Ionic complexation improves wound healing in deep second-degree burns and reduces in-vitro ciprofloxacin cytotoxicity in fibroblasts.

The development of new treatments capable of controlling infections and pain related to burns continues to be a challenge. Antimicrobials are necessary tools, but these can be cytotoxic for regenerating cells. In this study, antibiotic-anesthetic (AA) smart systems obtained by ionic complexation of polyelectrolytes with ciprofloxacin and lidocaine were obtained as films and hydrogels. Ionic complexation with sodium alginate and hyaluronate decreased cytotoxicity of ciprofloxacin above 70% in a primary culture of isolated fibroblasts (p < 0.05). In addition, the relative levels of the proteins involved in cell migration, integrin ß1 and p-FAK, increased above 1.5 times (p < 0.05) with no significant differences in cell mobility. Evaluation of the systems in a deep second-degree burn model revealed that reepithelization rate was AA-films = AA-hydrogels > control films > no treated > reference cream (silver sulfadiazine cream). In addition, appendage conservation and complete dermis organization were achieved in AA-films and AA-hydrogels. Encouragingly, both the films and the hydrogels showed a significantly superior performance compared to the reference treatment. This work highlights the great potential of this smart system as an attractive dressing for burns, which surpasses currently available treatments.

Immunogenicity and reactogenicity of heterologous immunization against SARS CoV-2 using Sputnik V, ChAdOx1-S, BBIBP-CorV, Ad5-nCoV, and mRNA-1273.

Heterologous vaccination against coronavirus disease 2019 (COVID-19) provides a rational strategy to rapidly increase vaccination coverage in many regions of the world. Although data regarding messenger RNA (mRNA) and ChAdOx1 vaccine combinations are available, there is limited information about the combination of these platforms with other vaccines widely used in developing countries, such as BBIBP-CorV and Sputnik V. Here, we assess the immunogenicity and reactogenicity of 15 vaccine combinations in 1,314 participants. We evaluate immunoglobulin G (IgG) anti-spike response and virus neutralizing titers and observe that a number of heterologous vaccine combinations are equivalent or superior to homologous schemes. For all cohorts in this study, the highest antibody response is induced by mRNA-1273 as the second dose. No serious adverse events are detected in any of the schedules analyzed. Our observations provide rational support for the use of different vaccine combinations to achieve wide vaccine coverage in the shortest possible time.

Estado de situación de las áreas de investigación provinciales / Progress report on provincial health research areas

INTRODUCCIÓN: A través de la Red Ministerial de Investigación en Salud (REMINSA) se actualizó el estado de situación de las áreas provinciales de investigación en salud pública. MÉTODOS: Se realizaron reuniones virtuales de debate con los referentes REMINSA y una encuesta en Google Forms® sobre funcionamiento normativo, organizacional, presupuestario, alcance de tareas y necesidades de mejoras. RESULTADOS: Se recibieron 21 respuestas de un total de 21 provincias con referentes. Se verificó la existencia de un amplio marco de normativas regulatorias de la investigación en salud humana y, en menor medida, para impulsar la investigación en el marco de la salud pública. El 71% tiene cierta estructura institucional, el 20% ofrece becas de investigación, y el 20% posee residencias con perfil en investigación. La principal actividad es la regulación o participación en comités de ética. La promoción, difusión de resultados y elaboración de proyectos de investigación basada en evidencia quedaron relegadas (20%). Las áreas de investigación están consolidadas en la mayoría de las provincias. DISCUSIÓN: El desafío consiste en promover el desarrollo de estos sistemas en las provincias que no cuentan con áreas ministeriales y fortalecer las provincias que sí las poseen. REMINSA ha identificado oportunidades de mejorar la comunicación entre jurisdicciones, las normativas de promoción de la investigación y el trabajo en red para la investigación, la gestión y la toma de decisiones.

Agenda Nacional de Investigación Salud Pública 2021-2022 / National Agenda for Public Health Research 2021-2022

INTRODUCCIÓN: Una Agenda Nacional de Investigación en Salud Pública (ANISP) participativa y con priorización temática constituye un elemento estratégico para generar recomendaciones y políticas públicas basadas en evidencia, que impacten positivamente en la salud de las poblaciones y permitan lograr los objetivos sanitarios. En la actualización de la ANISP participaron la Dirección de Investigación en Salud (DIS) del Ministerio de Salud de la Nación (MSAL), a través de la Red Ministerial de Investigación en Salud (REMINSA), y actores de los niveles gubernamentales provinciales y nacionales pertenecientes a los sectores público, privado, de la salud, académico y de investigación. Se adaptó la herramienta original propuesta por la Organización Panamericana de la Salud, utilizada en el proceso en 2019. La actualización abarcó diferentes etapas. La selección de los temas contó con la legitimidad, reconocimiento y participación de los actores vinculados a la salud, a la gestión gubernamental y privada y a la investigación científica; se trabajó de manera federal y transversal, por consenso con las redes provinciales y un Comité Central Asesor en el MSAL. A partir de los lineamientos preliminares obtenidos, se elaboró una encuesta en línea semiestructurada, que fue distribuida a todos los actores federales y recibió 431 respuestas. El proceso resultó en 55 lineamientos priorizados, divididos en 6 áreas temáticas y 33 subtemas, seleccionados por votación según importancia, impacto y factibilidad.

Proceso de actualización de la Agenda Nacional de Investigación Salud Pública 2021-2022 / Update process of the National Agenda for Public Health Research 2021-2022

INTRODUCCIÓN: Una Agenda Nacional de Investigación en Salud Pública (ANISP) participativa y con priorización temática constituye un elemento estratégico para generar recomendaciones y políticas públicas basadas en evidencia, que impacten positivamente en la salud de las poblaciones y permitan lograr los objetivos sanitarios. En la actualización de la ANISP participaron la Dirección de Investigación en Salud (DIS) del Ministerio de Salud de la Nación (MSAL), a través de la Red Ministerial de Investigación en Salud (REMINSA), y actores de los niveles gubernamentales provinciales y nacionales pertenecientes a los sectores público, privado, de la salud, académico y de investigación. Se adaptó la herramienta original propuesta por la Organización Panamericana de la Salud, utilizada en el proceso en 2019. La actualización abarcó diferentes etapas. La selección de los temas contó con la legitimidad, reconocimiento y participación de los actores vinculados a la salud, a la gestión gubernamental y privada y a la investigación científica; se trabajó de manera federal y transversal, por consenso con las redes provinciales y un Comité Central Asesor en el MSAL. A partir de los lineamientos preliminares obtenidos, se elaboró una encuesta en línea semiestructurada, que fue distribuida a todos los actores federales y recibió 431 respuestas. El proceso resultó en 55 lineamientos priorizados, divididos en 6 áreas temáticas y 33 subtemas, seleccionados por votación según importancia, impacto y factibilidad

Beneficial effects of fish oil enriched in omega-3 fatty acids on the development and maintenance of neuropathic pain.

OBJECTIVE: The aim of this work was to assess the preventive effect of an eicosapentaenoic acid/docosahexaenoic acid-concentrate fish oil on neuropathic pain development and regenerative features of sciatic nerve in rats. METHODS: In the present study, rats with chronic constriction injury (CCI) of the sciatic nerve and sham-operated ones received fish oil enriched in omega-3 fatty acids (0.36 or 0.72 g/kg per day, oral) or saline solution for 21 days, with thermal hyperalgesia and mechanical allodynia being assessed before and 3, 7, 14 and 21 days after injury. KEY FINDINGS: Fish oil enriched in omega-3 fatty acids (0.72 g/kg) reversed thermal hyperalgesia and significantly reduced mechanical allodynia. In addition, ω-3 treatment (0.72 g/kg) promoted the recovery of the Sciatic Functional Index as well as restored axonal density and morphology, without the formation of neuroma in the injured sciatic nerves after 21 days. CONCLUSION: We conclude that the fish oil enriched in omega-3 fatty acids administration relieves thermal hyperalgesia and mechanical allodynia effectively and also enhances the recovery process in rats with CCI of the sciatic nerve. These findings might contribute to new therapeutic approaches including omega-3 fatty acids in neuropathic pain treatment.

Antidepressant and antinociceptive activities in animal models and in vitro assessment of the anti-thyroid activity of bis(DL-pyroglutamate)magnesium complex.

BACKGROUND: Magnesium is an essential element related with biochemistry of the brain and different types of depression have been associated with its deficiency. METHODS: The structure of a novel magnesium bis(DL-pyroglutamate) (Mg(DL-pGlu)2) was elucidated by X-ray crystallography. Wistar rats were used in the in vivo experiments. The antidepressant-like effect was assessed by the forced swim test (FST) and the antinociceptive activity was evaluated using hot plate test. In both, non-specific effects were evaluated by the open field test. Anti-thyroid activity was examined using Lang's method. Albumin binding behavior was evaluated by 3D fluorescence spectroscopy. RESULTS: For the Mg(DL-pGlu)2 complex (30 mg/kg), the FST test on Wistar rats revealed a decrease of 22% in the immobility time and an increment of 106% in the swimming time. The compound alters neither the locomotor activity nor the body weight after chronic administration. At the same dose, it showed antinociceptive activity, increasing the response latency. It blocks iodination reactions generating a charge transfer complex with iodine hence indicating anti-thyroid activity (Kc = 45366.5 ±â€¯29 M-1). Albumin 3D fluorescence spectroscopy experiments showed intensity increase of peak A and decrease of peak B. CONCLUSIONS: The results showed that the new compound produced a lowering of the immobility time and an increment of the swimming ability of the rats. The compound is able to increase the response latency in 70.0%, to capture iodine (anti-thyroid activity) and to interact with albumin through covalent type of interaction of the free NH groups.

Evidence of promising biological-pharmacological activities of the sertraline-based copper complex: (SerH2)2[CuCl4].

In the current study the ability of copper complex to exert multiple biological activities is combined with the pharmacological action of sertraline (SerH2Cl, antidepressant drug). The hydrated and anhydrous forms of the tetrachlorocuprate(II) salts, namely (SerH2)2[CuCl4]·½H2O and (SerH2)2[CuCl4], were synthesized and characterized by physicochemical methods. The crystal structures were determined by X-ray diffraction methods. The hydrate complex crystallizes in the monoclinic P21 space group with a=8.0807(2) Å, b=36.2781(8) Å, c=12.6576(3) Å, ß=95.665(2)°, and Z=4 molecules per unit cell and the un-hydrate in P21 with a=13.8727(6) Å, b=7.5090(3) Å, c=18.618(1) Å, ß=104.563(6)°, and Z=2. It has been suggested that Cu(II) ions might be critical in the development of mood disorders, showed potent biocidal activity, and also acted as analgesic adjuvant. To improve sertraline efficiency, the antidepressant and analgesic activities of the complex have been assessed in rats denoting a marked synergistic effect. Antithyroid and antimicrobial activities were also evaluated. Because depressive disorders and hyperthyroidism diseases led to an oxidative stress state, antioxidant capability has also been tested. The complex behaved as a good superoxide radical scavenger (IC50=6.3×10-6M). The ability of the complex to act as bromoperoxidase mimic was assessed. A pseudo-first order constant of k=0.157±0.007min-1 has been determined. The complex evidences promising biological-pharmacological activities and the albumin binding studies showed a Kb of 2.90×103M-1 showing an improvement in the uptake of sertraline by albumin at 8h incubation (time required for effective interaction of sertraline with the protein).

Improving the antidepressant action and the bioavailability of sertraline by co-crystallization with coumarin 3-carboxylate. Structural determination.

To improve the antidepressant action of sertraline a new salt with coumarin-3-carboxylate anion (SerH-CCA) has been synthesized by two different methods and characterized by FTIR spectroscopy and structural determinations by X-ray diffraction methods. The new salt is stabilized by strong intermolecular H-bonds involving the protonated amine group of SerH and the deprotonated carboxylate group of CCA. These findings can be correlated with the interpretation of the infrared spectrum. The salt, sertraline (SerHCl) and the sodium salt of coumarin-3-carboxylate (NaCCA) were orally administered male Wistar rats (10 mg/kg, based on sertraline). Rats were evaluated in separate groups by means of the forced swimming (FST). SerH-CCA produced antidepressant effects in a magnitude that exceeded SerHCl individual effects. None of these treatments affected activity levels by the open field OFT tests. We have also determined that the ion pair also improve the binding to bovine serum albumin (BSA) of the drug but retain its antimicrobial activity. It is reasonable to conclude that the replacement of chloride anion by a large organic anion in sertraline strengthens the pharmacological action of the native drug, binding to BSA with higher activity and retaining the antimicrobial activity of the antidepressant compound.

Biological activities of Zn(II)-S-methyl-cysteine complex as antiradical, inhibitor of acid phosphatase enzyme and in vivo antidepressant effects.

The antidepressant effect of simple Zn(II) salts has been proved in several animal models of depression. In this study, a coordination metal complex of Zn(II) having a sulfur containing ligand is tested as antidepressant for the first time. Forced swimming test method on male Wistar rats shows a decrease in the immobility and an increase in the swimming behavior after treatment with [Zn(S-Met)2] (S-Met=S-methyl-l-cysteine) being more effective and remarkable than ZnCl2. The thiobarbituric acid and the pyranine consumption (hydroxyl and peroxyl radicals, respectively) methods were applied to evaluate the antioxidant activity of S-Met and [Zn(S-Met)2] showing evidence of attenuation of hydroxyl but not peroxyl radicals activities. UV-vis studies on the inhibition of acid phosphatase enzyme (AcP) demonstrated that S-methyl-l-cysteine did not produce any effect but, in contrast, [Zn(S-Met)2] complex behaved as a moderate inhibitor. Finally, bioavailability studies were performed by fluorescence spectroscopy denoting the ability of the albumin to transport the complex.

Analgesia enhancement and prevention of tolerance to morphine: beneficial effects of combined therapy with omega-3 fatty acids.

OBJECTIVES: Recent evidence associates omega-3 fatty acids (O3) with pain reduction. The aim of this work was to evaluate the antinociceptive effect of O3, either alone or in combination with morphine after acute and chronic administration in rats. As well, a new pharmaceutical mixture that allows the concomitant administration of O3 and morphine as an oral solution was developed. METHODS: Animals were fed on a control or an experimental diet supplemented with O3. They were subjected to the hot-plate test to assess analgesic effect and tolerance to the analgesic effect of morphine. The open-field test was carried out to determine if the differences in the response latency can be related to non-specific sedative effects. KEY FINDINGS: O3 dietary supplementation increased the response latency compared with the control group. Acute treatment with morphine in these groups resulted in an additive antinociceptive effect not related to locomotor activity. Chronic coadministration of morphine with O3 attenuated the development of tolerance. Oral administration of the new pharmaceutical mixture showed analgesic activity with a subtherapeutic dose of morphine. CONCLUSION: This finding suggests a role for O3 as adjuncts to opioids in pain therapy and might contribute to the reduction of the occurrence of morphine side-effects.

Fluoxetine potentiation of omega-3 fatty acid antidepressant effect: evaluating pharmacokinetic and brain fatty acid-related aspects in rodents.

We previously reported that combined fluoxetine administration at antidepressant doses renders additive antidepressant effects, whereas non-antidepressant doses potentiate the omega-3 fatty acid antidepressant effect. In the present study, we aimed to evaluate putative pharmacokinetic and brain omega-3 fatty acid-related aspects for fluoxetine potentiation of omega-3 fatty acid antidepressant effect in rats. Coadministration of omega-3 fatty acids with a non-antidepressant dose of fluoxetine (1 mg/kg day) failed to affect both brain fluoxetine concentration and norfluoxetine plasma concentration profile. Fluoxetine plasma concentrations remained below the sensitivity limit of the detection method. Either antidepressant (10 mg/kg day) or non-antidepressant (1 mg/kg day) doses of fluoxetine in combination with omega-3 fatty acids increased hippocampal docosapentaenoic acid (DPA, 22:5 omega-3) levels. Although individual treatments had no effects on DPA concentration, DPA increase was higher when omega-3 were combined with the non-antidepressant dose of fluoxetine. Chronic DPA administration exerted antidepressant-like effects in the forced swimming test while increasing hippocampal docosahexaenoic (22:6 omega-3) and DPA levels. Our results suggest no pharmacokinetic interaction and reveal specific hippocampal DPA changes after fluoxetine and omega-3 combined treatments in our experimental conditions. The DPA role in the synergistic effect of fluoxetine and omega-3 combined treatments will be for sure the focus of future studies. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3316-3325, 2014.

Sertraline and its iodine product: experimental and theoretical vibrational studies: potential in vitro anti-thyroid activity of sertraline and iodine product toxicity with respect to male Wistar rats.

Mayor depression, obsessive-compulsive panic, social anxiety disorders are common diseases that are usually treated with sertraline hydrochloride which is the active ingredient of the well known drugs as Zoloft and Lustral. In this work, we presented a more complete vibrational characterization of the solid phase FT-IR spectra of Sertraline hydrochloride and its sertraline-iodine product in which the conformational space of the molecules was investigated performing molecular dynamic simulations within an NVT ensemble. Geometrical, electronic and vibrational properties were calculated with the density functional theory. Comparison of the simulated spectra with the experimental spectra provides important information about the ability of the computational method to describe the vibrational modes of both molecules. In addition, for the first time we present the evaluation of anti-thyroid activity of sertraline hydrochloride by using the Lang's method. Also, with the aim to evaluate the antidepressant effect of its iodine product we demonstrated for this compound the toxic effect towards the male Wistar rats.

Potentiation of omega-3 fatty acid antidepressant-like effects with low non-antidepressant doses of fluoxetine and mirtazapine.

Despite the advances in psychopharmacology, the treatment of depressive disorders is still not satisfactory. Side effects and resistance to antidepressant drugs are the greatest complications during treatment. Based on recent evidence, omega-3 fatty acids may influence vulnerability and outcome in depressive disorders. The aim of this study was to further characterize the omega-3 antidepressant-like effect in rats in terms of its behavioral features in the depression model forced swimming test either alone or in combination with antidepressants fluoxetine or mirtazapine. Ultimately, we prompted to determine the lowest dose at which omega-3 fatty acids and antidepressant drugs may still represent a pharmacological advantage when employed in combined treatments. Chronic diet supplementation with omega-3 fatty acids produced concentration-dependent antidepressant-like effects in the forced swimming test displaying a behavioral profile similar to fluoxetine but different from mirtazapine. Fluoxetine or mirtazapine at antidepressant doses (10 and 20 mg/kg/day, respectively) rendered additive effects in combination with omega-3 fatty acid supplementation (720 mg/kg/day). Beneficial effects of combined treatment were also observed at sub-effective doses (1 mg/kg/day) of fluoxetine or mirtazapine, since in combination with omega-3 fatty acids (720 mg/kg/day), antidepressants potentiated omega-3 antidepressant-like effects. The antidepressant-like effects occurred in the absence of changes in brain phospholipid classes. The therapeutic approach of combining omega-3 fatty acids with low ineffective doses of antidepressants might represent benefits in the treatment of depression, especially in patients with depression resistant to conventional treatments and even may contribute to patient compliance by decreasing the magnitude of some antidepressant dose-dependent side effects.