ABSTRACT
Disseminated triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options beyond chemotherapy. Therefore, identification of druggable vulnerabilities is an important aim. Protein kinases play a central role in cancer and particularly in TNBC. They are involved in many oncogenic functions including migration, proliferation, genetic stability or maintenance of stem-cell like properties. In this article we describe a novel multi-kinase inhibitor with antitumor activity in this cancer subtype. EC-70124 is a hybrid indolocarbazole analog obtained by combinatorial biosynthesis of Rebeccamycin and Staurosporine genes that showed antiproliferative effect and in vivo antitumoral activity. Biochemical experiments demonstrated the inhibition of the PI3K/mTOR and JAK/STAT pathways. EC-70124 mediated DNA damage leading to cell cycle arrest at the G2/M phase. Pathway analyses identified several deregulated functions including cell proliferation, migration, DNA damage, regulation of stem cell differentiation and reversion of the epithelial-mesenchymal transition (EMT) phenotype, among others. Combination studies showed a synergistic interaction of EC-70124 with docetaxel, and an enhanced activity in vivo. Furthermore, EC-70124 had a good pharmacokinetic profile. In conclusion these experiments demonstrate the antitumor activity of EC-70124 in TNBC paving the way for the future clinical development of this drug alone or in combination with chemotherapy.
Subject(s)
Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/pharmacology , Triple Negative Breast Neoplasms/pathology , Animals , Apoptosis/drug effects , Blotting, Western , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Epithelial-Mesenchymal Transition/drug effects , Female , Humans , Immunohistochemistry , Mice , Mice, Inbred BALB C , Oligonucleotide Array Sequence Analysis , Reverse Transcriptase Polymerase Chain Reaction , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVES: To analyse the acceptance of the replacement of patent medicines by generic medicines at community pharmacies and to study the variability of the answers in terms of the characteristics of the user, prescription and community pharmacy. DESIGN: Observational, cross-sectional study. SETTING: Community pharmacies in Albacete and its province, Spain. PARTICIPANTS: Consecutive selection of 769 users in 21 pharmacies during February 2005. METHOD: Users of community pharmacies who were asked to replace a prescribed drug by a generic one when the prescribed one was unavailable. The proposals were recorded in a register and the data were processed with the SPSS statistical package. RESULTS: 90.8% of the population accepted the replacement (n=698; 95% CI, 88.5%-92.7%). The main cause of non-acceptance was that the patient did not want changes in his/her medical prescription (50.7%). The acceptance of the change was inversely proportional to the age of the patient (P=.005) and directly proportional to the number of inhabitants of the population centre where the pharmacy was located (P< .001). Non-acceptance was higher for "fantasy brands" than generic ones (P=.005), in repeated treatments versus first-time prescriptions (P< .001) and in free prescriptions versus those involving a contribution (P=.002). CONCLUSIONS: A high acceptance of replacement by generic drugs in community pharmacies (90.8%) was seen. The main cause of non-acceptance of the replacement was because the patient did not want any changes in the prescription.
Subject(s)
Community Pharmacy Services , Drugs, Generic , Patient Satisfaction/statistics & numerical data , Adult , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , SpainABSTRACT
Objetivo. Analizar la aceptación de la sustitución por medicamentos genéricos en la farmacia comunitaria y estudiar la variabilidad de la respuesta en función de las características del usuario, la prescripción y la oficina de farmacia (OF). Diseño. Observacional, transversal. Emplazamiento. Oficinas de farmacia de Albacete y provincia. Participantes. Selección consecutiva de 769 usuarios en 21 farmacias durante febrero de 2005. Método. Usuarios a los que, en caso de que el medicamento prescrito no se encontrara disponible en la OF, se les proponía la sustitución por un genérico. Las propuestas fueron reflejadas en una hoja-registro. Resultados. Un 90,8% de la población acepta la sustitución (n = 698; intervalo de confianza [IC] del 95%, 88,5-92,7%). La principal causa de rechazo fue que el paciente no quiere cambios en la prescripción médica (50,7%). La aceptación del cambio fue inversamente proporcional a la edad del paciente (p = 0,005) y directamente proporcional al número de habitantes del núcleo de población donde se encuentra ubicada la OF (p < 0,001). El rechazo fue superior cuando se partía de nombres comerciales respecto a genéricos (p = 0,005), en tratamientos repetidos frente a los de primera prescripción (p < 0,001) y en recetas sin aportación frente a las que sí llevaban (p = 0,002). Conclusiones. Se constata una elevada aceptación de la sustitución por medicamentos genéricos en las OF (90,8%). La principal causa que genera un rechazo a la sustitución es que el paciente no quiere cambios en la prescripción
Objectives. To analyse the acceptance of the replacement of patent medicines by generic medicines at community pharmacies and to study the variability of the answers in terms of the characteristics of the user, prescription and community pharmacy. Design. Observational, cross-sectional study. Setting. Community pharmacies in Albacete and its province, Spain. Participants. Consecutive selection of 769 users in 21 pharmacies during February 2005. Method. Users of community pharmacies who were asked to replace a prescribed drug by a generic one when the prescribed one was unavailable. The proposals were recorded in a register and the data were processed with the SPSS statistical package. Results. 90.8% of the population accepted the replacement (n=698; 95% CI, 88.5%-92.7%). The main cause of non-acceptance was that the patient did not want changes in his/her medical prescription (50.7%). The acceptance of the change was inversely proportional to the age of the patient (P=.005) and directly proportional to the number of inhabitants of the population centre where the pharmacy was located (P<.001). Non-acceptance was higher for "fantasy brands" than generic ones (P=.005), in repeated treatments versus first-time prescriptions (P<.001) and in free prescriptions versus those involving a contribution (P=.002). Conclusions. A high acceptance of replacement by generic drugs in community pharmacies (90.8%) was seen. The main cause of non-acceptance of the replacement was because the patient did not want any changes in the prescription
