Pharmacokinetics of Intravitreal Anti-VEGF Drugs in Age-Related Macular Degeneration

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)S

Recent Research in Ocular Cystinosis: Drug Delivery Systems, Cysteamine Detection Methods and Future Perspectives

Cystinosis is a rare genetic disorder characterized by the accumulation of cystine crystals in different tissues and organs. Although renal damage prevails during initial stages, the deposition of cystine crystals in the cornea causes severe ocular manifestations. At present, cysteamine is the only topical effective treatment for ocular cystinosis. The lack of investment by the pharmaceutical industry, together with the limited stability of cysteamine, make it available only as two marketed presentations (Cystaran® and Cystadrops®) and as compounding formulations prepared in pharmacy departments. Even so, new drug delivery systems (DDSs) need to be developed, allowing more comfortable dosage schedules that favor patient adherence. In the last decades, different research groups have focused on the development of hydrogels, nanowafers and contact lenses, allowing a sustained cysteamine release. In parallel, different determination methods and strategies to increase the stability of the formulations have also been developed. This comprehensive review aims to compile all the challenges and advances related to new cysteamine DDSs, analytical determination methods, and possible future therapeutic alternatives for treating cystinosisThis research was funded by Fundación Española de Farmacia Hospitalaria (FEFH 18-19), Fundación Mutua Madrileña (XVI Convocatoria de Ayudas a la Investigación en Salud) and “Asociación La Lucha de Iker”. C.M.-G. and A.F.-F. have funding research grants from Instituto de Salud Carlos III (C.M.-G.-Río Hortega CM18/00090 and A.F.-F.-Juan Rodés JR18/0004)S

Ethics Committee experience during COVID-19 emergency. A brief report

La crisis sanitaria motivada por el COVID-19 hace necesaria la puesta en marcha, con celeridad, de investigaciones encaminadas a generar evidencias científicas que incidan en el control de sus devastadores efectos. Por ello, fue necesario realizar ajustes en la dinámica de trabajo de los Comités de Ética de la Investigación así como priorizar y agilizar la evaluación de los proyectos relacionados con dicha enfermedad. Este trabajo pretende analizar la actividad la actividad evaluadora del Comité de Ética de la Investigación con Medicamentos de Galicia (CEIm-G) durante dicho período de emergencia sanitaria. Se evaluaron 81 proyectos de investigación, 73 de ellos de ámbito autonómico (62 unicéntricos), 4 nacionales y 4 internacionales. En 57 proyectos el dictamen fue favorable, 4 fueron retirados por los promotores, en 6 no procedía dictamen y 14 no respondieron a las aclaraciones solicitadas hasta la fecha del cierre del estudio. La causas más frecuentes de solicitud de aclaraciones estaban relacionadas con la metodología y a continuación con la hoja de información al paciente y el consentimiento informado. También es imprescindible abordar los aspectos relacionados con la intimidad de los datos personales y las muestras y tener en cuenta la carga de trabajo de los investigadores. Como propuesta de mejora, consideramos que se debe incidir en una mayor coordinación entre los diferentes equipos de investigación para tratar de obtener resultados más robustos

Current Situation and Challenges in Vitreous Substitutes

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 substitutionC.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)S

Ocular Biodistribution Studies using Molecular Imaging

Classical methodologies used in ocular pharmacokinetics studies have difficulties to obtain information about topical and intraocular distribution and clearance of drugs and formulations. This is associated with multiple factors related to ophthalmic physiology, as well as the complexity and invasiveness intrinsic to the sampling. Molecular imaging is a new diagnostic discipline for in vivo imaging, which is emerging and spreading rapidly. Recent developments in molecular imaging techniques, such as positron emission tomography (PET), single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI), allow obtaining reliable pharmacokinetic data, which can be translated into improving the permanence of the ophthalmic drugs in its action site, leading to dosage optimisation. They can be used to study either topical or intraocular administration. With these techniques it is possible to obtain real-time visualisation, localisation, characterisation and quantification of the compounds after their administration, all in a reliable, safe and non-invasive way. None of these novel techniques presents simultaneously high sensitivity and specificity, but it is possible to study biological procedures with the information provided when the techniques are combined. With the results obtained, it is possible to assume that molecular imaging techniques are postulated as a resource with great potential for the research and development of new drugs and ophthalmic delivery systems

Efficacy, safety and cost-efficiency of adalimumab 80 mg every other week in previously intensified IBD patients under treatment with adalimumab 40 mg every week

Background Dose escalation is often recommended for loss of response in patients with inflammatory bowel disease (IBD) under maintenance treatment with anti-TNF, but in normal conditions this strategy considerably increases the cost. A new presentation of Adalimumab (ADA) 80 mg has been approved in our hospital with the same price per unit as the ADA 40 mg presentation. The aim of this study was to evaluate the efficacy, safety and cost-efficiency of ADA 80 mg every other week (eow) in IBD patients under previously intensified treatment with ADA 40 mg every week. Methods A prospective and observational study was performed. Inclusion criteria were all IBD patients under intensified maintenance therapy with ADA 40 mg every week. Physicians informed all patients the reasons (cost and convenience) for changing to a ADA 80 mg eow dose and asked for their consent. So far we have evaluated a period of 1 month, although the complete follow-up period will be 12 months. The Harvey?Bradshaw index (HBI ?4) and the Mayo partial index (Mayo partial index ?2) were used to evaluate clinical remission in Crohn?s disease (CD) and ulcerative colitis (UC) patients, respectively. Adverse events were monitored. Faecal calprotectin (FC) and C reactive protein (CRP) were collected at baseline (week 0, before first dose of subcutaneous injection of ADA 80 mg) and after 1 month. Biological remission was defined as clinical remission and FC < 250 ?g/g and CRP < 5 mg/dl. A descriptive analysis was performed and data are shown as percentage, median and range. Cost efficiency analysis was also performed. Results We offered to 18 consecutive IBD patients the possibility of participating in the study, but only 16 agreed to participate. We included 15 CD and 1 extensive UC with a median age of 40. 56.3% were male, 37.5% non-smokers and 31.3% ex-smokers. In CD, 46.7% had ileal disease, 13.3% colonic disease and 40% ileocolonic disease. 46.7% CD patients presented fistulising behaviour. At baseline, 86.7% of patients were in clinical remission and 92.3% were in clinical remission after 1 month. Median FC concentration at inclusion was 210 (range 6?1900) and 1 month later 91 (range 10?3754). Median CRP concentration at inclusion was 0.14 (range 0?19) and 0.21 (range 0.01?2.94) at month 1. 60% of patients at month 0 and 53.3% at month 1 were in biological remission. No adverse events were registered. After 1 month in total we had saved more than 13.000 euros and if all patients complete 1 year of treatment we predict savings of more than 150.000 euros with our new schedule of treatment. Conclusions Changing to a single dose ADA 80 mg eow is an efficacy, safety and cost-efficient strategy in IBD patients under intensified maintenance therapy with ADA 40 mg every week

Ampicillin Stability in a Portable Elastomeric Infusion Pump: A Step Forward in Outpatient Parenteral Antimicrobial Therapy

Outpatient parenteral antimicrobial therapy (OPAT) with continuous infusion pumps is postulated as a very promising solution to treat complicated infections, such as endocarditis or osteomyelitis, that require patients to stay in hospital during extended periods of time, thus reducing their quality of life and increasing the risk of complications. However, stability studies of drugs in elastomeric devices are scarce, which limits their use in OPAT. Therefore, we evaluated the stability of ampicillin in sodium chloride 0.9% at two different concentrations, 50 and 15 mg/mL, in an elastomeric infusion pump when stored in the refrigerator and subsequently in real-life conditions at two different temperatures, 25 and 32 °C, with and without the use of a cooling device. The 15 mg/mL ampicillin is stable for up to 72 h under refrigeration, allowing subsequent dosing at 25 °C for 24 h with and without a cooling device, but at 32 °C its concentration drops below 90% after 8 h. In contrast, 50 mg/mL ampicillin only remains stable for the first 24 h under refrigeration, and subsequent administration at room temperature is not possible, even with the use of a cooling system. Our data support that 15 mg/mL AMP is suitable for use in OPAT if the volume and rate of infusion are tailored to the dosage needs of antimicrobial treatments

Cysteamine Eye Drops in Hyaluronic Acid Packaged in Innovative Single-Dose Systems: Stability and Ocular Biopermanence

Cystinosis is a rare genetic disorder characterized by the accumulation of cystine crystals in different tissues and organs causing, among other symptoms, severe ocular manifestations. Cysteamine eye drops are prepared in hospital pharmacy departments to facilitate access to treatment, for which vehicles that provide adequate biopermanence, as well as adaptable containers that maintain its stability, are required. Difficulties related to cysteamine preparation, as well as its tendency to oxidize to cystamine, show the importance of conducting rigorous galenic characterization studies. This work aims to develop and characterize an ophthalmic compounded formulation of cysteamine prepared with hyaluronic acid and packaged in innovative single-dose systems. For this task, the effect of different storage temperatures and the presence/absence of nitrogen on the physicochemical stability of the formulation and its packaging was studied in a scaled manner, until reaching the optimal storage conditions. The results showed that 0.55% cysteamine, prepared with hyaluronic acid and packaged in single-dose containers, is stable for 30 days when stored at &minus;20 &deg;C. In addition, opening vials every 4 h at room temperature after 30 days of freezing maintains the stability of the cysteamine formulation for up to 16 h. Moreover, ocular biopermanence studies were conducted using molecular imaging, concluding that the biopermanence offered by the vehicle is not affected by the freezing process, where a half-life of 31.11 min for a hyaluronic acid formulation stored for 30 days at &minus;20 &deg;C was obtained, compared with 14.63 min for 0.9% sodium chloride eye drops