Quimioterapia nanométrica a base de cannabinoides para el tratamiento de tumores ginecológicos / Cannabinoid based chemo-nanotherapy for the treatment of gynecological malignancies

El cannabidiol está despertando un creciente interés como agente antitumoral. Sin embargo, no se ha estudiado su efecto en cáncer de ovario, uno de los tumores más agresivos en mujeres. En el presente trabajo se ha evaluado, por primera vez, el potencial uso del cannabidiol en solución y encapsulado en nanopartículas funcionalizadas con ácido fólico en cáncer de ovario, ya que estos tumores sobreexpresan los receptores de ácido fólico, permitiendo una acumulación selectiva de estas nanoformulaciones en las células tumorales. El cannabidiol en solución inhibe la proliferación y migración de las células SKOV-3. En terapia de combinación, aumenta significativamente la eficacia antitumoral del paclitaxel, presentando un efecto sensibilizador y sinérgico. En los modelos in ovo, la administración previa de cannabidiol en solución seguido de su coadministración con paclitaxel muestra un efecto inhibitorio sobre el crecimiento tumoral significativamente superior al paclitaxel en monoterapia. Las nanopartículas desarrolladas son eficazmente internalizadas por las células SKOV-3, presentando las nanopartículas con ácido fólico una captación más rápida. Aunque en los estudios de eficacia antitumoral in vitro las nanopartículas funcionalizadas no presentan una actividad antiproliferativa superior al cannabidiol en solución o a las nanopartículas no funcionalizadas, en los modelos in ovo su eficacia antitumoral es significativamente superior, indicando que el desarrollo de nanopartículas funcionalizadas con ácido fólico es una buena estrategia para vectorizar el cannabidiol a tumores de ovario. Por último, las nanopartículas de cannabidiol potencian el efecto antitumoral del paclitaxel, presentando las formulaciones funcionalizadas con ácido fólico una mayor eficacia que el cannabidiol en solución. (AU)

Cannabidiol has become in a potential anticancer agent. Nevertheless, it has not been evaluated in ovarian cancer, one of the most aggressive tumors in women. In this work, the potential use of cannabidiol in solution and encapsulated into polymeric nanoparticles coated with folic acid was evaluated for the first time for the treatment of ovarian cancer. Ovarian tumors over-express folic acid receptors and folic-acid-coated nanoformulations trend to be selectively accumulated at tumor site. Cannabidiol in solution administered as monotherapy inhibits the proliferation and migration of SKOV-3 cells. In combination therapy, it significantly increases the antitumor efficacy of paclitaxel, showing a sensitizer and synergistic effect. In ovo, the previous administration of cannabidiol in solution followed by its co-administration with paclitaxel, shows a significantly higher inhibitory effect on ovarian tumor growth than single paclitaxel. The developed nanoparticles are efficiently uptaken by SKOV-3 cells, showing folic acid coated formulations a faster internalization. Although coated formulations do not exhibit a higher in vitro antiproliferative effect compared to cannabidiol in solution or non-coated formulations, in ovo its antitumoral efficacy is significantly higher. This indicates thatfolic acid-coated nanoparticles represent a good strategy to target cannabidiol to ovarian tumors. Finally, cannabidiol-loaded nanoparticles improve the in vitro antiproliferative effect of paclitaxel, showing folic acid-coated-formulations a better efficacy than cannabidiol in solution. (AU)

Functionalization of Morin-Loaded PLGA Nanoparticles with Phenylalanine Dipeptide Targeting the Brain.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, with its incidence constantly increasing. To date, there is no cure for the disease, with a need for new and effective treatments. Morin hydrate (MH) is a naturally occurring flavonoid of the Moraceae family with antioxidant and anti-inflammatory properties; however, the blood-brain barrier (BBB) prevents this flavonoid from reaching the CNS when aiming to potentially treat AD. Seeking to use the LAT-1 transporter present in the BBB, a nanoparticle (NPs) formulation loaded with MH and functionalized with phenylalanine-phenylalanine dipeptide was developed (NPphe-MH) and compared to non-functionalized NPs (NP-MH). In addition, two formulations were prepared using rhodamine B (Rh-B) as a fluorescent dye (NPphe-Rh and NP-Rh) to study their biodistribution and ability to cross the BBB. Functionalization of PLGA NPs resulted in high encapsulation efficiencies for both MH and Rh-B. Studies conducted in Wistar rats showed that the presence of phenylalanine dipeptide in the NPs modified their biodistribution profiles, making them more attractive for both liver and lungs, whereas non-functionalized NPs were predominantly distributed to the spleen. Formulation NPphe-Rh remained in the brain for at least 2 h after administration.

DoE-based development of celecoxib loaded PLGA nanoparticles: In ovo assessment of its antiangiogenic effect.

Abnormal angiogenesis plays a main role in the pathogenesis of many diseases such as cancer, and inflammatory autoimmune disorders among others, and its inhibition represents a potential strategy for their management. Celecoxib (CXB) that is one of the most prescribed selective COX-2 inhibitors and is currently approved for the treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis inhibits angiogenesis. The objective of this manuscript was to design, develop, and characterize polymeric nanoparticles for the parenteral administration of CXB which the aim of facilitating its administration and improving its antiangiogenic activity while decreasing its adverse effects. A Plackett-Burman design was used to optimize the formulation. The PVA concentration, the sonication time, the sonicator amplitude and the CXB:PLGA ratio were selected as independent variables and particle size, polydispersity index, drug loading, and entrapment efficiency as responses. Optimized nanoparticles (formulations F2, F6 and F9) showed a particle size around 280 nm, a low polydispersion (PDI ≤ 0.2), a negative zeta potential around -25 mV, a high entrapment efficiency (above 88 %) and a controlled drug release for at least 10 days. Moreover, they were physically and chemically stable for at least 3 months when stored at 4 °C. Interestingly, CXB-loaded nanoparticles showed a higher angiogenesis inhibition than CXB in solution administered at the same concentration. F9 nanoparticles that were prepared using PVA at 0.5 %, a sonication time of 7 min, a sonicator amplitude of 80 % and a CXB:PLGA ratio of 20:100 were selected as the most suitable CXB-formulation. It represents a promising strategy to administer CXB and improve its efficacy in disorders with pathological angiogenesis such as cancer and arthritic diseases.

Celecoxib Microparticles for Inhalation in COVID-19-Related Acute Respiratory Distress Syndrome.

Inhalation therapy is gaining increasing attention for the delivery of drugs destined to treat respiratory disorders associated with cytokine storms, such as COVID-19. The pathogenesis of COVID-19 includes an inflammatory storm with the release of cytokines from macrophages, which may be treated with anti-inflammatory drugs as celecoxib (CXB). For this, CXB-loaded PLGA microparticles (MPs) for inhaled therapy and that are able to be internalized by alveolar macrophages, were developed. MPs were prepared with 5% and 10% initial percentages of CXB (MP-C1 and MP-C2). For both systems, the mean particle size was around 5 µm, which was adequate for macrophage uptake, and the mean encapsulation efficiency was >89%. The in vitro release of CXB was prolonged for more than 40 and 70 days, respectively. The uptake of fluorescein-loaded PLGA MPs by the RAW 264.7 macrophage cell line was evidenced by flow cytometry, fluorescence microscopy and confocal microscopy. CXB-loaded PLGA MPs did not produce cytotoxicity at the concentrations assayed. The anti-inflammatory activity of CXB (encapsulated and in solution) was evaluated by determining the IL-1, IL-6 and TNF-α levels at 24 h and 72 h in RAW 264.7 macrophages, resulting in a higher degree of reduction in the expression of inflammatory mediators for CXB in solution. A potent degree of gene expression reduction was obtained with the developed CXB-loaded MPs.

Micro- and Nano-Systems Developed for Tolcapone in Parkinson's Disease.

To date there is no cure for Parkinson's disease (PD), a devastating neurodegenerative disorder with levodopa being the cornerstone of its treatment. In early PD, levodopa provides a smooth clinical response, but after long-term therapy many patients develop motor complications. Tolcapone (TC) is an effective adjunct in the treatment of PD but has a short elimination half-life. In our work, two new controlled delivery systems of TC consisting of biodegradable PLGA 502 (poly (D,L-lactide-co-glycolide acid) microparticles (MPs) and nanoparticles (NPs) were developed and characterized. Formulations MP-TC4 and NP-TC3 were selected for animal testing. Formulation MP-TC4, prepared with 120 mg TC and 400 mg PLGA 502, exhibited a mean encapsulation efficiency (EE) of 85.13%, and zero-order in vitro release of TC for 30 days, with around 95% of the drug released at this time. Formulation NP-TC3, prepared with 10 mg of TC and 50 mg of PLGA 502, exhibited mean EE of 56.69%, particle size of 182 nm, and controlled the release of TC for 8 days. Daily i.p. (intraperitoneal) doses of rotenone (RT, 2 mg/kg) were given to Wistar rats to induce neurodegeneration. Once established, animals received TC in saline (3 mg/kg/day) or encapsulated within formulations MP-TC4 (amount of MPs equivalent to 3 mg/kg/day TC every 14 days) and NP-TC3 (amount of NPs equivalent to 3 mg/kg/day TC every 3 days). Brain analyses of Nissl-staining, GFAP (glial fibrillary acidic protein), and TH (tyrosine hydroxylase) immunohistochemistry as well as behavioral testing (catalepsy, akinesia, swim test) showed that the best formulation was NP-TC3, which was able to revert PD-like symptoms of neurodegeneration in the animal model assayed.

Matrix tablets based on a novel poly (magnesium acrylate) hydrogel for the treatment of inflammatory bowel diseases.

The objective of this work was to evaluate the potential use of a new polymer (PAMgA) in the development sustained release matrix tablets for the treatment of bowel inflammatory diseases. For this purpose, budesonide, a highly lipophilic compound, was used as model drug. Tablets with two reticulation grades of PAMgA (PAMgA 5 and 40) and with 9 mg of budesonide were developed and characterized. All the studies were carried out using biorelevant media (FaSSGF and FaSSIF). Swelling and erosion of PAMgA tablets was influenced by the reticulation grade of the polymer and the biorelevant media assayed, being water uptake higher for PAMgA 40 tablets in intestinal fluid, whereas PAMgA 5 showed more intense erosion in this biorelevant medium. Budesonide was released slowly from PAMgA tablets, both in gastric and intestinal environment, following Super case II transport kinetics (relaxation-controlled delivery), with a lag time of around 1-2 h. When the dissolution medium was changed sequentially throughout the trial, 75% of the budesonide dose was released in a sustained manner between 4 and 20 h of testing from PAMgA tablets, showing a more controlled budesonide release than Entocort® and Budenofalk® (commercially available sustained release formulations of budesonide). In conclusion, PAMgA polymer allows controlling the release of highly lipophilic drugs as budesonide, being an useful excipient for the development of sustained release matrix tablets.

Sulfasalazine Microparticles Targeting Macrophages for the Treatment of Inflammatory Diseases Affecting the Synovial Cavity.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with sulfasalazine (SSZ) extensively used for long-term treatment of both juvenile and adult RA. Its use is associated with adverse effects and toxicity due to its non-selective biodistribution. Macrophages play an important role in inflammatory processes. In order to target SSZ to macrophages in this work two microparticulate systems (MPs) are developed: SSZ-loaded PLGA MPs without and with α-tocopherol, with particle sizes lower than 5 µm and encapsulation efficiencies of 81.07 ± 11% and 63.50 ± 6.62%, respectively. Release of SSZ from MPs prepared with α-tocopherol was prolonged for 20 days. In RAW 264.7 cell macrophages MPs prepared with α-tocopherol were captured faster. Cell viability studies confirmed that SSZ-loaded MPs prepared without and with α-tocopherol did not produce cytotoxicity at the concentrations assayed. The anti-inflammatory activity of SSZ-loaded MPs was studied by quantifying interleukins IL-1, IL-6 and TNF-α in macrophages. All formulations produced a significant reduction of cytokine concentrations after 24 and 72 h, indicating that release of SSZ from the MPs was able to inhibit the inflammatory response induced by lipopolysaccharide (LPS). Gene expression of IL-1, IL-6 and TNF-α was decreased by SSZ-loaded MPs. SSZ-loaded MPs prepared with α-tocopherol will potentially allow increasing the residence time of SSZ in the synovial cavity, prolonging its duration of action, and reducing the adverse effects associated with its non-selective biodistribution.

Limitations and Challenges in the Stability of Cysteamine Eye Drop Compounded Formulations.

Accumulation of cystine crystals in the cornea of patients suffering from cystinosis is considered pathognomonic and can lead to severe ocular complications. Cysteamine eye drop compounded formulations, commonly prepared by hospital pharmacy services, are meant to diminish the build-up of corneal cystine crystals. The objective of this work was to analyze whether the shelf life proposed for six formulations prepared following different protocols used in hospital pharmacies is adequate to guarantee the quality and efficacy of cysteamine eye drops. The long-term and in-use stabilities of these preparations were studied using different parameters: content of cysteamine and its main degradation product cystamine; appearance, color and odor; pH and viscosity; and microbiological analysis. The results obtained show that degradation of cysteamine was between 20% and 50% after one month of storage in the long-term stability study and between 35% and 60% in the in-use study. These data confirm that cysteamine is a very unstable molecule in aqueous solution, the presence of oxygen being the main degradation factor. Saturation with nitrogen gas of the solutions offers a means of reducing cysteamine degradation. Overall, all the formulae studied presented high instability at the end of their shelf life, suggesting that their clinical efficacy might be dramatically compromised.

Active Targeted Nanoformulations via Folate Receptors: State of the Art and Future Perspectives.

In normal tissues, the expression of folate receptors is low and limited to cells that are important for embryonic development or for folate reabsorption. However, in several pathological conditions some cells, such as cancer cells and activated macrophages, overexpress folate receptors (FRs). This overexpression makes them a potential therapeutic target in the treatment of cancer and inflammatory diseases to obtain a selective delivery of drugs at altered cells level, and thus to improve the therapeutic efficacy and decrease the systemic toxicity of the pharmacological treatments. Two strategies have been used to achieve this folate receptor targeting: (i) the use of ligands with high affinity to FRs (e.g., folic acid or anti-FRs monoclonal antibodies) linked to the therapeutic agents or (ii) the use of nanocarriers whose surface is decorated with these ligands and in which the drug is encapsulated. This manuscript analyzes the use of FRs as a target to develop new therapeutic tools in the treatment of cancer and inflammatory diseases with an emphasis on the nanoformulations that have been developed for both therapeutic and imaging purposes.

Quimioterapia nanométrica a base de cannabinoides para el tratamiento de tumores ginecológicos / Cannabinoid based chemo-nanotherapy for the treatment of gynecological

El cannabidiol está despertando un creciente interés como agente antitumoral. Sin embargo, no se ha estudiado su efecto en cáncer de ovario, uno de los tumores más agresivos en mujeres. En el presente trabajo se ha evaluado, por primera vez, el potencial uso del cannabidiol en solución y encapsulado en nanopartículas funcionalizadas con ácido fólico en cáncer de ovario, ya que estos tumores sobre expresan los receptores de ácido fólico, permitiendo una acumulación selectiva de estas nanoformulaciones en las células tumorales. El cannabidiol en solución inhibe la proliferación y migración de las células SKOV-3. En terapia de combinación, aumenta significativamente la eficacia antitumoral del paclitaxel, presentando un efecto sensibilizador y sinérgico. En los modelos in ovo, la administración previa de cannabidiol en solución seguido de su coadministración con paclitaxel muestra un efecto inhibitorio sobre el crecimiento tumoral significativamente superior al paclitaxel en monoterapia. Las nanopartículas desarrolladas son eficazmente internalizadas por las células SKOV-3, presentando las nanopartículas con ácido fólico una captación más rápida. Aunque en los estudios de eficacia antitumoral in vitro las nanopartículas funcionalizadas no presentan una actividad antiproliferativa superior al cannabidiol en solución o a las nanopartículas no funcionalizadas, en los modelos in ovo su eficacia antitumoral es significativamente superior, indicando que el desarrollo de nanopartículas funcionalizadas con ácido fólico es una buena estrategia para vectorizar el cannabidiol a tumores de ovario. Por último, las nanopartículas de cannabidiol potencian el efecto antitumoral del paclitaxel, presentando las formulaciones funcionalizadas con ácido fólico una mayor eficacia que el cannabidiol en solución

Cannabidiol has become in a potential anticancer agent. Nevertheless, it has not been evaluated in ovarian cancer, one of the most aggressive tumors in women. In this work, the potential use of cannabidiol in solution and encapsulated into polymeric nanoparticles coated with folic acid was evaluated for the first time for the treatment of ovarian cancer. Ovarian tumors over-express folic acid receptors and folic-acid-coated nanoformulations trend to be selectively accumulated at tumor site. Cannabidiol in solution administered as monotherapy inhibits the proliferation and migration of SKOV-3 cells. In combination therapy, it significantly increases the antitumor efficacy of paclitaxel, showing a sensitizer and synergistic effect. In ovo, the previous administration of cannabidiol in solution followed by its co-administration with paclitaxel, shows a significantly higher inhibitory effect on ovarian tumor growth than single paclitaxel. The developed nanoparticles are efficiently uptaken by SKOV-3 cells, showing folic acid coated formulations a faster internalization. Although coated formulations do not exhibit a higher in vitro antiproliferative effect compared to cannabidiol in solution or non-coated formulations, in ovo its antitumoral efficacy is significantly higher. This indicates that folic acid-coated nanoparticles represent a good strategy to target cannabidiol to ovarian tumors. Finally, cannabidiol-loaded nanoparticles improve the in vitro antiproliferative effect of paclitaxel, showing folic acid-coated-formulations a better efficacy than cannabidiol in solution

PLGA Nanoparticles for the Intraperitoneal Administration of CBD in the Treatment of Ovarian Cancer: In Vitro and In Ovo Assessment.

The intraperitoneal administration of chemotherapeutics has emerged as a potential route in ovarian cancer treatment. Nanoparticles as carriers for these agents could be interesting by increasing the retention of chemotherapeutics within the peritoneal cavity. Moreover, nanoparticles could be internalised by cancer cells and let the drug release near the biological target, which could increase the anticancer efficacy. Cannabidiol (CBD), the main nonpsychotropic cannabinoid, appears as a potential anticancer drug. The aim of this work was to develop polymer nanoparticles as CBD carriers capable of being internalised by ovarian cancer cells. The drug-loaded nanoparticles (CBD-NPs) exhibited a spherical shape, a particle size around 240 nm and a negative zeta potential (-16.6 ± 1.2 mV). The encapsulation efficiency was high, with values above 95%. A controlled CBD release for 96 h was achieved. Nanoparticle internalisation in SKOV-3 epithelial ovarian cancer cells mainly occurred between 2 and 4 h of incubation. CBD antiproliferative activity in ovarian cancer cells was preserved after encapsulation. In fact, CBD-NPs showed a lower IC50 values than CBD in solution. Both CBD in solution and CBD-NPs induced the expression of PARP, indicating the onset of apoptosis. In SKOV-3-derived tumours formed in the chick embryo model, a slightly higher-although not statistically significant-tumour growth inhibition was observed with CBD-NPs compared to CBD in solution. To sum up, poly-lactic-co-glycolic acid (PLGA) nanoparticles could be a good strategy to deliver CBD intraperitoneally for ovarian cancer treatment.

Controlled Release of Highly Hydrophilic Drugs from Novel Poly(Magnesium Acrylate) Matrix Tablets.

The potential of a new poly(magnesium acrylate) hydrogel (PAMgA) as a pharmaceutical excipient for the elaboration of matrix tablets for the extended release of highly hydrophilic drugs was evaluated. The polymer was synthetized with two different crosslinking degrees that were characterized by FTIR and DSC. Their acute oral toxicity was determined in a mouse model, showing no toxicity at doses up to 10 g/kg. Matrix tablets were prepared using metformin hydrochloride as a model drug and the mechanisms involved in drug release (swelling and/or erosion) were investigated using biorrelevant media. This new hydrogel effectively controlled the release of small and highly hydrophilic molecules as metformin, when formulated in matrix tablets for oral administration. The rate of metformin release from PAMgA matrices was mainly controlled by its diffusion through the gel layer (Fickian diffusion). The swelling capacity and the erosion of the matrix tablets influenced the metformin release rate, that was slower at pH 6.8, where polymer swelling is more intensive, than in gastric medium, where matrix erosion is slightly more rapid. The crosslinking degree of the polymer significantly influenced its swelling capacity in acid pH, where swelling is moderate, but not in intestinal fluid, where swelling is more intense.

Potential Active Targeting of Gatifloxacin to Macrophages by Means of Surface-Modified PLGA Microparticles Destined to Treat Tuberculosis.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis and represents one of the leading causes of mortality worldwide due to multidrug-resistant TB (MDR-TB). In our work, a new formulation of biodegradable PLGA microparticles was developed for pulmonary administration of gatifloxacin, using a surface modifier agent to actively target alveolar macrophages thereby allowing to gain access of the drug to Mycobacterium tuberculosis. For this, rapid uptake of the particles by macrophages is beneficial. This process was evaluated with fluorescein-loaded microparticles using PLGA 502 or PLGA 502H as polymers and labrafil as surface modifier. Cell phagocytosis was studied in raw 264.7 mouse macrophage cell line after 3, 5, 24, and 48 h incubation with the microparticles. Labrafil enhanced the uptake rate of PLGA 502H microparticles by macrophages which was directly related to the modification of the polymer matrix. Gatifloxacin-loaded PLGA microparticles using PLGA 502 or PLGA 502H and labrafil were prepared. From our results, only microparticles prepared with PLGA 502H and labrafil exhibited high encapsulation efficiency (89.6 ± 0.2%), rapid phagocytosis by macrophages (3 h), and remained inside the cells for at least 48 h, thereby resulting in a suitable carrier to potentially treat MDR-TB.

Perfil de seguridad de capecitabina formulación innovadora y formulación genérica en adyuvancia del cáncer colorrectal no metastásico / Capecitabine safety profile, innovative and generic adjuvant formulation of nonmetastatic colorectal cancer

Objetivo: Analizar las reacciones adversas en pacientes con cáncer colorrectal no metastásico debidas al tratamiento con capecitabina innovadora o genérica, y/o al régimen quimioterápico empleado, capecitabina en monoterapia o en combinación con oxaliplatino (XELOX). Método: Estudio descriptivo retrospectivo llevado a cabo en un hospital de segundo nivel en dos periodos de estudio (noviembre de 2013-abril de 2014 y agosto de 2016-mayo de 2017). Las variables recogidas fueron variables de exposición (esquema quimioterápico y/o medicamento recibido), variables de control (datos demográficos, de enfermedad y de tratamiento) y variables de respuesta (reacciones adversas). El análisis estadístico de los datos se efectuó con el programa SPSS(R) 15.0. Resultados: Se incluyeron 50 pacientes. Según el esquema quimioterápico administrado, se encontraron diferencias estadísticamente significativas en la aparición de eritrodisestesia palmo-plantar, más frecuente con monoterapia (p < 0,05), y neurotoxicidad, trombopenia y neutropenia, más frecuentes con XELOX (p < 0,05). Según el medicamento de capecitabina administrado, no se observaron diferencias estadísticamente significativas en las reacciones adversas estudiadas. Conclusiones: El perfil de seguridad de dos formulaciones de capecitabina, innovadora y genérica, parece estar asociado al esquema quimioterápico empleado, y no al medicamento en cuestión. La mayor eritrodisestesia palmo-plantar para monoterapia se debe probablemente a la mayor dosis de capecitabina empleada en dicho esquema, y la mayor neurotoxicidad, trombopenia y neutropenia para XELOX se debe probablemente a la toxicidad acumulada de dos fármacos antineoplásicos

Objective: To analyze adverse reactions in patients with nonmetastatic colorectal cancer due to treatment with either innovative or generic capecitabine and/or to the chemotherapeutic regimen employed, to the capecitabine alone, or in combination with oxaliplatin (XELOX). Method: Descriptive retrospective study carried out in a secondary level hospital in two study periods (November 2013-April 2014 and August 2016-May 2017). The collected variables were: exposure (chemotherapy scheme and/or received medication), control (demographics, disease and treatment data), and response (adverse reactions). The statistical analysis of data was performed with the SPSS(R) 15.0 program. Results: Fifty patients were included. According to the administered chemotherapeutic scheme, statistically significant differences were found in the appearance of palmar-plantar erythrodysesthesia, which is more frequent with monotherapy (p < 0.05), and neurotoxicity, thrombocytopenia and neutropenia, which is more frequent with XELOX (p < 0.05). Concerning the capecitabine drug administered, no statistically significant differences were found in the studied adverse reactions. Conclusions: The safety profile of two capecitabine formulations -innovative and generic- appears to be associated with the chemotherapy scheme employed, and not the drug itself. Most palmar-plantar erythrodysesthesia for monotherapy is likely due to the higher dose of capecitabine used in said scheme. The increase in neurotoxicity, thrombocytopenia and neutropenia for XELOX is probably due to cumulative toxicity of two antineoplastic drugs

Capecitabine safety profile, innovative and generic adjuvant formulation of nonmetastatic colorectal cancer.

OBJECTIVE: To analyze adverse reactions in patients with nonmetastatic colorectal cancer due to treatment with either innovative  or generic capecitabine and/or to the chemotherapeutic regimen  employed, to the capecitabine alone, or in combination with oxaliplatin  (XELOX). METHOD: Descriptive retrospective study carried out in a secondary level hospital in two study periods (November 2013-April 2014 and  August 2016-May 2017). The collected variables were: exposure  (chemotherapy scheme and/or received medication), control  (demographics, disease and treatment data), and response (adverse  reactions). The statistical analysis of data was performed with the  SPSS® 15.0 program. Results: Fifty patients were included. According to the administered chemotherapeutic scheme, statistically significant  differences were found in the appearance of palmar-plantar  erythrodysesthesia, which is more frequent with monotherapy (p <  0.05), and neurotoxicity, thrombocytopenia and neutropenia, which is  more frequent with XELOX (p < 0.05). Concerning the capecitabine drug  administered, no statistically significant differences were found in  the studied adverse reactions. CONCLUSIONS: The safety profile of two capecitabine formulations - innovative and generic- appears to be associated with the  chemotherapy scheme employed, and not the drug itself. Most palmar- plantar erythrodysesthesia for monotherapy is likely due to the higher  dose of capecitabine used in said scheme. The increase in neurotoxicity,  thrombocytopenia and neutropenia for XELOX is probably due to  cumulative toxicity of two antineoplastic drugs.

Objetivo: Analizar las reacciones adversas en pacientes con cáncer colorrectal no metastásico debidas al tratamiento con  capecitabina innovadora o genérica, y/o al régimen quimioterápico  empleado, capecitabina en monoterapia o en combinación con  oxaliplatino (XELOX).Método: Estudio descriptivo retrospectivo llevado a cabo en un hospital de segundo nivel en dos periodos de estudio (noviembre de  2013-abril de 2014 y agosto de 2016-mayo de 2017). Las variables  recogidas fueron variables de exposición (esquema quimioterápico y/o  medicamento recibido), variables de control (datos demográficos, de  enfermedad y de tratamiento) y variables de respuesta (reacciones  adversas). El análisis estadístico de los datos se efectuó con el  programa SPSS® 15.0.Resultados: Se incluyeron 50 pacientes. Según el esquema  quimioterápico administrado, se encontraron diferencias  estadísticamente significativas en la aparición de eritrodisestesia palmo- plantar, más frecuente con monoterapia (p < 0,05), y neurotoxicidad,  trombopenia y neutropenia, más frecuentes con XELOX (p < 0,05).  Según el medicamento de capecitabina administrado, no se observaron  diferencias estadísticamente significativas en las reacciones adversas  estudiadas.Conclusiones: El perfil de seguridad de dos formulaciones de  capecitabina, innovadora y genérica, parece estar asociado al esquema  quimioterápico empleado, y no al medicamento en cuestión. La mayor  eritrodisestesia palmo-plantar para monoterapia se debe probablemente  a la mayor dosis de capecitabina empleada en dicho  esquema, y la mayor neurotoxicidad, trombopenia y neutropenia para  XELOX se debe probablemente a la toxicidad acumulada de dos  fármacos antineoplásicos.

Calidad de vida en pacientes con carcinoma colorrectal no metastásico tratados con esquema FOLFOX o XELOX / Quality of life in non-metastasic colorectal cancer patients in FOLFOX or XELOX therapy

Objetivo: Evaluar y comparar la calidad de vida de pacientes con cáncer colorrectal no metastásico tratados con el esquema FOLFOX o XELOX. Método: Estudio descriptivo prospectivo de 24 meses de duración (octubre 2015-octubre 2017) en pacientes con cáncer colorrectal no metastásico en tratamiento quimioterápico adyuvante. Se pasó a los pacientes el cuestionario de calidad de vida EORTC QLQ-C30 al inicio del tratamiento y a las 12 semanas. Variables recogidas: exposición (esquema quimioterápico), control (datos demográficos, de la enfermedad y del tratamiento) y respuesta (puntuaciones del cuestionario). El análisis estadístico se efectuó con el programa SPSS(R) 15.0. Resultados: Se incluyeron 30 pacientes, encontrándose diferencias estadísticamente significativas en el ítem rol emocional a las 12 semanas de tratamiento (FOLFOX 92 puntos versus XELOX 82 puntos; p = 0,036). Además, los pacientes tratados con FOLFOX presentaron un empeoramiento clínicamente relevante en actividades cotidianas, estreñimiento e insomnio; mientras que los tratados con XELOX mostraron un empeoramiento clínicamente relevante en actividades cotidianas, estreñimiento, fatiga, náuseas, vómitos, anorexia y diarrea. Conclusiones: Los pacientes tratados con el esquema XELOX se encontraron peor emocionalmente a las 12 semanas del tratamiento adyuvante que los tratados con FOLFOX y presentaron empeoramiento en fatiga, náuseas, vómitos, anorexia y diarrea

Objective: To evaluate and to compare quality of life of patients with non-metastasic colorectal cancer treated either with FOLFOX or with XELOX scheme. Method: Descriptive prospective study during 24 months (October 2015-October 2017) for patients with non-metastasic colorectal cancer in chemotherapy adyuvant treatment. EORTC QLQ-C30 questionnaire was filled by patients at the beginning and at week 12 of adjuvant treatment. Variables collected: exposure (chemotherapeutic scheme administered), control (demographic data, disease data, treatment data) and response (scores obtained from the questionnaire). The data statistical analysis was carried out with the SPSS(R) 15.0 programme. Results: 30 patients were included. Statistically significant differences were found in emotional role item at the middle of the treatment (FOLFOX 92 points vs. XELOX 82 points; p = 0,036). Patients with FOLFOX presented a clinically relevant worsening in terms of daily activities, constipation and insomnia. Patients treated with XELOX a clinically relevant worsening in daily activities, constipation, fatigue, nausea, vomiting, anorexia and diarrhoea were observed. Conclusions: Patients with XELOX scheme referred to have worse emotionally status in the middle of the adjuvant treatment than patients treated with FOLFOX scheme and presented a worsening in items fatigue, nausea, vomiting, anorexia and diarrhoea

Quality of life in non-metastasic colorectal cancer patients in FOLFOX or XELOX therapy.

OBJECTIVE: To evaluate and to compare quality of life of patients with non- metastasic colorectal cancer treated either with FOLFOX or with XELOX  scheme. METHOD: Descriptive prospective study during 24 months (October 2015- October 2017) for patients with non-metastasic colorectal cancer in chemotherapy adyuvant treatment. EORTC QLQ-C30 questionnaire was filled by patients at the beginning and at week 12 of adjuvant treatment. Variables collected: exposure (chemotherapeutic scheme administered), control (demographic data, disease data, treatment data) and response (scores obtained from the questionnaire). The data statistical  analysis was carried out with the SPSS® 15.0 programme. RESULTS: 30 patients were included. Statistically significant differences were  found in emotional role item at the middle of the treatment (FOLFOX 92  points vs. XELOX 82 points; p = 0,036). Patients with FOLFOX presented a  clinically relevant worsening in terms of daily activities, constipation and  insomnia. Patients treated with XELOX a clinically relevant worsening in daily  activities, constipation, fatigue, nausea, vomiting, anorexia and diarrhoea were observed. CONCLUSIONS: Patients with XELOX scheme referred to have worse  emotionally status in the middle of the adjuvant treatment than patients  treated with FOLFOX scheme and presented a worsening in items fatigue,  nausea, vomiting, anorexia and diarrhoea.

Objetivo: Evaluar y comparar la calidad de vida de pacientes con cáncer colorrectal no metastásico tratados con el esquema FOLFOX o XELOX.Método: Estudio descriptivo prospectivo de 24 meses de duración (octubre 2015-octubre 2017) en pacientes con cáncer colorrectal no  metastásico en tratamiento quimioterápico adyuvante. Se pasó a los  pacientes el cuestionario de calidad de vida EORTC QLQ-C30 al inicio del  tratamiento y a las 12 semanas. Variables recogidas: exposición (esquema quimioterápico), control (datos demográficos, de la enfermedad y  del tratamiento) y respuesta (puntuaciones del cuestionario). El análisis  estadístico se efectuó con el programa SPSS® 15.0.Resultados: Se incluyeron 30 pacientes, encontrándose diferencias  estadísticamente significativas en el ítem rol emocional a las 12 semanas de tratamiento (FOLFOX 92 puntos versus XELOX 82 puntos; p = 0,036).  Además, los pacientes tratados con FOLFOX presentaron un empeoramiento clínicamente relevante en actividades cotidianas,  estreñimiento e insomnio; mientras que los tratados con XELOX mostraron  un empeoramiento clínicamente relevante en actividades cotidianas,  estreñimiento, fatiga, náuseas, vómitos, anorexia y diarrea.Conclusiones: Los pacientes tratados con el esquema XELOX se  encontraron peor emocionalmente a las 12 semanas del tratamiento  adyuvante que los tratados con FOLFOX y presentaron empeoramiento en  fatiga, náuseas, vómitos, anorexia y diarrea.

New Trends in the Therapeutic Approach to Metastatic Colorectal Cancer.

Important developments in chemotherapy for metastatic colorectal cancer over the last years are reviewed, with an emphasis on the most recently published data from clinical trials. The systematic review of current literature was conducted involving Pubmed Central® research and full articles were obtained and analyzed when appropriate. Fluorouracil still constitutes the backbone of metastatic colorectal cancer treatment; fluorouracil combination plus either irinotecan (FOLFIRI), oxaliplatin (FOLFOX) or capecitabine (CAPOX or XELOX) are chemotherapy protocols established as treatments producing similar outcomes. Actual treatment involves these chemotherapy protocols in combination with new molecular targeted drugs: bevacizumab and aflibercept (anti-vascular endothelial growth factor monoclonal antibody) and cetuximab and panitumumab (anti-epidermal growth factor receptor monoclonal antibody for patients with wild type KRAS) which confer significant survival benefits in select patients as first- or second-line therapies. The factors affecting the decisions for one treatment over other are related to the patient and toxicity drug. Finally, metastatic colorectal cancer patients progressing after all standard therapies (maintaining a good ECOG performance status) could be candidates for further therapies such as regorafenib and TAS-102. Regarding the future, promising therapies are under development for the metastatic colorectal cancer treatment and several agents are currently being evaluated in different clinical trials.

Nanotechnology-based drug delivery of ropinirole for Parkinson's disease.

A new drug delivery system is developed for ropinirole (RP) for the treatment of Parkinson's disease (PD) consisting of biodegradable poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs). The formulation selected was prepared with 8 mg RP and 50 mg PLGA 502. This formulation exhibited mean encapsulation efficiency of 74.8 ± 8.2%, mean particle size lower than 155 nm, the zeta potential of -14.25 ± 0.43 mV and zero-order in vitro release of RP (14.13 ± 0.17 µg/h/10 mg NPs) for 5 d. Daily doses of the neurotoxin rotenone (2 mg/kg) given i.p. to male Wistar rats induced neuronal and behavioral changes similar to those of PD. Once neurodegeneration was established (15 d) animals received RP in saline (1 mg/kg/d for 35 d) or encapsulated within PLGA NPs (amount of NPs equivalent to 1 mg/kg/d RP every 3 d for 35 d). Brain histology and immunochemistry (Nissl-staining, glial fibrillary acidic protein and tyrosine hydroxylase immunohistochemistry) and behavioral testing (catalepsy, akinesia, rotarod and swim test) showed that RP-loaded PLGA NPs were able to revert PD-like symptoms of neurodegeneration in the animal model assayed.

Biomarcadores empleados en sepsis / Sepsis biomarkers: A review

Las enfermedades infecciosas, como la sepsis, constituyen un grave problema de salud en el mundo, asociándose con una elevada morbilidad y mortalidad en todos los ámbitos de la asistencia sanitaria. Se trata de enfermedades tiempo dependientes en las que la aplicación precoz de una serie de medidas diagnostico terapéuticas mejoran de forma significativa la supervivencia y el pronóstico del paciente. Para ello se disponen de herramientas como los biomarcadores que nos ayudan tanto en el diagnóstico como pronóstico de estas patologías; biomarcadores clásicos y ampliamente utilizados como la PCR, procalcitonina o citocinas y otros menos conocidos como presepsina, pro-adrenomedulina (pro-ADM), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), soluble urokinase-type plasminogen activator receptor (suPAR), Pancreatic Stone Protein (PSP) o sCD25 (AU)

Infectious diseases, such as sepsis, are a serious health problem in the world, associated with high morbidity and mortality in all areas of health care. These are time dependent diseases in which the early application of diagnostic therapeutic actions, significantly improve patient survival and prognosis. To carry out this, we have tools such as biomarkers that help us in the diagnosis and prognosis of these pathologies; There are biomarkers widely used such as PCR, Procalcitonin or cytokines, and others that are less known as pro-adrenomedullin (pro-ADM), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), soluble urokinase-type plasminogen activator receptor (SuPAR), Pancreatic Stone Protein (PSP) or sCD25 (AU)