabolic and catabolic reactions; and water-use efficiency as a time-integrated approximation of the carbon gain to stomatal O(3) uptake ratio. The scientific background is solid, and simple enough (although expensive) to be translated into modelling and routine use. In the last decade, several approaches have been developed, mostly by using photosynthesis as a metric of defence. All these approaches should be experimentally tested in different and realistic conditions, before the results are transferred to the field and used in effective O(3) flux modelling and assessment.

Ozone risk assessment for plants: central role of metabolism-dependent changes in reducing power.

The combination of stomatal-dependent ozone flux and total ascorbate level is currently presented as a correct indicator for determining the degree of sensitivity of plants to ozone. However, the large changes in carbon metabolism could play a central role in the strategy of the foliar cells in response to chronic ozone exposure, participating in the supply of reducing power and carbon skeletons for repair and detoxification, and modifying the stomatal mode of functioning. To reinforce the accuracy of the definition of the threshold for ozone risk assessment, it is proposed to also consider the redox pool (NAD(P)H), the ratio between carboxylases and the water use efficiency as indicators of the differential ozone tolerance of plants.

Ozone oxidative preconditioning inhibits inflammation and apoptosis in a rat model of renal ischemia/reperfusion injury.

Ischemia/reperfusion injury, which is commonly seen in the field of renal surgery or transplantation, is a major cause of acute renal failure. Previous studies showed that ozone oxidative preconditioning (OzoneOP) attenuated renal ischemia/reperfusion injury. The objective of this study was to examine the role of the OzoneOP in modulating inflammation and apoptosis after renal ischemia/reperfusion injury. Rats were subjected to 45 min of renal ischemia, with or without treatment with OzoneOP (1 mg/kg). Renal function, inflammation and apoptosis were compared at 24 h after renal injury. OzoneOP improved the renal dysfunction and reduced inflammation and apoptosis after ischemia/reperfusion injury. In conclusion, OzoneOP has potent anti-apoptotic and anti-inflammatory properties. These findings may have major implications in the treatment of human ischemic acute renal failure.

Increasing risk for negative ozone impacts on vegetation in northern Sweden.

Trends were found for increasing surface ozone concentrations during April-September in northern Sweden over the period 1990-2006 as well as for an earlier onset of vegetation growing season. The highest ozone concentrations in northern Sweden occurred in April and the ozone concentrations in April showed a strong increasing trend. A model simulation of ozone flux for Norway spruce indicated that the provisional ozone flux based critical level for forests in Europe is exceeded in northern Sweden. Future climate change would have counteracting effects on the stomatal conductance and needle ozone uptake, mediated on the one hand by direct effect of increasing air temperatures and on the other through increasing water vapour pressure difference between the needles and air. Thus, there is a substantial and increasing risk for negative impacts of ozone on vegetation in northern Sweden, related mainly to increasing ozone concentrations and an earlier onset of the growing season.

Promoting the O3 flux concept for European forest trees.

Tropospheric ozone (O3) levels are predicted to stay high, being a factor within "global change" with potential effects on the carbon sink strength of forest trees. Hence, new approaches to O3 risk assessment and their validation are required, although appropriate databases for adult trees are scant. Approaches based on external O3 exposure are presently being evaluated against the ones on O3 flux into leaves, as the cumulative uptake has the capacity for deriving O3 risk from cause-effect relationships. The effective dose, however, needs to account for the trees' O3 defence and tolerance in addition to O3 uptake. The current status of promoting the preferable mechanistic O3 flux concept is highlighted for major regions of Europe, addressing refinements and simplifications needed for routine use. At the pan-European scale, however, the flux-based concept is ready for use in O3 risk assessment and has the potential of meso-scale application at the forest ecosystem level.

Risk assessments for forest trees: the performance of the ozone flux versus the AOT concepts.

Published ozone exposure-response relationships from experimental studies with young trees performed at different sites across Europe were re-analysed in order to test the performance of ozone exposure indices based on AOTX (Accumulated exposure Over a Threshold of X nmol mol(-1)) and AF(st)Y (Accumulated Stomatal Flux above a threshold of Y nmol m(-2) s(-1)). AF(st)1.6 was superior, as compared to AOT40, for explaining biomass reductions, when ozone sensitive species with differing leaf morphology were included in the analysis, while this was not the case for less sensitive species. A re-analysis of data with young black cherry trees, subject to different irrigation regimes, indicated that leaf visible injuries were more strongly related to the estimated stomatal ozone uptake, as compared to the ozone concentration in the air. Experimental data with different clones of silver birch indicated that leaf thickness was also an important factor influencing the development of ozone induced leaf visible injury.

High-resolution modelling of AOT40 and stomatal ozone uptake in wheat and grassland: a comparison between 2000 and the hot summer of 2003 in Switzerland.

The aim was to compare the ozone risk for agricultural crops in Switzerland during the hot and dry year 2003 with the more 'normal' situation in 2000. An improved version of the Ozone DEposition Model ODEM was used at a 2 x 2 km resolution. The distribution of the index AOT40 was compared with the accumulated stomatal ozone flux, AF(st). Averaged AOT40 at 2 m and at canopy height was much higher in 2003 than in 2000, but inter-annual differences in AF(st) for wheat and grasslands were small due to the limiting effect of low soil water contents in 2003. AOT40 suggested larger potential yield losses in wheat in 2003, while using AF(st) with a threshold of 6 nmol m(-2) s(-1) (AF(st)6) yielded similar estimates for both years. The data show that modelling of AF(st) can be used to differentiate ozone risks between regions and years at a national scale.

Implications of climate change for the stomatal flux of ozone: a case study for winter wheat.

Climate change factors such as elevated CO2 concentrations, warming and changes in precipitation affect the stomatal flux of ozone (O3) into leaves directly or indirectly by altering the stomatal conductance, atmospheric O3 concentrations, frequency and extent of pollution episodes and length of the growing season. Results of a case study for winter wheat indicate that in a future climate the exceedance of the flux-based critical level of O3 might be reduced across Europe, even when taking into account an increase in tropospheric background O3 concentration. In contrast, the exceedance of the concentration-based critical level of O3 will increase with the projected increase in tropospheric background O3 concentration. The influence of climate change should be considered when predicting the future effects of O3 on vegetation. There is a clear need for multi-factorial, open-air experiments to provide more realistic information for O3 flux-effect modelling in a future climate.