Evaluation of Current Amikacin Dosing Recommendations and Development of an Interactive Nomogram: The Role of Albumin.

This study aimed to evaluate the potential efficacy and safety of the amikacin dosage proposed by the main guidelines and to develop an interactive nomogram, especially focused on the potential impact of albumin on initial dosage recommendation. The probability of target attainment (PTA) for each of the different dosing recommendations was calculated through stochastic simulations based on pharmacokinetic/pharmacodynamic (PKPD) criteria. Large efficacy and safety differences were observed for the evaluated amikacin dosing guidelines together with a significant impact of albumin concentrations on efficacy and safety. For all recommended dosages evaluated, efficacy and safety criteria of amikacin dosage proposed were not achieved simultaneously in most of the clinical scenarios evaluated. Furthermore, a significant impact of albumin was identified: The higher is the albumin, (i) the higher will be the PTA for maximum concentration/minimum inhibitory concentration (Cmax/MIC), (ii) the lower will be the PTA for the time period with drug concentration exceeding MIC (T>MIC) and (iii) the lower will be the PTA for toxicity (minimum concentration). Thus, accounting for albumin effect might be of interest for future amikacin dosing guidelines updates. In addition, AMKnom, an amikacin nomogram builder based on PKPD criteria, has been developed and is freely available to help evaluating dosing recommendations.

Amikacin initial dosage in patients with hypoalbuminaemia: an interactive tool based on a population pharmacokinetic approach.

OBJECTIVES: To characterize amikacin population pharmacokinetics in patients with hypoalbuminaemia and to develop a model-based interactive application for amikacin initial dosage. METHODS: A population pharmacokinetic model was developed using a non-linear mixed-effects modelling approach (NONMEM) with amikacin concentration-time data collected from clinical practice (75% hypoalbuminaemic patients). Goodness-of-fit plots, minimum objective function value, prediction-corrected visual predictive check, bootstrapping, precision and bias of parameter estimates were used for model evaluation. An interactive model-based simulation tool was developed in R (Shiny and R Markdown). Cmax/MIC ratio, time above MIC and AUC/MIC were used for optimizing amikacin initial dose recommendation. Probabilities of reaching targets were calculated for the dosage proposed. RESULTS: A one-compartment model with first-order linear elimination best described the 873 amikacin plasma concentrations available from 294 subjects (model development and external validation groups). Estimated amikacin population pharmacokinetic parameters were CL (L/h) = 0.525 + 4.78 × (CKD-EPI/98) × (0.77 × vancomycin) and V (L) = 26.3 × (albumin/2.9)-0.51 × [1 + 0.006 × (weight - 70)], where CKD-EPI is calculated with the Chronic Kidney Disease Epidemiology Collaboration equation. AMKdose is a useful interactive model-based application for a priori optimization of amikacin dosage, using individual patient and microbiological information together with predefined pharmacokinetic/pharmacodynamic (PKPD) targets. CONCLUSIONS: Serum albumin, total bodyweight, estimated glomerular filtration rate (using the CKD-EPI equation) and co-medication with vancomycin showed a significant impact on amikacin pharmacokinetics. A powerful interactive initial dose-finding tool has been developed and is freely available online. AMKdose could be useful for guiding initial amikacin dose selection before any individual pharmacokinetic information is available.

Tipos de tratamientos prescritos en un grupo de pacientes diabéticos en una farmacia comunitaria / Types of treatments prescribed in a group of diabetic patients in a community pharmacy

OBJETIVO: conocer el porcentaje de pacientes que tienen prescrito tratamiento para la diabetes mellitus, tipo de tratamiento y comparativa con el Plan Integral de Diabetes de Andalucía. MÉTODOS: se incluyó en el estudio a todos aquellos pacientes que accedieron a la Farmacia Felisa Baena de Linares (Jaén) y quisieron facilitar su tratamiento completo (n = 500). A través de un estudio observacional se comprobó el tipo de tratamiento y su coincidencia con el Plan Integral de Diabetes. RESULTADOS: se comprobó que el 19,2 % de los pacientes objeto de estudio presentaban diabetes, de estos, el 75 % solo estaba en tratamiento por vía oral y el 9 % solo con insulina. De los resultados obtenidos se comprobó que un 80 % de los pacientes tenía prescrita metformina ya fuese en monoterapia, en combinación con otros antidiabéticos orales o con insulina. Del total de los pacientes con diabetes solo el 1 % tenía prescrito glucagón y un 16 % tiras reactivas, muy por debajo de lo establecido en el Plan Integral de Diabetes, que debería haberse encontrado en este caso en un 47 % de los pacientes. CONCLUSIONES: en nuestro entorno existe un alto número de pacientes con diabetes, predominando la terapia con metformina. Hay un bajo porcentaje de pacientes que tiene prescrito glucagon y tiras reactivas, comparado con el Plan Integral de Diabetes, lo que supone un riesgo para la salud del paciente. De aquí la importancia de desarrollar programas de salud desde la farmacia para que los pacientes conozcan los controles de la diabetes

OBJECTIVE: To determine the percentage of patients who are prescribed treatment for diabetes mellitus, type of treatment and comparison with the Plan Integral Diabetes (Junta Andalucía). METHODS: The study included all patients who accessed the Felisa Baena Pharmacy Linares (Jaen) and wanted to facilitate complete treatment (n = 500). Through an observational study the type of treatment of patients and the relationship with the Plan Integral Diabetes. RESULTS: It was found that 19.2% of patients in the study had diabetes, of these, 75% were only treatable orally and 9% only with insulin. From the results obtained it was found that 80% of patients were prescribed metformin either in monotherapy, in combination with other oral agents or insulin. Of all patients with diabetes only 1% had prescribed glucagon and 16% test strips, well below the provisions of the Plan Integral Diabetes, which should have been in this case 47% of patients. CONCLUSIONS: In our environment there is a high number of patients with diabetes, metformin therapy predominating. There is a low percentage of patients who have been prescribed glucagon and test strips compared with the Plan Integral Diabetes, which pos-es a risk to patient health. Hence the importance of developing health programs from the pharmacy so that patients are aware how to control diabetes

Evaluation of renal function equations to predict amikacin clearance.

Objective: To evaluate the predictive performance of eight renal function equations to describe amikacin elimination in a large standard population with a wide range of age. Methods: Retrospective study of adult hospitalized patients treated with amikacin and monitored in the clinical pharmacokinetics laboratory of a pharmacy service. Renal function was calculated as Cockcroft-Gault with total, adjusted and ideal body weight, MDRD-4, CKD-EPI, rLM, BIS1, and FAS. One compartment model with first-order elimination, including interindividual variability on clearance and volume of distribution and combined residual error model was selected as a base structural model. A pharmaco-statistical analysis was performed following a non-linear mixed effects modeling approach (NONMEM 7.3 software). Results: 198 patients (61 years [18-93]) and 566 measured amikacin plasma concentrations were included. All the estimated glomerular filtration rate and creatinine clearance equations evaluated described properly the data. The linear relationship between clearance and glomerular filtration rate based on rLM showed a statistically significant improvement in the fit of the data. rLM must be evaluated carefully in renal failure for amikacin dose adjustment. Conclusions: Revised Lund-Malmö (rLM) and CKD-EPI showed the superior predictive performance of amikacin drug elimination comparing to all the alternative metrics evaluated.

Magnetic solid lipid nanoparticles in hyperthermia against colon cancer.

A reproducible double emulsion/solvent evaporation procedure is developed to formulate magnetic solid lipid nanoparticles (average size≈180 nm) made of iron oxide cores embedded within a glyceryl trimyristate solid matrix. The physicochemical characterization of the nanocomposites ascertained the efficacy of the preparation conditions in their production, i.e. surface properties (electrokinetic and thermodynamic data) were almost indistinguishable from those of the solid lipid nanomatrix, while electron microscopy characterizations and X-ray diffraction patterns confirmed the satisfactory coverage of the magnetite nuclei. Hemocompatibility of the particles was established in vitro. Hysteresis cycle determinations defined the appropriate magnetic responsiveness of the nanocomposites, and their heating characteristics were investigated in a high frequency alternating gradient of magnetic field: a constant maximum temperature of 46 °C was obtained within 40 min. Finally, in vitro tests performed on human HT29 colon adenocarcinoma cells demonstrated a promising decrease in cell viability after treatment with the nanocomposites and exposure to that alternating electromagnetic field. To the best of our knowledge, this is the first time that such type of nanoformulation with very promising hyperthermia characteristics has been developed for therapeutic aims.

Nano-engineering of 5-fluorouracil-loaded magnetoliposomes for combined hyperthermia and chemotherapy against colon cancer.

The present investigation aimed to develop magnetoliposome nanoparticles loaded with 5-fluorouracil by following a reproducible thin film hydration technique. The physicochemical characterization (including electron microscopy analysis, dynamic light scattering, infrared spectrometry, X-ray diffractometry, electrophoresis, and surface thermodynamics) suggested that superparamagnetic magnetite nuclei were successfully embedded into a multilamellar lipid vesicle. Magnetic responsiveness of these nanocomposites was quantitatively analyzed by determining the hysteresis cycle and qualitatively confirmed by microscopic visualizations. A high frequency alternating electromagnetic field was further used to define their heating properties. The absence of cytotoxicity in human colon fibroblast CCD-18 and in human colon carcinoma T-84 cell lines and excellent hemocompatibility of these core/shell particles were demonstrated. Additionally, 5-fluorouracil incorporation was investigated by two procedures: (i) entrapment into the nanoparticulate matrix and (ii) surface deposition onto already formed magnetoliposome particles. The former method reported greater drug loading values and a sustained release profile. Interestingly, 5-fluorouracil release was also triggered by the heating properties of the nanoparticles (hyperthermia-triggered drug release). Hence, we put forward that magnetoliposome particles hold important properties, that is, magnetically targeted delivery, hyperthermia inducing capability, high 5-fluorouracil loading capability, and hyperthermia-triggered burst drug release, suggestive of their potential for a combined antitumor therapy against colon cancer.

Biocompatible gemcitabine-based nanomedicine engineered by Flow Focusing for efficient antitumor activity.

We investigated the incorporation of gemcitabine into a colloidal carrier based on the biodegradable and biocompatible poly(d,l-lactide-co-glycolide) (PLGA) to optimize its anticancer activity. Two synthesis techniques (double emulsion/solvent evaporation, and Flow Focusing) were compared in terms of particle geometry, electrophoretic properties (surface charge), gemcitabine vehiculization capabilities (drug loading and release), blood compatibility, and in vitro antitumor activity. To the best of our knowledge, the second formulation methodology (Flow Focusing) has never been applied to the synthesis of gemcitabine-loaded PLGA particles. With the aim of achieving the finest (nano)formulation, experimental parameters associated to these preparation procedures were analyzed. The electrokinetics of the particles suggested that the chemotherapy agent was incorporated into the polymeric matrix. Blood compatibility was demonstrated in vitro. Flow Focusing led to a more appropriate geometry, higher gemcitabine loading and a sustained release profile. In addition, the cytotoxicity of gemcitabine-loaded particles prepared by Flow Focusing was tested in MCF-7 human breast adenocarcinoma cells, showing significantly greater antitumor activity compared to the free drug and to the gemcitabine-loaded particles synthesized by double emulsion/solvent evaporation. Thus, it has been identified the more adequate formulation conditions in the engineering of gemcitabine-loaded PLGA nanoparticles for the effective treatment of tumours.

Potenciación de la actividad antitumoral de doxorrubicina mediante su formulación en nanoplataformas magnéticas / Improvement of the antitumor activity of doxorubicin by the use of magnetic nanoplatforms

El diseño de sistemas transportadores basados en nanopartículas magnéticas pretende la acumulación en el tejido tumoral de la dosis de fármaco administrada. Así debe obtenerse una mejora significativa del efecto anticanceroso, junto con la minimización de la toxicidad asociada. En este contexto, desarrollamos una metodología reproducible de formulación de nanopartículas constituidas por núcleos de óxido de hierro (magnetita) embebidos en una matriz de poli (E- caprolactona). La extensa caracterización fisicoquímica de estos nanocompuestos permitió definir las condiciones óptimas de formulación para asegurar el transporte eficaz de fármacos. Se estudió la capacidad de la nanoplataforma para desarrollar un efecto antitumoral de hipertermia, su compatibilidad sanguínea y su utilización por vía intravenosa como sistema transportador de doxorrubicina hasta el tejido canceroso. Las nanopartículas magnetita/pol i(E-caprolactona) presentaron una adecuada vehiculización de este fármaco, junto con una muy significativa susceptibilidad magnética. Finalmente, se analizó la actividad antitumoral de los nanocompuestos cargados con doxorrubicina en un modelo de tumor subcutáneo EMT6 inducido en ratones. Se observó que éstos presentaban un marcado efecto quimioterápico en comparación con tratamientos alternativos (p.ej., la administración de estas nanopartículas sin guiado magnético hasta la masa tumoral, o el tratamiento con una solución intravenosa de doxorrubicina). Los resultados obtenidos resaltan las interesantes propiedades que presenta la nanoformulación diseñada para el desarrollo de una terapia eficaz contra el cáncer(AU)

The introduction of magnetic nanoplatforms in the cancer arena is intended to optimize the accumulation of the drug dose into the tumor interstitium with the help of a magnetic gradient. As a result, the chemotherapeutic agent may exhibit an enhanced anticancer efficacy and a negligible systemic toxicity. In these contexts, we have developed a reproducible methodology for the design of magnetite/poly (E-caprolactone) core/shell nanoparticles. A detailed physicochemical characterization of these nanocomposites suggested that their heterogeneous structure allows their use in drug delivery, thanks to an excellent responsiveness to magnetic gradients. In vitro heating characteristics (hyperthermia inducing capability) of the core/shell nanoparticles were investigated in a high frequency alternating magnetic gradient. Blood compatibility of the nanoformulation was defined in vitro. Finally, this nanodevice was used to enhance the intravenous delivery of the anticancer agent doxorubicin to the tumor tissue. The nanocomposites were characterized by an adequate doxorubicin loading, a significant magnetic susceptibility, and a low burst drug release. When injected to the EMT6 subcutaneous mice tumor model, these doxorubicin-loaded core/shell nanoparticles were magnetically guided, and they displayed considerably greater anticancer activity than the other anticancer treatments (i.e., doxorubicin-loaded nanocomposites non-magnetically guided, or doxorubicin free in solution). Thus, the here-described stimuli-sensitive nanomedicine possesses important characteristics for effective therapy of cancer(AU)

Synthesis of a biodegradable magnetic nanomedicine based on the antitumor molecule tegafur.

The introduction of magnetic nanocarriers in chemotherapy aims to enhance the anticancer activity of antitumor molecules whereas keeping their toxicity to a very minimum. Magnetite/poly(hexylcyanoacrylate) (core/shell) nanoplatforms were synthesized by an emulsion/polymerization procedure. An exhaustive physicochemical characterization (including infrared spectrometry, electrophoresis, and thermodynamic analysis) suggested that the magnetite nuclei were embedded into a polymeric nanomatrix. The very good magnetic responsiveness of such core/shell nanoparticles was defined by the hysteresis cycle. To improve the intravenous delivery of tegafur to cancer, we investigated its incorporation into the nanoplatform. Compared to surface adsorption, drug entrapment into the polymeric shell yielded higher tegafur loading values, and a much slower release profile. A high frequency alternating magnetic gradient was used to elucidate the heating characteristics of the nanoparticles: a stable maximum temperature of 46 °C was successfully achieved within 32 min. Thus, we put forward that such kind of multifunctional nanomedicine hold very important characteristics (i.e., high drug loading, little burst release, hyperthermia, and magnetically targeted tegafur delivery), suggestive of its potential for combined antitumor therapy against cancer.

Role of the electrokinetic properties on the stability of mebendazole suspensions for veterinary applications.

This work is focused on the analysis of the effect of basic physicochemical aspects (surface thermodynamic and electrokinetic characteristics) on the stability and redispersibility properties of mebendazole aqueous suspensions. To our knowledge, previous investigations on the formulation of mebendazole suspensions have been not devoted to the elucidation of the colloidal behavior of this benzimidazole carbamate. A deep thermodynamic and electrokinetic characterization, considering the effect of both pH and ionic strength, was carried out with that purpose. It was found that the hydrophobicity and, the surface charge and electrical double layer thickness of the drug play a significant role in the stability of the colloid. Mebendazole aqueous suspensions display a controllable "delayed" or "hindered" sedimentation and a very easy redispersion which may contribute to the formulation of veterinary liquid dosage forms.

Formulation and physicochemical characterization of poly(epsilon-caprolactone) nanoparticles loaded with ftorafur and diclofenac sodium.

Even though conventional pharmacotherapy has been demonstrated to display very efficient activity against a wide variety of diseases, several active agents (e.g., anti-tumor drugs and non-steroidal anti-inflammatory drugs) are generally needed to be administered at high doses to elicit the required therapeutic action, simultaneously leading to severe side effects. This fact is usually due to unfavourable pharmacokinetic profiles (poor biological half-life) and to the possibility of induction of resistance. In order to increase the therapeutic activity of ftorafur and diclofenac sodium along with an overcome of their important drawbacks, we investigated their formulation into a colloidal carrier based on the biodegradable polymer poly(epsilon-caprolactone). Two drug loading methods were studied: (i) surface adsorption in already formed nanoparticles after incubation in a drug solution; (ii) drug addition before interfacial polymer disposition leading to drug entrapment into the polymeric network. We hypothesized that such nanocarrier possessed very significant characteristics (e.g., unusually high drug loading and low burst release), suggesting their potential application for efficient drug delivery to targeted sites.