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In recent years, many studies on population pharmacokinetics of linezolid have been conducted. This comprehensive review aimed to summarize population pharmacokinetic models of linezolid, by focusing on dosage optimization to maximize the probability of attaining a certain pharmacokinetic-pharmacodynamic parameter in special populations. We searched the PubMed and EMBASE databases for population pharmacokinetic analyses of linezolid using a parametric non-linear mixed-effect approach, including both observational and prospective trials. Of the 32 studies, 26 were performed in adults, four in children, and one in both adults and children. High between-subject variability was determined in the majority of the models, which was in line with the variability of linezolid concentrations previously detected in observational studies. Some studies found that patients with renal impairment, hepatic failure, advanced age, or low body weight had higher exposure and adverse reactions rates. In contrast, lower concentrations and therapeutic failure were associated with obese patients, young patients, and patients who had undergone renal replacement techniques. In critically ill patients, the inter-individual and intra-individual variability was even greater, suggesting that this population is at an even higher risk of underexposure and overexposure. Therapeutic drug monitoring may be warranted in a large proportion of patients given that the Monte Carlo simulations demonstrated that the one-size-fits-all labeled dosing of 600 mg every 12 h could lead to toxicity or therapeutic failure for high values of the minimum inhibitory concentration of the target pathogen. Further research on covariates, including renal function, hepatic function, and drug-drug interactions related to P-glycoprotein could help to explain variability and improve linezolid dosing regimens.

Vitreo-retinal disorders constitute a significant portion of treatable ocular diseases. These pathologies often require vitreo-retinal surgery and, as a consequence, the use of vitreous substitutes. Nowadays, the vitreous substitutes that are used in clinical practice are mainly divided into gases (air, SF6, C2F6, C3F8) and liquids (perfluorocarbon liquids, silicone oils, and heavy silicone oils). There are specific advantages and drawbacks to each of these, which determine their clinical indications. However, developing the ideal biomaterial for vitreous substitution continues to be one of the most important challenges in ophthalmology, and a multidisciplinary approach is required. In this sense, recent research has focused on the development of biocompatible, biodegradable, and injectable hydrogels (natural, synthetic, and smart), which also act as medium and long-term internal tamponade agents. This comprehensive review aims to cover the main characteristics and indications for use of the extensive range of vitreous substitutes that are currently used in clinical practice, before going on to describe the hydrogels that have been developed recently and which have emerged as promising biomaterials for vitreous substitution C.M.-G., E.B.-V., L.G.-Q., and A.F.-F. are grateful to the Carlos III Health Institute for financing the CM18/00090, CM20/00135, CM20/00024, and JR18/00014 personnel contracts. This work was partially supported by the following projects of Carlos III Health Institute (PI17/00940 and PI20/00719) SI

The health crisis resulting from the rapid spread of SARS-CoV-2 worlwide, added to the low evidence of currently used treatments has led to the development of a large number of clinical trials (CT) and observational studies. Likewise, important measures have been adopted in healthcare and research centers aimed at halting the pandemic as soon as possible. The objective of this study is to gather the main aspects of the clinical research studies undertaken by the Departments of Hospital Pharmacy (DHP) of Spain during the COVID-19 crisis. The decision of the Spanish Society of Hospital Pharmacy (SEFH) to sponsor CTs made it possible that 13% of DHP had been led at least one CT. The Spanish Agency for Medicines and Medical Devices (AEMPS), in coordination with Institutional Review Boards, has adopted a fast-track review procedure to accelerate authorizations for CTs related to the treatment or prevention of COVID-19. There have also been numerous public and private calls for financing research projects aimed at contributing to the fight against this virus. Despite the pandemic, actions have been taken to continue ongoing CTs and studies while the safety and well-being of patients are guaranteed. More specifically, the AEMPS and the European Medicines Agency (EMA) have issued guidelines that incorporate changes to CT protocols that will have to be applied until the pandemic is over. In this health emergency, the scientific community has found itself in a race against time to generate evidence. It is at this moment that hospital pharmacists emerge as key players in clinical research and are contributing to a rational, effective and safe healthcare decision-making.La presente crisis sanitaria derivada de la rápida expansión del virus SARS-CoV- 2 a nivel mundial, así como la falta de evidencia de los tratamientos empleados actualmente, ha provocado la aparición de un gran número de ensayos clínicos y estudios observacionales. Del mismo modo, ha ocasionado la puesta en marcha de importantes medidas en el entorno sanitario e investigador con el fin de conseguir detener la evolución de la pandemia lo antes posible. El objetivo del actual trabajo es recopilar aspectos fundamentales relacionados con la investigación clínica desarrollada por los servicios de farmacia hospitalaria durante la crisis provocada por la COVID-19. La iniciativa de la Sociedad Española de Farmacia Hospitalaria de actuar como promotor de ensayos clínicos ha posibilitado que el 13% de estos servicios de farmacia hospitalaria haya podido liderar uno. En este sentido, la Agencia Española de Medicamentos y Productos Sanitarios, junto con los Comités de Ética de Investigación, ha acelerado los procedimientos de autorización de nuevos ensayos clínicos destinados a tratar o prevenir la COVID-19. Asimismo, han sido numerosas las convocatorias públicas y privadas destinadas a la financiación de proyectos de diversa índole con el fin de contribuir a la lucha contra este virus. A pesar de la irrupción de la pandemia, también han surgido acciones destinadas a mantener las actividades de los ensayos clínicos y estudios puestos previamente en marcha, garantizando la seguridad y bienestar del paciente. Concretamente, la Agencia Española de Medicamentos y Productos Sanitarios y la Agencia Europea de Medicamentos han publicado guías que incluyen cambios en los protocolos de los ensayos clínicos que deben mantenerse mientras dure la pandemia. La emergencia sanitaria actual ha obligado a la comunidad científica a la generación de evidencia a contrarreloj. Por ello, en este momento en el que se requiere del mayor rigor posible, el farmacéutico de hospital debe alzarse como una figura clave en la investigación en salud, contribuyendo a que las decisiones sanitarias sean racionales, eficientes y seguras.

Econazole is a feasible alternative treatment in the management of fungal keratitis. Nevertheless, its low water solubility is considered the main limitation to the incorporation into ophthalmic formulations. In this work, econazole nitrate is solubilized by using cyclodextrins to achieve an optimum therapeutic concentration. Phase solubility diagrams suggest α-cyclodextrin as the most effective cyclodextrin and later the inclusion complex formed with this one was characterized in solution by 1D, 2D-NMR, and molecular modeling. Econazole-α-cyclodextrin inclusion complex was included in 2 types of ocular hydrogels: a natural polysaccharides ion-sensitive hydrogel and a hyaluronic acid hydrogel. Both of them show no ocular irritation in the hen's egg test on chorioallantoic membrane assay and a controlled econazole release over time. Permeability studies suggest that hydrogels do not modify the econazole nitrate permeability through bovine cornea in comparison with an econazole-α-cyclodextrin inclusion complex solution. Finally, ocular biopermanence studies performed using positron emission tomography show these hydrogels present a high retention time on the eye. Results suggest the developed formulations have a high potential as vehicles for the econazole topical ocular administration as fungal keratitis treatment.

Intravitreal administration of anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for Age-Related Macular Degeneration; however, the knowledge of their pharmacokinetics is limited. A comprehensive review of the preclinical and clinical pharmacokinetic data that were obtained in different studies with intravitreal bevacizumab, ranibizumab, and aflibercept has been conducted. Moreover, the factors that can influence the vitreous pharmacokinetics of these drugs, as well as the methods that were used in the studies for analytical determination, have been exposed. These anti-VEGF drugs present different charge and molecular weights, which play an important role in vitreous distribution and elimination. The pharmacokinetic parameters that were collected differ depending on the species that were involved in the studies and on physiological and pathological conditions, such as vitrectomy and lensectomy. Knowledge of the intravitreal pharmacokinetics of the anti-VEGF drugs that were used in clinical practice is of vital importance. This work was partially supported by the ISCIII (PI17/00940, RETICS Oftared, RD16/0008/0003 and RD12/0034/0017) cofunded by FEDER and by the Spanish Ministry of Science, Innovation and Universities (RTI2018-099597-B-100) SI

The current review is focussing different factors that contribute and directly correlate to the onset and progression of Age-related Macular Degeneration (AMD). In particular, the susceptibility to AMD due to genetic and non-genetic factors and the establishment of risk scores, based on the analysis of different genes to measure the risk of developing the disease. A correlation with the actual therapeutic landscape to treat AMD patients from the point of view of pharmacokinetics and pharmacogenetics is also exposed. Treatments commonly used, as well as different regimes of administration, will be especially important in trying to classify individuals as “responders” and “non-responders”. Analysis of different genes correlated with drug response and also the emerging field of microRNAs (miRNAs) as possible biomarkers for early AMD detection and response will be also reviewed. : This article aims to provide the reader a review of different publications correlated with AMD from the molecular and kinetic point of view as well as its commonly used treatments, major pitfalls and future directions that, to our knowledge, could be interesting to assess and follow in order to develop a personalized medicine model for AMD.

Inhaled administration of ethanol in the early stages of COVID-19 would favor its location on the initial replication sites, being able to reduce the progression of the disease and improving its prognosis. Before evaluating the efficacy and safety of this novel therapeutic strategy in humans, its characterization is required. The developed 65° ethanol formulation is stable at room temperature and protected from light for 15 days, maintaining its physicochemical and microbiological properties. Two oxygen flows have been tested for its administration (2 and 3 L/min) using an automated headspace gas chromatographic analysis technique (HS-GC-MS), with that of 2 L/min being the most appropriate one, ensuring the inhalation of an ethanol daily dose of 33.6 ± 3.6 mg/min and achieving more stable concentrations during the entire treatment (45 min). Under these conditions of administration, the formulation has proven to be safe, based on histological studies of the respiratory tracts and lungs of rats. On the other hand, these results are accompanied by the first preclinical molecular imaging study with radiolabeled ethanol administered by this route. The current ethanol formulation has received approval from the Spanish Agency of Medicines and Medical Devices for a phase II clinical trial for early-stage COVID-19 patients, which is currently in the recruitment phase (ALCOVID-19, EudraCT number: 2020-001760-29).

Background Ensuring the safety of products made in pharmacy departments is an essential parameter in the development of any ophthalmic formulation. Purpose The aim of this study was to show the cytotoxic effect of tacrolimus 0.03 mg/mL eye drops on human primary corneal epithelial cells using real time monitoring of dynamic changes based on bioimpedance measurements induced by cell–toxicant interactions. Material and methods Initially, tacrolimus 0.03 mg/mL eye drops (TED) were prepared as a pharmaceutical compound in the department of pharmacy. The effect of the TED on the viability of cells was studied on ATCC normal human primary corneal epithelial cells. We used the xCELLigence real time cell analyser system (ACEA Biosciences, San Diego, California, USA) for monitoring the growth of cell cultures in real time. The cell index , based on the measured electric impedance across the cell culture, was used to represent the number of cells. 3000 cells/well (16 wells E-plates) were incubated for 20 hours. Subsequently, the original culture medium was aspirated and different TED concentrations (7.5 µg/mL, 15 µg/mL, 22 µg/mL, 30 µg/mL, 37 µg/mL and 45 µg/mL) were added to different wells. The results are represented as dose response curves versus time, and IC50 was calculated in different times. Results Surviving rate kinetic curves showed that TED induced a gradual decline in the cell surviving rate over a 20 hour exposure period. This behaviour suggests that TED cause significant corneal cellular toxicity. An analysis of the kinetic curve of the cell surviving rate showed that these effects were time and dose dependent. The IC50 at 30 min was 0.0139 mg/mL, at 4 hours 0.0125 mg/mL and at 16 hours 0.00836 mg/mL. Conclusion These results may be particularly relevant to estimate the optimal TED concentration in clinical situations to avoid a toxic effect. References and/or acknowledgements Acknowledgements: Fundacion Mutua Madrilena and Fundacion Espanola Farmacia Hospitalaria. No conflict of interest

Background Corticosteroids and cyclosporine eye drops are common treatments in inflammatory ocular surface diseases. In some cases, patients do not respond to standard therapy and therefore it is necessary to search for new alternative formulations. Purpose The aim of this study was to present an ophthalmic compounded alternative to common therapy for inflammatory ocular surface diseases and to evaluate the efficacy in three paediatric patients. Material and methods Initially, a bibliographic research was conducted to find active ingredients and compatible excipients that could potentially be included in an ophthalmic formula (Martindale, Pubmed and Micromedex). Subsequently, tacrolimus eye drops (TED) were formulated and then its pH (pHmeter, WTW Inolab) and osmolality (VAPRO 5520) were measured. Finally, an ophthalmologist assessed the efficacy of the treatment over 3 months in 3 paediatric patients with inflammatory ocular surface disease in which previous treatments had failed. Results Each 1 mL of TED pharmaceutical compound contained 0.3 mg of tacrolimus, obtained from the intravenous presentation (Prograf). This ophthalmic formulation contained the following excipients: polyvinyl alcohol, benzalkonium chloride, sodium phosphate dibasic, sodium chloride, sodium phosphate monobasic, disodium edetate, hydrochloric acid or sodium hydroxide and purified water, all from the commercial presentation Liquifilm tears. The TED were developed in a horizontal laminar flow cabin, filtered through a 0.22 micron filter and packed into 5 mL sterile amber glass bottles. The osmolality of TED was 451.3±12.5 mmol/kg and the pH was 7. The ophthalmologist noticed a dramatic improvement in the evolution of the pathology in these 3 patients during the follow-up period; however, he noted that ocular tolerance should be improved as ocular itching was found after instillation of the eye drops. Conclusion The TED, presented as an ophthalmic pharmaceutical compounding alternative, were safe and effective for paediatric patients with inflammatory ocular surface diseases who did not respond to cyclosporine eye drops. References and/or acknowledgements Acknowledgements: Fundacion Mutua Madrilena and Fundacion Espanola de Farmacia Hospitalaria. No conflict of interest

Background Oropharyngeal candidiasis is a common local infection usually caused by candida species. The primary treatment is usually nystatin or topical azoles but both drugs are known to be teratogenic, at least during first semester of pregnancy. Purpose The aim was to present a new buccal formulation of amphotericin and determine its effectiveness in the treatment of oropharyngeal candidiasis in pregnant women. Material and methods A bibliographic research was conducted to find the appropriate active substance that could be used during pregnancy and, as a result, amphotericin was chosen as it is considered the safest antifungal (it is classified in the B group of the FDA list) compared with other antifungal agents. Regarding excipients, we searched on Martindale, European Pharmacopoeia, etc, to find ones suitable that were compatible with the oropharyngeal mucosae. Results The formulation was prepared from the amphotericin in powder form and dissolved in propylenglycol, Tween 80 and finally water. Strawberry extract was added. This topical solution had an amphotericin concentration of 25 mg/mL. The patient showed an improvement during treatment with amphotericin mouthwash, mentioning that the ulcers and little haemorrhages started to decrease after 3 days and that all symptoms remitted after 8 days. No relapses have occurred. The formulation was tolerated well without any adverse effects. Conclusion Amphotericin formulated as a mouthwash is an attractive alternative for oropharyngeal candidiasis in pregnant women. No conflict of interest