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.

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.

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.

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.

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.

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.

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.

Efficacy of Ropinirole-Loaded PLGA Microspheres for the Reversion of Rotenone- Induced Parkinsonism.

A new controlled delivery system has been developed for ropinirole (RP) for the treatment of Parkinson´s Disease (PD) consisting in PLGA microparticles (MPs) which exhibited in vitro constant release of RP (78.23 µg/day/10 mg MPs) for 19 days. The neuroprotective effects of RP released from MPs were evaluated in SKN-AS cells after exposure to rotenone (20 µM). Cell apoptosis was significantly reduced by RP (100-120 µM). Daily doses of rotenone (2 mg/kg) given i.p. to rats induced neuronal and behavioral changes similar to those of PD. After 15 days, animals received RP in saline (1 mg/kg/day for 45 days) or as MPs at two dose levels (amount of MPs equivalent to 7.5 mg/kg or 15 mg/kg RP given on days 15 and 30). Brain immunochemistry (Nisslstaining, GFAP and TH immunohistochemistry) and behavioral testing (catalepsy, akinesia, rotarod and swim test) showed that animals receiving RP either in solution or encapsulated within the MPs reverted the PD symptoms with the best results obtained in animals receiving RP microspheres at the highest dose assayed, thereby confirming the potential therapeutic interest of the new RP delivery system.

Compatibiliity and stability of furosemide and dexamethasone combined in infusion solutions.

AIM: The goal of palliative care is the achievement of the best quality of life for patients and their families. For this, the administration of drugs by subcutaneous infusion is frequently used since many patients have great difficulties in taking drugs orally and regular intramuscular injections are painful. Usually, drugs are combined in infusion solutions. The objective was therefore to study the compatibility and stability of dexamethasone sodium phosphate (CAS 2392-39-4) and sodium furosemide (CAS 54-31-9) combined in solutions destined to subcutaneous administration in palliative medicine. METHODS: Twelve different solutions were assessed during 15 days. Drug admixtures were prepared in polypropylene syringes using 0.9 % saline as diluent and stored at 4 degrees C and 25 degrees C in the dark. Initial concentrations were 3.33-10.0 mg/ ml for sodium furosemide (dose range 40-120 mg/day) and 0.33-3.33 mg/ml (dose range 4-40 mg/day) for dexamethasone sodium phosphate. Quantification of both drugs was performed by high-performance liquid chromatography. RESULTS: After 5 days of storage at both temperatures, the maximum losses obtained were lower than 10 % for both drugs. However, after 15 days, slight precipitation/turbidity was observed in all mixtures. At this time, maximum losses of 20 % were obtained for both drugs. CONCLUSION: These results confirm the stability of mixtures prepared with sodium furosemide (< or = 120 mg/day) and dexamethasone sodium phosphate (< or = 40 mg/day) for a period of 5 days and with independence of their storage at 4 degrees C or 25 degrees C.