Determination of compatibility and stability of haloperidol and morphine mixtures used in palliative care

With the aim of controlling various symptoms, possible to use mixtures of different drugs within infusion devices. This should take into account the compatibility of the mixture. Factors influence the compatibility and stability of the mixtures are: drug type, concentration, solvent, temperature and light. When evaluating the compatibility of the mixtures for infusion for subcutaneous via is important to consider infusion devices used and the conditions of light and temperature should simulate as far as possible the conditions in practice assistance. There are diverse studies that analyze the compatibility of drug mixtures, but there are still many possible combinations of drugs for which evidence is not available. The objective of this work is to study the compatibility and stability of several mixtures of haloperidol and morphine that can be used in solution for subcutaneous infusion

Compatibility and stability of morphine and furosemide admixture

Background: In order to avoid separate injections of different drugs, admixtures of opioids with other drugs used in palliative care are frequently used. There are different factors that can influence the compatibility and stability of the mixture: drug type, concentration, solvent, container, temperature and light. There are some mixtures of opioids with other drugs with proven stability, but there is lack of evidence about the stability and compatibility of the combination of morphine and furosemide. Purpose: To evaluate the compatibility and stability of the admixture morphine 1.0 mg/ml - furosemide 0.6 mg/ml in NaCl 0.9% stored at ambient room temperature under normal light for at least 30 days. Material and method: On study day 0, a mixture was prepared and diluted in NaCl 0.9% to obtain 1.0 mg/ml of morphine and 0.6 mg/ml of furosemide and stored at ambient room temperature under normal light. The concentration of each constituent drug was periodically determined using a HPLC-UV method. The drugs were chromatographed on a C18 reverse phase column; the mobile phase was acetonitrile-water 80:20 (v/v); flow rate 1.5 ml/min. Morphine and furosemide concentrations were determined at 235 nm by interpolation from the calibration curves prepared at (0, 1, 2, 5, 7, 9, 12, 15, 19, 23, 26, 30) days from the standards. Results and discussion: The admixture remained physically and chemically stable during study period, with no precipitation or colour change and non-significant loss of morphine or furosemide. Statgraphics centurion XVI program has been used to data treatment. Conclusion: Morphine and furosemide mixture diluted in NaCl 0.9% (concentration 1.0 and 0.6 mg/ml, respectively), is physically and chemically stable from at least 30 days.Universidad de Málaga, Campus de Excelencia Internacional Andalucía Tec

Compatibilidad y estabilidad físico-química de mezclas de medicamentos en infusores para vía subcutánea suceptibles de ser utilizadas en pacientes de cuidados paliativos en Andalucía

Partiendo de los objetivos anteriormente mencionados, esta memoria está estructurada en cinco capítulos. En el capítulo I se hace referencia al uso de los Cuidados Paliativos, la utilización de la vía subcutánea para la administración de fármacos como vía alternativa a las otras vías existentes, la infusión subcutánea continua mediante infusores elastoméricos, los fármacos empleados así como las posibles mezclas de los mismos, uso de la guía metodológica de estudios de estabilidad de preparaciones farmacéuticas, finalizando el mismo con un resumen de algunos estudios publicados sobre la compatibilidad de mezclas. El segundo capítulo hace referencia al proyecto de investigación obtenido en convocatoria pública en el año 2013, financiado por la Consejería de Igualdad, Salud y Políticas Sociales de la Junta de Andalucía en su convocatoria de 2013 (PI-0013-2013). Los resultados de dicho proyecto se estructuran en tres fases: PRIMERA FASE. Identificación de las mezclas de fármacos utilizadas y susceptibles de ser utilizadas en pacientes de CP en Andalucía. SEGUNDA FASE. Análisis de la evidencia disponible sobre la estabilidad de las mezclas identificadas: Revisión bibliográfica. TERCERA FASE. Análisis de la estabilidad química y física de las mezclas identificadas y de las que no existen suficientes datos en la literatura científica. El capítulo III recoge las cinco publicaciones que avalan la tesis doctoral presentada. En el capítulo IV se presenta un estudio sobre la estabilidad de las mezclas identificadas en la encuesta. En el capítulo V se lleva a cabo una discusión de los resultados y se exponen las conclusiones finales de este estudio. Finalmente se incluye la bibliografía y los anexos I y II. Fecha de lectura de Tesis Doctoral: 30 abril 2020La utilización de la vía subcutánea para la administración de medicamentos en Cuidados Paliativos es una vía muy interesante cuando la vía oral no está disponible. El empleo de infusores para la perfusión continua permite el control de síntomas de una manera sencilla. En muchos casos es necesaria la administración de más de un fármaco, por lo que mezclarlos en un mismo infusor es la mejor alternativa. Sin embargo, hay pocos datos publicados sobre la estabilidad de las mezclas, y menos aún si nos centramos en datos de estabilidad fisicoquímica de mezclas de medicamentos en sistemas de administración de tipo infusor y conservadas en condiciones de temperatura y luminosidad similares a las de la práctica asistencial. Los objetivos del presente trabajo son: 1) Identificar las mezclas de fármacos utilizadas y susceptibles de ser utilizadas en pacientes de Cuidados Paliativos de Andalucía mediante la realización de encuesta a profesionales sanitarios que les atienden. 2) Analizar la evidencia disponible sobre la estabilidad de las mezclas identificadas mediante revisión bibliográfica en fuentes terciarias. Dicha consulta se completará con una búsqueda bibliográfica en las principales bases de datos biomédicas: EMBASE y PubMed y con la revisión de las fuentes primarias de interés resultantes de la búsqueda anterior. 3) Medir la estabilidad física, mediante inspección visual, y química, mediante cromatografía líquida de alta resolución, de las mezclas identificadas y de las que no existan suficientes datos en la literatura científica. Partiendo de los objetivos anteriormente mencionados, esta memoria está estructurada en cinco capítulos.Junta de Andalucía, Consejería de Salud

Compatibility and stability of ondansetron and midazolam mixtures used in palliative care

Background and importance Different factors can influence the compatibility and stability of the mixture: drug type, concentration, solvent, container, temperature and light. There are some mixtures of drugs with proven stability, but there is a lack of evidence about the stability and compatibility of the combination of ondansetron and midazolam. The objective of this investigation was to study the compatibility and stability of a binary mixture of these drugs in solution for subcutaneous infusion in palliative care Aim and objectives To evaluate the compatibility and stability of two admixtures of ondansetron and midazolam at two different temperatures (25°C and 37°C). The concentrations of the admixtures were 0.1 g/L–0.1 g/L and 0.5 g/L–1.0 g/L in NaCl 0.9% stored in elastomeric infusors protected from light Material and methods Samples were prepared and diluted in NaCl 0.9% in elastomeric infusors in triplicate to obtain four different conditions of concentration and/or storage temperature (0.1 g/L–0.1 g/L; 0.5 g/L–1.0 g/L for ondansetron and midazolam, respectively, stored at temperatures of 25°C and 37°C). The concentration of each drug was periodically determined using HPLC-UV and UV-Vis spectrophotometry methods in the analytical chemistry laboratory between February and June 2019. Conditions: C18 column, mobile phase methanol: KH2PO40.05 M, adjusted to pH 3 with H3PO3 (60:40, v/v) delivered at a flow rate of 1.0 mL/min. The sample injection volume was 20 mL, and triplicate injections were performed for every sample. The signal was recorded over 14 min and the retention times were 4.1 min for ondansetron and 7.8 min for midazolam. Ondansetron and midazolam concentrations were determined at 254 nm. Results The stability of the admixtures diluted in NaCl 0.9% were as follow: ondansetron–midazolam (0.1 mg/mL–0.1 mg/mL and 0.5 mg/mL –1.0 mg/mL) were stable(retained >90% of their initial concentrations) for only 1 day at 25°C and 37°C, respectivelyUniversidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Setup and validation of shake-flask procedures for the determinationof partition coefficients (log D) from low drug amounts

Several procedures based on the shake-flask method and designed to require a minimum amount of drug for octanol-water partition coefficient determination have been established and developed. The procedures have been validated by a 28 substance set with a lipophilicity range from -2.0 to 4.5 (logD7.4). The experimental partition is carried out using aqueous phases buffered with phosphate (pH 7.4) and n-octanol saturated with buffered water and the analysis is performed by liquid chromatography. In order to have accurate results, four procedures and eight different ratios between phase volumes are proposed. Each procedure has been designed and optimized (for partition ratios) for a specific range of drug lipophilicity (low, regular and high lipophilicity) and solubility (high and low aqueous solubility). The procedures have been developed to minimize the measurement in the octanolic phase. Experimental logD7.4 values obtained from different procedures and partition ratios show a standard deviation lower than 0.3 and there is a nice agreement when these values are compared with the reference literature one

16 derivas hipermínimas

Postprint (published version

Adherence and Toxicity during the Treatment of Latent Tuberculous Infection in a Referral Center in Spain

Latent tuberculosis infection; Toxicity; Tuberculosis screeningInfecció tuberculosa latent; Toxicitat; Cribratge de tuberculosiInfección tuberculosa latente; Toxicidad; Cribado de tuberculosisThe screening and treatment of latent tuberculosis infection (LTBI) in countries with a low incidence of TB is a key strategy for the elimination of tuberculosis (TB). However, treatment can result in adverse events (AEs) and have poor adherence. This study aimed to describe treatment outcomes and AEs for LTBI patients at two departments in Vall d'Hebron University Hospital in Barcelona, Spain. A retrospective study was conducted on all persons treated for LTBI between January 2018 and December 2020. Variables collected included demographics, the reason for LTBI screening and treatment initiation, AEs related to treatment, and treatment outcome. Out of 261 persons who initiated LTBI treatment, 145 (55.6%) were men, with a median age of 42.1 years. The indications for LTBI screening were household contact of a TB case in 96 (36.8%) persons, immunosuppressive treatment in 84 (32.2%), and recently arrived migrants from a country with high TB incidence in 81 (31.0%). Sixty-three (24.1%) persons presented at least one AE during treatment, and seven (2.7%) required definitive discontinuation of treatment. In the multivariate analysis, AE development was more frequent in those who started LTBI treatment due to immunosuppression. Overall, 226 (86.6%) completed treatment successfully. We concluded that LTBI screening and treatment groups had different risks for adverse events and treatment outcomes. Persons receiving immunosuppressive treatment were at higher risk of developing AEs, and recently arrived immigrants from countries with a high incidence of TB had greater LTFU. A person-centered adherence and AE management plan is recommended.A.M.L. was supported by a postdoctoral grant “Juan Rodés” (JE21/00027) from the Instituto de Salud Carlos through the Ministry of Economy and Competitiveness, Spain

Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma

Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor of children and young adults in which the principal driver is a fusion gene, EWSR1-FLI1. Although the essential role of EWSR1-FLI1 protein in the regulation of oncogenesis, survival, and tumor progression processes has been described in-depth, little is known about the regulation of chimeric fusion-gene expression. Here, we demonstrate that the active nuclear HDAC6 in EWS modulates the acetylation status of specificity protein 1 (SP1), consequently regulating the SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 impairs binding of the activator complex SP1/P300, thereby inducing EWSR1-FLI1 downregulation and significantly reducing its oncogenic functions. In addition, sensitivity of EWS cell lines to HDAC6 inhibition is higher than other tumor or non-tumor cell lines. High expression of HDAC6 in primary EWS tumor samples from patients correlates with a poor prognosis in two independent series accounting 279 patients. Notably, a combination treatment of a selective HDAC6 and doxorubicin (a DNA damage agent used as a standard therapy of EWS patients) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could lead to suitable and promising therapeutic alternatives for patients with EWS.Research in the E.D.A. lab is supported by Asociación Española Contra el Cáncer (AECC), the Ministry of Science of Spain-FEDER (CIBERONC, PI1700464, PI2000003, RD06/0020/0059)S. D.G.D. and L.H.P. are supported by CIBERONC (CB16/12/00361). D.G.D., M.J.R. and L.H.P. are PhD researchers funded by the Consejería de Salud, Junta de Andalucía (PI-0197-2016, ECAI F2-0012-2018 and PI-0013-2018, respectively).Peer reviewe

BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer

Altres ajuts: Fellowship Award of the International Association for the Study of Lung Cancer i grant of the Italian Association for Cancer Research (AIRC My First AIRC Grant n° 14282).Abstract.BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.info:eu-repo/semantics/publishedVersio