In situ forming PLA and PLGA implants for the parenteral administration of Cannabidiol.

Cannabidiol (CBD) is the main non-psychotropic cannabinoid. It has attracted a great deal of interest in the treatment of several diseases such as inflammatory disorders and cancer. Despite its promising clinical interest, its administration is very challenging. In situ forming implants (ISFIs) could be a simple and cheap strategy to administer CBD while obtaining a prolonged effect with a single administration. This work aims to design, develop, and characterize for the first time ISFIs for the parenteral administration of CBD with potential application in cancer disease. Formulations made of PLGA-502, PLGA-502H, and PLA-202 in NMP or DMSO and PLA-203 in DMSO at a polymer concentration of 0.25 mg/µL and loaded with CBD at a drug: polymer ratio of 2.5:100 and 5:100 (w/w) were developed. The formulations prepared with NMP exhibited a faster drug release. CBD implants elaborated with PLGA-502 and DMSO with the highest CBD: polymer ratio showed the most suitable drug release for one month. This formulation was successfully formed in ovo onto the chorioallantoic chick membrane without exhibiting signs of toxicity and exhibited a superior antiangiogenic activity than CBD in solution administered at the same doses. Consequently, implants made of PLGA-502 and DMSO represent a promising strategy to effectively administer CBD subcutaneously as combination therapy in cancer disease.

Development and Characterization of a Microemulsion Containing a Cannabidiol Oil and a Hydrophilic Extract from Sambucus ebulus for Topical Administration.

Cannabidiol (CBD) is a safe and non-psychotropic phytocannabinoid with a wide range of potential therapeutic anti-inflamatory and antioxidant activities. Due to its lipophilicity, it is normally available dissolved in oily phases. The main aim of this work was to develop and characterize a new formulation of a microemulsion with potential anti-inflammatory and antioxidant activity for the topical treatment of inflammatory skin disorders. The microemulsion system was composed of a 20% CBD oil, which served as the hydrophobic phase; Labrasol/Plurol Oleique (1:1), which served as surfactant and cosurfactant (S/CoS), respectively; and an aqueous vegetal extract obtained from Sambucus ebulus L. (S. ebulus) ripe fruits, which has potential anti-oxidant and anti-inflammatory activity and which served as the aqueous phase. A pseudo-ternary phase diagram was generated, leading to the selection of an optimal proportion of 62% (S/CoS), 27% CBD oil and 11% water and, after its reproducibility was tested, the aqueous phases were replaced by the vegetal hydrophilic extract. The defined systems were characterized in terms of conductivity, droplet size (by laser scattering), compatibility of components (by differential scanning calorimetry) and rheological properties (using a rotational rheometer). The designed microemulsion showed good stability and slight pseudo-plastic behavior. The release properties of CBD from the oil phase and caffeic acid from the aqueous phase of the microemulsion were studied via in vitro diffusion experiments using flow-through diffusion cells and were compared to those of a CBD oil and a microemulsion containing only CBD as an active substance. It was found that the inclusion of the original oil in microemulsions did not result in a significant modification of the release of CBD, suggesting the possibility of including hydrophilic active compounds in the formulation and establishing an interesting strategy for the development of future formulations.

Assessment of In Vitro Release Testing Methods for Colloidal Drug Carriers: The Lack of Standardized Protocols.

Although colloidal carriers have been in the pipeline for nearly four decades, standardized methods for testing their drug-release properties remain to be established in pharmacopeias. The in vitro assessment of drug release from these colloidal carriers is one of the most important parameters in the development and quality control of drug-loaded nano- and microcarriers. This lack of standardized protocols occurs due to the difficulties encountered in separating the released drug from the encapsulated one. This review aims to compare the most frequent types of release testing methods (i.e., membrane diffusion techniques, sample and separate methods and in situ detection techniques) in terms of the advantages and disadvantages of each one and of the key parameters that influence drug release in each case.

Polycaprolactone microparticles for the subcutaneous administration of cannabidiol: in vitro and in vivo release.

Cannabidiol (CBD) has become a highly attractive entity in therapeutics. However, its low aqueous solubility, instability and handling problems limit the development of effective CBD formulations. Subcutaneously administered CBD-loaded polycaprolactone microparticles (MP) represent an interesting strategy to overcome these challenges. This work focuses on evaluating the pharmacokinetics of CBD formulated in polymer microparticles for subcutaneous administration and characterising its release. The mean release time (MRLT) parameter is used to compare the release of CBD from two microparticle formulations in vitro and in a mouse model. After the administration of CBD in solution, a bicompartmental distribution is observed due to the extensive diffusion to the brain, being the brain/blood AUC ratio 1.29. The blood and brain mean residence time (MRT) are 0.507 ± 0.04 and 0.257 ± 0.0004 days, respectively. MP prepared with two drug/polymer ratios (15/150-MP and 30/150-MP) are designed, showing similar in vitro dissolution profiles (similarity factor (f2) is 63.21), without statistically significant differences between MRLTin vitro values (4.68 ± 0.63 and 4.32 ± 0.05 days). However, considerable differences in blood and brain profiles between both formulations are detected. The blood and brain MRT values of 15/150-MP are 6.44 ± 0.3 days and 6.15 ± 0.25 days, respectively, whereas significantly lower values 3.91 ± 0.29 days and 2.24 ± 0.64 days are obtained with 30/150-MP. The extended release of CBD during 10 days after a single subcutaneous administration is achieved.

An overview of in vitro 3D models of the blood-brain barrier as a tool to predict the in vivo permeability of nanomedicines.

The blood-brain barrier (BBB) prevents efficient drug delivery to the central nervous system. As a result, brain diseases remain one of the greatest unmet medical needs. Understanding the tridimensional structure of the BBB helps gain insight into the pathology of the BBB and contributes to the development of novel therapies for brain diseases. Therefore, 3D models with an ever-growing sophisticated complexity are being developed to closely mimic the human neurovascular unit. Among these 3D models, hydrogel-, spheroid- and organoid-based static BBB models have been developed, and so have microfluidic-based BBB-on-a-chip models. The different 3D preclinical models of the BBB, both in health and disease, are here reviewed, from their development to their application for permeability testing of nanomedicines across the BBB, discussing the advantages and disadvantages of each model. The validation with data from in vivo preclinical data is also discussed in those cases where provided.

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)

Embolization therapy with microspheres for the treatment of liver cancer: State-of-the-art of clinical translation.

Embolization with microspheres is a therapeutic strategy based on the selective occlusion of the blood vessels feeding a tumor. This procedure is intraarterially performed in the clinical setting for the treatment of liver cancer. The practice has evolved over the last decade through the incorporation of drug loading ability, biodegradability and imageability with the subsequent added functionality for the physicians and improved clinical outcomes for the patients. This review highlights the evolution of the embolization systems developed through the analysis of the marketed embolic microspheres for the treatment of malignant hepatocellular carcinoma, namely the most predominant form of liver cancer. Embolic microspheres for the distinct modalities of embolization (i.e., bland embolization, chemoembolization and radioembolization) are here comprehensively compiled with emphasis on material characteristics and their impact on microsphere performance. Moreover, the future application of the embolics under clinical investigation is discussed along with the scientific and regulatory challenges ahead in the field. STATEMENT OF SIGNIFICANCE: Embolization therapy with microspheres is currently used in the clinical setting for the treatment of most liver cancer conditions. The progressive development of added functionalities on embolic microspheres (such as biodegradability, imageability or drug and radiopharmaceutical loading capability) provides further benefit to patients and widens the therapeutic armamentarium for physicians towards truly personalized therapies. Therefore, it is important to analyze the possibilities that advanced biomaterials offer in the field from a clinical translational perspective to outline the future trends in therapeutic embolization.

Actively Targeted Nanomedicines in Breast Cancer: From Pre-Clinal Investigation to Clinic.

Breast cancer is one of the most frequently diagnosed tumors and the second leading cause of cancer death in women worldwide. The use of nanosystems specifically targeted to tumor cells (active targeting) can be an excellent therapeutic tool to improve and optimize current chemotherapy for this type of neoplasm, since they make it possible to reduce the toxicity and, in some cases, increase the efficacy of antineoplastic drugs. Currently, there are 14 nanomedicines that have reached the clinic for the treatment of breast cancer, 4 of which are already approved (Kadcyla®, Enhertu®, Trodelvy®, and Abraxane®). Most of these nanomedicines are antibody-drug conjugates. In the case of HER-2-positive breast cancer, these conjugates (Kadcyla®, Enhertu®, Trastuzumab-duocarmycin, RC48, and HT19-MMAF) target HER-2 receptors, and incorporate maytansinoid, deruxtecan, duocarmicyn, or auristatins as antineoplastics. In TNBC these conjugates (Trodelvy®, Glembatumumab-Vedotin, Ladiratuzumab-vedotin, Cofetuzumab-pelidotin, and PF-06647263) are directed against various targets, in particular Trop-2 glycoprotein, NMB glycoprotein, Zinc transporter LIV-1, and Ephrin receptor-4, to achieve this selective accumulation, and include campthotecins, calicheamins, or auristatins as drugs. Apart from the antibody-drug conjugates, there are other active targeted nanosystems that have reached the clinic for the treatment of these tumors such as Abraxane® and Nab-rapamicyn (albumin nanoparticles entrapping placlitaxel and rapamycin respectively) and various liposomes (MM-302, C225-ILS-Dox, and MM-310) loaded with doxorubicin or docetaxel and coated with ligands targeted to Ephrin A2, EPGF, or HER-2 receptors. In this work, all these active targeted nanomedicines are discussed, analyzing their advantages and disadvantages over conventional chemotherapy as well as the challenges involved in their lab to clinical translation. In addition, examples of formulations developed and evaluated at the preclinical level are also discussed.

The tale of microencapsulated rifampicin: is it useful for the treatment of periprosthetic joint infection?

PURPOSE: Microencapsulation techniques have allowed the addition of rifampicin to bone cement, but its in vivo efficacy has not been proven. The aim of our study is to determine the superiority of cement containing gentamicin and rifampicin microcapsules in the treatment of PJI versus cement exclusively containing gentamicin. METHODS: An S. aureus PJI was induced in 15 NZW rabbits. A week after inoculation, the first stage of replacement was carried out, and the animals were divided into two groups: group R received a spacer containing gentamicin and rifampicin microcapsules, and group C received a spacer containing gentamicin. Intra-articular release curve of rifampicin and infection and toxicity markers were monitored for four weeks post-operatively, when microbiological analysis was performed. RESULTS: The microbiological cultures showed a significantly lower growth of S. aureus in soft tissue (2.3·104 vs 0; p = 0.01) and bone (5.7·102 vs 0; p = 0.03) in the group with rifampicin microcapsules. No differences were found in systemic toxicity markers. Rifampicin release from the cement spacer showed higher concentrations than the staphylococcal MIC throughout the analysis. CONCLUSION: The in vivo analyses demonstrated the superiority of cement containing gentamicin and rifampicin microcapsules versus the isolated use of gentamicin in the treatment of PJI in the rabbit model without serious side effects due to the systemic absorption of rifampicin. Given the increasing incidence of staphylococci-related PJI, the development of new strategies for intra-articular administration of rifampicin for its treatment has a high clinical impact.

The Chick Embryo Chorioallantoic Membrane Model: A Research Approach for Ex Vivo and In Vivo Experiments.

BACKGROUND: The chick chorioallantoic membrane (CAM) model has attracted a great deal of interest in pharmaceutical and biological research as an alternative or complimentary in vivo assay to animal models. Traditionally, CAM assay has been widely used to perform some toxicological studies, specifically to evaluate the skin, ocular and embryo toxicity of new drugs and formulations, and to perform angiogenesis studies. Due to the possibility to generate the tumors onto the CAM, this model has also become an excellent strategy to evaluate the metastatic potential of different tumours and to test the efficacy of novel anticancer therapies in vivo. Moreover, in the recent years, its use has considerably grown in other research areas, including the evaluation of new anti-infective agents, the development of biodistribution studies and in tissue engineering research. OBJECTIVE: This manuscript provides a critical overview of the use of CAM model in pharmaceutical and biological research, especially to test the toxicity of new drugs and formulations and the biodistribution and the efficacy of novel anticancer and antiinfective therapies, analyzing its advantages and disadvantages in comparison to animal models. CONCLUSION: The chick chorioallantoic membrane model shows a great utility in several research areas, such as cancer, toxicology, biodistribution studies and anti-infective therapies. In fact, it has become an intermediate stage between in vitro experiments and animal studies, and, in the case of toxicological studies (skin and ocular toxicity), it has even replaced the animal models.

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives.

In the last decade, antibody-drug conjugates (ADCs), normally formed by a humanized antibody and a small drug via a chemical cleavable or non-cleavable linker, have emerged as a potential treatment strategy in cancer disease. They allow to get a selective delivery of the chemotherapeutic agents at the tumor level, and, consequently, to improve the antitumor efficacy and, especially to decrease chemotherapy-related toxicity. Currently, nine antibody-drug conjugate-based formulations have been already approved and more than 80 are under clinical trials for the treatment of several tumors, especially breast cancer, lymphomas, and multiple myeloma. To date, no ADCs have been approved for the treatment of gynecological formulations, but many formulations have been developed and have reached the clinical stage, especially for the treatment of ovarian cancer, an aggressive disease with a low five-year survival rate. This manuscript analyzes the ADCs formulations that are under clinical research in the treatment of gynecological carcinomas, specifically ovarian, endometrial, and cervical tumors.

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.

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.

Perspectives in Breast and Ovarian Cancer Chemotherapy by Nanomedicine Approach: Nanoformulations in Clinical Research.

BACKGROUND: Breast and ovarian carcinomas represent major health problems in women worldwide. Chemotherapy constitutes the main treatment strategy, and the use of nanocarriers, a good tool to improve it. Several nanoformulations have already been approved, and others are under clinical trials for the treatment of both types of cancers. OBJECTIVE: This review focuses on the analysis of the nanoformulations that are under clinical research in the treatment of these neoplasms. RESULTS: Currently, there are 6 nanoformulations in clinical trials for breast and ovarian carcinomas, most of them in phase II and phase III. In the case of breast cancer treatment, these nanomedicines contain paclitaxel; and, for ovarian cancer, nanoformulations containing paclitaxel or camptothecin analogs are being evaluated. The nanoencapsulation of these antineoplastics facilitates their administration and reduces their systemic toxicity. Nevertheless, the final approval and commercialization of nanoformulations may be limited by other aspects like lack of correlation between the efficacy results evaluated at in vitro and in vivo levels, difficulty in producing large batches of nanoformulations in a reproducible manner and high production costs compared to conventional formulations of antineoplastics. However, these challenges are not insurmountable and the number of approved nanoformulations for cancer therapy is growing. CONCLUSION: Reviewed nanoformulations have shown, in general, excellent results, demonstrating a good safety profile, a higher maximum tolerated dose and a similar or even slightly better antitumor efficacy compared to the administration of free drugs, reinforcing the use of nano-chemotherapy in both breast and ovarian tumors.

Development of Innovative Formulations for Breast Cancer Chemotherapy.

Breast cancer is the most frequent neoplasm in the female population [...].

Timeline of Translational Formulation Technologies for Cancer Therapy: Successes, Failures, and Lessons Learned Therefrom.

Over the past few decades, the field of cancer therapy has seen a significant change in the way in which formulations are designed and developed, resulting in more efficient products that allow us to ultimately achieve improved drug bioavailability, efficacy, and safety. However, although many formulations have entered the market, many others have fallen by the wayside leaving the scientific community with several lessons to learn. The successes (and failures) achieved with formulations that have been approved in Europe and/or by the FDA for the three major types of cancer therapy (peptide-based therapy, chemotherapy, and radiotherapy) are reviewed herein, covering the period from the approval of the first prolonged-release system for hormonal therapy to the appearance of the first biodegradable microspheres intended for chemoembolization in 2020. In addition, those products that have entered phase III clinical trials that have been active over the last five years are summarized in order to outline future research trends and possibilities that lie ahead to develop clinically translatable formulations for 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.

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.