Physicochemical and microbiological stability study of two new preservative-free methylprednisolone eye drops. / Estudio de estabilidad fisicoquímica y microbiológica de 2 nuevos colirios de metilprednisolona sin conservantes.

OBJECTIVE: To study the physicochemical and microbiological stability over 90 days of two preservative-free methylprednisolone sodium succinate (MTPSS) 1 mg/ml and 10 mg/ml eye drops for use in ocular pathologies such as Sjögren's syndrome and dry eye syndrome. METHOD: The two eye drops were prepared from injectable MTPSS (Solu-moderin® and Urbason®), water for injection and normal saline solution. In accordance with ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines, they were then stored in triplicate under refrigerated conditions (5 ±3 °C), at room temperature (25 ± 2 °C), and at 40 °C (±2 °C). In accordance with the USP (United States Pharmacopeia), physicochemical controls of the active ingredient content were carried out by HPLC-UV (High Performance Liquid Chromatography with Ultraviolet detection), together with controls of pH, osmolality, and visual examination. Microbiological sterility was also tested under refrigerated conditions up to 30 days in open containers and up to 90 days in closed ones. RESULTS: The eye drops stored at 5 °C were the most stable; in the 1 mg/ml eye drops, degradation of the drug fell below 90% from day 21, and in the 10 mg/ml eye drops, from day 42. pH change did not vary by ≥1 unit in formulations stored at 5 °C, unlike the other formulations. Changes in osmolality did not exceed 5% on day 90 in any storage conditions. Samples of non refrigerate eye drops at 10 mg/ml, presented a white precipitate from day 14 and 28 respectively. Non-refrigerated 1 mg/ml eye drops presented suspended particles on day 90. There were no color changes. Microbiological analysis showed that sterility was maintained for over 90 days in the closed containers, although microbial contamination was detected from day 21 in the open containers. CONCLUSIONS: 1 mg/ml MTPSS eye drops show physicochemical and microbiological stability for 21 days under refrigeration, compared to 42 days for 10 mg/ml eye drops stored under the same conditions. However, since they do not include preservatives in their composition, they should not be used for more than 7 days after opening.

A Simple, Safe, and Effective Method for Preparing Autologous Bio-Based Fibrin Glue for Ophthalmic Use.

This study proposes a method to prepare autologous bio-based fibrin glue (FG) for use in ophthalmic surgery. FGs containing three fibrinogen concentrations and a thrombin concentrate were prepared using human blood from five donors (FG1: physiological fibrinogen concentration; FG2 and FG3: concentrated fibrinogen). The adhesion strength was tested, and the clinical safety and efficacy were studied in rabbit eyes in conjunctival surgery. A commercial FG was used as a control. From each donor, 2 mL of FG was prepared, containing 1 mL of 3.49 ± 0.78 (FG1), 17.74 ± 4.66 (FG2), or 47.46 ± 9.36 mg/mL (FG3) of fibrinogen and 1 mL of 2248.12 ± 604.20 UI/mL of thrombin. The average adhesion strength increased with the fibrinogen concentration, from 1.49 ± 0.39 kPa (FG1) to 3.14 ± 1.09 kPa (FG3). FG1 showed poor results when used for autograft adhesion. In contrast, the conjunctival autografts were successfully grafted using FG2 and FG3, revealing equivalent adhesion properties compared with commercial FG, but with less inflammation. In conclusion, FGs could be prepared on demand within minutes from small volumes of human blood, using a method that results in FGs which exhibit good adhesion capacity and are also safe and effective in a preclinical study.

Mini Cleanroom for the Manufacture of Advanced Therapy Medicinal Products (ATMP): Bioengineered Corneal Epithelium.

Among several requirements for the manufacture of Advanced Therapy Medicinal Products (ATMP) are: following the guidelines of a pharmaceutical quality system, complying with Good Manufacturing Practice (GMP) and access to a cleanroom fulfilling strict environmental conditions (Class A work area and Class B environment). This makes ATMP expensive. Moreover, the production of many of these therapeutic products may also be unprofitable, as in most cases their use is limited to a few patients and to a single batch per manufacturing unit. To reduce costs, ATMP may be produced in a scaled-down system isolated from the external environment (isolator), allowing for placement of this facility in a Class D environment, which is much more permissive and less costly. In this work, we confirm that it is possible to manufacture bioengineered corneal epithelium inside an isolator while fulfilling all the safety assurance standards at an affordable cost for patients. This small-scale ultra-clean working environment complies with GMP guidelines and could be a solution for the high costs associated with conventional cleanroom ATMP production.

Fibrin-Plasma Rich in Growth Factors Membrane for the Treatment of a Rabbit Alkali-Burn Lesion.

The purpose of this work is to describe the use of Fibrin-Plasma Rich in Growth Factors (PRGF) membranes for the treatment of a rabbit alkali-burn lesion. For this purpose, an alkali-burn lesion was induced in 15 rabbits. A week later, clinical events were evaluated and rabbits were divided into five treatment groups: rabbits treated with medical treatment, with a fibrin-PRGF membrane cultured with autologous or heterologous rabbit Limbal Epithelial Progenitor Cells (LEPCs), with a fibrin-PRGF membrane in a Simple Limbal Epithelial Transplantation and with a fibrin-PRGF membrane without cultured LEPCs. After 40 days of follow-up, corneas were subjected to histochemical examination and immunostaining against corneal or conjunctival markers. Seven days after alkali-burn lesion, it was observed that rabbits showed opaque cornea, new blood vessels across the limbus penetrating the cornea and epithelial defects. At the end of the follow-up period, an improvement of the clinical parameters analyzed was observed in transplanted rabbits. However, only rabbits transplanted with cultured LEPCs were positive for corneal markers. Otherwise, rabbits in the other three groups showed positive staining against conjunctival markers. In conclusion, fibrin-PRGF membrane improved the chemically induced lesions. Nonetheless, only fibrin-PRGF membranes cultured with rabbit LEPCs were able to restore the corneal surface.

Hospital Pharmacy Compounding against COVID-19 pandemic.

As in other areas of the health system, COVID-19 has had a dramatic impact on  hospital compounding. This area has faced numerous challenges, including the  shortage of frequent-use products (hydroalcoholic solutions, lopinavir/ritonavir  suspension), the use of new preparations for SARS-CoV-2 (tocilizumab,  remdesivir), or requests from overwhelmed wards unable to assume the safe  preparation of a high volume of medications (intravenous solutions). The  demand for all types of preparations (topic and oral medications, intravenous  solutions) has increased dramatically. This increase has highlighted the shortage of resources allocated to this area, which has made it difficult to meet the high  demand for preparations. In addition, the pandemic has revealed the scarcity of  research on such basic aspects as agent stability and drug compatibility. One of  the most relevant conclusions drawn from the COVID-19 pandemic is that the  basic areas of hospital pharmacy, along with other, must be maintained and  reinforced, as these are the areas that make us essential.

Como todo el sector sanitario, la farmacotecnia hospitalaria ha sufrido el impacto de la pandemia de la COVID-19, enfrentándose a la necesidad de cubrir el  desabastecimiento de productos de uso frecuente (soluciones hidroalcohólicas,  lopinavir/ritonavir suspensión), a nuevas preparaciones surgidas de las nuevas  necesidades provocadas por el SARS-CoV-2 (tocilizumab, remdesivir), o a  peticiones de plantas desbordadas por la carga asistencial, incapaces de asumir  con un mínimo de seguridad la preparación de numerosos medicamentos  (mezclas intravenosas). El incremento de actividad ha sido en todo tipo de  preparados (tópicos, orales y mezclas intravenosas) y ha puesto de manifiesto la escasez de recursos destinados a esta área, que se ha traducido en serios  problemas para afrontar todas las elaboraciones necesarias, así como la falta de  investigación en aspectos tan básicos como la estabilidad o la compatibilidad de  medicamentos. Probablemente, una de las conclusiones más importantes que  podemos extraer tras la COVID-19 es que ­sin menospreciar otras áreas de la  farmacia hospitalaria que también deben desarrollarse­ debemos mantener y  potenciar las áreas básicas de nuestra profesión. Aquellas que nos hacen imprescindibles.

La farmacotecnia hospitalaria frente a la COVID-19 / Hospital Pharmacy Compounding against COVID-19 pandemic

Como todo el sector sanitario, la farmacotecnia hospitalaria ha sufrido el impacto de la pandemia de la COVID-19, enfrentándose a la necesidad de cubrir el desabastecimiento de productos de uso frecuente (soluciones hidroalcohólicas, lopinavir/ritonavir suspensión), a nuevas preparaciones surgidas de las nuevas necesidades provocadas por el SARS-CoV-2 (tocilizumab, remdesivir), o a peticiones de plantas desbordadas por la carga asistencial, incapaces de asumir con un mínimo de seguridad la preparación de numerosos medicamentos (mezclas intravenosas). El incremento de actividad ha sido en todo tipo de preparados (tópicos, orales y mezclas intravenosas) y ha puesto de manifiesto la escasez de recursos destinados a esta área, que se ha traducido en serios problemas para afrontar todas las elaboraciones necesarias, así como la falta de investigación en aspectos tan básicos como la estabilidad o la compatibilidad de medicamentos. Probablemente, una de las conclusiones más importantes que podemos extraer tras la COVID-19 es que -sin menospreciar otras áreas de la farmacia hospitalaria que también deben desarrollarse- debemos mantener y potenciar las áreas básicas de nuestra profesión. Aquellas que nos hacen imprescindibles

As in other areas of the health system, COVID-19 has had a dramatic impact on hospital compounding. This area has faced numerous challenges, including the shortage of frequent-use products (hydroalcoholic solutions, lopinavir/ritonavir suspension), the use of new preparations for SARS-CoV-2 (tocilizumab, remdesivir), or requests from overwhelmed wards unable to assume the safe preparation of a high volume of medications (intravenous solutions). The demand for all types of preparations (topic and oral medications, intravenous solutions) has increased dramatically. This increase has highlighted the shortage of resources allocated to this area, which has made it difficult to meet the high demand for preparations. In addition, the pandemic has revealed the scarcity of research on such basic aspects as agent stability and drug compatibility. One of the most relevant conclusions drawn from the COVID-19 pandemic is that the basic areas of hospital pharmacy, along with other, must be maintained and reinforced, as these are the areas that make us essential

Topical Tacrolimus for Corneal Subepithelial Infiltrates Secondary to Adenoviral Keratoconjunctivitis.

PURPOSE: The objective of this study was to determine the efficacy and safety of topical tacrolimus compounded in the Pharmacy Service for the treatment of subepithelial corneal infiltrates (SEIs) secondary to adenoviral keratoconjunctivitis. METHODS: This retrospective study included patients who had been dispensed topical tacrolimus for the treatment of SEIs during the previous year. Patients were treated with tacrolimus 0.03% eye drops twice daily or tacrolimus 0.02% ointment once daily. The following data were recorded: length of treatment, visual acuity before and after treatment, intraocular pressure before, during, and at the end of treatment, previous treatments, and the presence of SEIs after treatment. The subjective symptoms of the patients were also assessed. RESULTS: Fifty-five patients (85 eyes) were included, 54.5% with bilateral involvement. A total of 31 (36.5%) eyes were treated with tacrolimus ointment and 54 eyes (63.5%) with tacrolimus eye drops. The median length of treatment was 185 days (p25-75: 93.5-426), and the mean follow-up duration was 363 days (p25-75: 148-540). In 62.35% of the eyes, the SEIs were reduced in number and size, and in 31.76%, they were eliminated. The patients had better visual acuity after treatment with highly statistically significant differences. Tolerance was good overall, being better in the eye drops group. CONCLUSIONS: Topical tacrolimus, compounded in the pharmacy, seems to be an effective and safe alternative for the treatment of SEIs secondary to adenovirus keratoconjunctivitis.

Analisis de la calidad de la nutricion parenteral / Analisis of the quality of parenteral nutrition

Introducción: La nutrición parenteral, forma parte del tratamiento farmacológico de los pacientes hospitalizados, mejorando su evolución clínica. Sin embargo, se encuentra como gran inconveniente, las complicaciones derivadas de su uso inadecuado. Con esto motivo, se crearon las unidades de nutrición, formadas por farmacéuticos hospitalarios, cuyo objetivo es el uso apropiado de la nutrición parenteral tanto central como periférica. Objetivos: Estimar la calidad de la administración de la nutrición parenteral desde una unidad de nutrición clínica dentro del Servicio de Farmacia en un Hospital general privado. Métodos: Revisión de los pacientes con nutrición parenteral en el área de hospitalización durante un periodo de 4 meses y medio, por el equipo de la unidad de nutrición (grupo estudio), comparados con un grupo de pacientes, con nutrición parenteral previo a la implantación de dicha unidad de nutrición (grupo control). Resultados: Se observa una disminución del 24,2% del número de nutriciones que no cumplen con la indicación según las guías europeas en el grupo de estudio respecto al control, no llegando a cumplir los estándares de calidad establecidos; se ha obtenido una reducción del 50% de la nutrición parenteral de corta duración, el resto de los indicadores de calidad en el grupo de estudio sí que se cumplen en cuanto a aporte calórico recibido calculado adecuadamente, suspensión progresiva de la nutrición y monitorización de los pacientes. Conclusiones: La unidad de nutrición dentro del Servicio de Farmacia ha logrado reducir el uso inapropiado de la nutrición parenteral, así como el uso de la nutrición parenteral de corta duración. Cumpliendo los estándares de calidad en cuanto a requerimientos energéticos administrados y monitorización de los pacientes (AU)

Introduction: Parenteral nutrition is an important frame in the treatment of inpatients. It helps with the outcomes in the diseases. The big problem with it is their use, there are a lot of complications around the use of inappropriate nutrition. The nutrition support team is made by hospital pharmacist, their aim is to have a good use of the central and peripheral parenteral nutrition. Objective: In this study our aim is to measure the quality of the parenteral nutrition administration in the nutrition unit in our hospital Pharmacy in a private general hospital. Methods: We review the inpatients who have received parenteral nutrition during a period of 4,5months, by our nutrition support team, and we compare it with another group of inpatients with parenteral nutrition before the beginning of this team. Results: We have decreased from 41.4% to 17.2% the percentage of inappropriate indications of parenteral nutrition in compliance with mandatory European guidelines nutrition in control group and in the study group respectively, and we have a decreased of 50% in the number of the short administration of the parenteral nutrition too, but still do not accomplish quality standard. The rest of quality indicators are meet standards in all of them, good caloric intake, progressive suspension of the nutrition, and monitoring of patients. Conclusions: The nutrition support team in a Pharmacy Service has reduced inappropriate use of parenteral nutrition, as well as the use of short-term parenteral nutrition. Meet the target of quality standards in terms of energy requirements administered and patient monitoring (AU)

Dificultades en el diagnóstico de los pacientes con enfermedad de Wilson en la práctica clínica: experiencia de 15 casos / Complexity of the diagnosis of Wilson disease in clinical practice: Our experience in 15 patients

INTRODUCCIÓN: La enfermedad de Wilson (EW) es un trastorno hereditario que cursa con depósito de cobre (Cu), provocando principalmente clínica hepática, neurológica y/o psiquiátrica. Ante la ausencia de algunos de sus rasgos típicos, el diagnóstico de la EW es difícil y se basa en la combinación de pruebas clínicas, analíticas y genéticas. El objetivo del estudio fue reflejar la complejidad del diagnóstico de la EW en la práctica clínica. MÉTODOS: Se realizó un análisis retrospectivo de la historia clínica de los pacientes diagnosticados de EW, describiendo la presentación clínica, hallazgos histológicos, analíticos y evolución tras tratamiento. Además se hizo estudio genético y se aplicó el «score» diagnóstico de Leipzig. RESULTADOS: Incluimos un total de 15 pacientes, 4 sintomáticos: clínica hepática (1), neurológica (1), psiquiátrica (1) y mixta (1) y 11 pacientes presintomáticos: hipertransaminasemia (8) y estudio familiar (3). Se objetivó anillo Kayser-Fleischer en 2 pacientes, ambos sin clínica neurológica. El 73% presentaba ceruloplasmina ≤5mg/dL y el 40% Cuo 24h>100μg. El Cu hepático superaba los 250μg/g t.s. en el 85% de los pacientes. El estudio genético (mutaciones gen ATP7B) permitió el diagnóstico final en 5 pacientes con mínimos rasgos de la enfermedad, uno de ellos sintomático (clínica psiquiátrica). Se identificaron 5 mutaciones previamente descritas (p.M645R, p.R827W, p.H1069Q, p.P768L y p.G869R) y 3 inéditas (p.L1313R, p.I1311T y p.A1179D), siendo p.M645R la mutación más frecuentemente encontrada. Tras el tratamiento se objetivó una mejoría de los parámetros analíticos (transaminasas, cupruria) y de la sintomatología, excepto en los pacientes con clínica neuropsiquiátrica. CONCLUSIONES: Nuestra serie refleja el papel relevante del estudio genético en el diagnóstico de EW. La identificación en nuestro medio de la mutación p.M645R en la mayoría de nuestros pacientes debe tenerse en cuenta en la estrategia para el análisis molecular del gen ATP7B en nuestra población

BACKGROUND: Wilson disease (WD) is an inherited disorder that causes copper (Cu) accumulation, leading to mainly liver, neurological and/or psychiatric manifestations. In the absence of some of the typical features, diagnosis of WD is difficult and is based on the combination of clinical, biochemical and genetic testing. The aim of this study was to illustrate the complexity of the approach to WD in daily clinical practice. METHODS: We retrospectively analyzed the medical records of patients with WD, including the clinical presentation, histological and biochemical findings, and follow up after treatment. We also carried out genetic testing, and the Leipzig diagnostic score was applied. RESULTS: We included 15 patients. Four were symptomatic, with liver (n=1), neurological (n=1), psychiatric (n=1) and mixed clinical manifestations (n=1), and 11 were presymptomatic, with elevated transaminases (n=8) and family study (n=3). We observed Kayser-Fleischer ring in 2 patients, both without neurologic symptoms. Ceruloplasmin ≤5mg/dL was present in 73%, and 24-hour urinary Cu>100μg in 40%. Liver Cu was >250μg/g.d.t. in 85% of the patients. The final diagnosis of WD was given by genetic testing (ATP7B gene mutations) in 5 patients with minimal disease features, including one symptomatic patient (psychiatric symptoms). We identified 5 previously reported mutations (p.M645R, p.R827W, p.H1069Q, p.P768L and p.G869R) and 3 unpublished mutations (p.L1313R, p.I1311T and p.A1179D); the most frequent mutation was p.M645R. After treatment, biochemical parameters (transaminases, urinary cooper) and symptoms improved, except in patients with neurological and psychiatric manifestations. CONCLUSIONS: Our series illustrates the important role of genetic testing in the diagnosis of WD. The identification of the p.M645R mutation in most of our patients should be kept in mind in the molecular analysis of the ATP7B gene in our region

[Complexity of the diagnosis of Wilson disease in clinical practice: our experience in 15 patients]. / Dificultades en el diagnóstico de los pacientes con enfermedad de Wilson en la práctica clínica: experiencia de 15 casos.

BACKGROUND: Wilson disease (WD) is an inherited disorder that causes copper (Cu) accumulation, leading to mainly liver, neurological and/or psychiatric manifestations. In the absence of some of the typical features, diagnosis of WD is difficult and is based on the combination of clinical, biochemical and genetic testing. The aim of this study was to illustrate the complexity of the approach to WD in daily clinical practice. METHODS: We retrospectively analyzed the medical records of patients with WD, including the clinical presentation, histological and biochemical findings, and follow up after treatment. We also carried out genetic testing, and the Leipzig diagnostic score was applied. RESULTS: We included 15 patients. Four were symptomatic, with liver (n=1), neurological (n=1), psychiatric (n=1) and mixed clinical manifestations (n=1), and 11 were presymptomatic, with elevated transaminases (n=8) and family study (n=3). We observed Kayser-Fleischer ring in 2 patients, both without neurologic symptoms. Ceruloplasmin ≤ 5 mg/dL was present in 73%, and 24-hour urinary Cu> 100 µg in 40%. Liver Cu was >250 µg/g.d.t. in 85% of the patients. The final diagnosis of WD was given by genetic testing (ATP7B gene mutations) in 5 patients with minimal disease features, including one symptomatic patient (psychiatric symptoms). We identified 5 previously reported mutations (p.M645R, p.R827W, p.H1069Q, p.P768L and p.G869R) and 3 unpublished mutations (p.L1313R, p.I1311T and p.A1179D); the most frequent mutation was p.M645R. After treatment, biochemical parameters (transaminases, urinary cooper) and symptoms improved, except in patients with neurological and psychiatric manifestations. CONCLUSIONS: Our series illustrates the important role of genetic testing in the diagnosis of WD. The identification of the p.M645R mutation in most of our patients should be kept in mind in the molecular analysis of the ATP7B gene in our region.