Treatment of ocular disorders by gene therapy.

Gene therapy to treat ocular disorders is still starting, and current therapies are primarily experimental, with most human clinical trials still in research state, although beginning to show encouraging results. Currently 33 clinical trials have been approved, are in progress, or have been completed. The most promising results have been obtained in clinical trials of ocular gene therapy for Leber Congenital Amaurosis, which have prompted the study of several ocular diseases that are good candidates to be treated with gene therapy: glaucoma, age-related macular degeneration, retinitis pigmentosa, or choroideremia. The success of gene therapy relies on the efficient delivery of the genetic material to target cells, achieving optimum long-term gene expression. Although viral vectors have been widely used, their potential risk associated mainly with immunogenicity and mutagenesis has promoted the design of non-viral vectors. In this review, the main administration routes and the most studied delivery systems, viral and non-viral, for ocular gene therapy are presented. The primary ocular disease candidates to be treated with gene therapy have been also reviewed, including the genetic basis and the most relevant preclinical and clinical studies.

[Challenges in the pharmacotherapeutic management of the hospitalised patient with Parkinson's disease]. / Desafíos en el manejo farmacoterapéutico del paciente ingresado con enfermedad de Parkinson.

Patients with Parkinson's disease (PD) are admitted to hospital more frequently and for a longer time than other patients from the same age group. The reason they are hospitalised is often different from their underlying baseline disease and they are usually attended in services with little knowledge of the disease. Both the errors made when administering levodopa and the inappropriate use of pharmacological agents with a central antidopaminergic action are relatively common during their stay in hospital. This study reports on an analysis of the literature available on the challenges and complications that patients with PD have to deal with when they are admitted to hospital, especially those that have to do with pharmacotherapy. Likewise, the authors also propose a series of strategies that lead to better care of the patients during the time they are in hospital, including aspects such as controlling the supplies of antiparkinsonian medication and establishing protocols for the therapeutic exchange of antiparkinsonian agents, as well as protocols for a suitable management of comorbidities in this kind of patients. Other strategies involve encouraging self-management of the antiparkinsonian treatment by the hospitalised patients, conducting follow-up studies to monitor inappropriate prescriptions or creating the figure of 'specialist in PD'. To do so, it will be necessary to raise the awareness of the healthcare staff at the hospital, as well as that of both patients and their relatives, about the problems derived from an inappropriate management of pharmacotherapy in PD.

TITLE: Desafios en el manejo farmacoterapeutico del paciente ingresado con enfermedad de Parkinson.Los pacientes con enfermedad de Parkinson (EP) ingresan en el hospital con mayor frecuencia y durante mas tiempo que los pacientes del mismo grupo etario. El motivo del ingreso es a menudo diferente de su enfermedad de base, y son habitualmente atendidos en servicios con un conocimiento pobre de la enfermedad. Tanto los errores en el momento de la administracion de levodopa como el uso inapropiado de farmacos con accion antidopaminergica central son relativamente comunes durante su estancia hospitalaria. En este estudio se lleva a cabo un analisis de la bibliografia disponible sobre los desafios y las complicaciones a los que se enfrentan los pacientes con EP cuando ingresan en el hospital, principalmente en aquellos relacionados con la farmacoterapia. Asimismo, se proponen una serie de estrategias que redunden en una atencion a los pacientes durante su ingreso hospitalario, que incluyen aspectos como el control de las existencias de medicamentos antiparkinsonianos y el establecimiento de protocolos de intercambio terapeutico de antiparkinsonianos, asi como de protocolos para el manejo adecuado de comorbilidades en este tipo de pacientes; el fomento de la autogestion del tratamiento antiparkinsoniano por parte de los pacientes ingresados; la realizacion de estudios de seguimiento de prescripciones inapropiadas o la creacion de la figura de 'especialista en EP'. Para ello sera necesario impulsar la concienciacion del personal sanitario del hospital, asi como de los pacientes y sus familiares, sobre los problemas derivados del manejo inapropiado de la farmacoterapia en EP.

Desafíos en el manejo farmacoterapéutico del paciente ingresado con enfermedad de Parkinson / Challenges in the pharmacotherapeutic management of the hospitalised patient with Parkinson’s disease

Los pacientes con enfermedad de Parkinson (EP) ingresan en el hospital con mayor frecuencia y durante más tiempo que los pacientes del mismo grupo etario. El motivo del ingreso es a menudo diferente de su enfermedad de base, y son habitualmente atendidos en servicios con un conocimiento pobre de la enfermedad. Tanto los errores en el momento de la administración de levodopa como el uso inapropiado de fármacos con acción antidopaminérgica central son relativamente comunes durante su estancia hospitalaria. En este estudio se lleva a cabo un análisis de la bibliografía disponible sobre los desafíos y las complicaciones a los que se enfrentan los pacientes con EP cuando ingresan en el hospital, principalmente en aquellos relacionados con la farmacoterapia. Asimismo, se proponen una serie de estrategias que redunden en una atención a los pacientes durante su ingreso hospitalario, que incluyen aspectos como el control de las existencias de medicamentos antiparkinsonianos y el establecimiento de protocolos de intercambio terapéutico de antiparkinsonianos, así como de protocolos para el manejo adecuado de comorbilidades en este tipo de pacientes; el fomento de la autogestión del tratamiento antiparkinsoniano por parte de los pacientes ingresados; la realización de estudios de seguimiento de prescripciones inapropiadas o la creación de la figura de ‘especialista en EP’. Para ello será necesario impulsar la concienciación del personal sanitario del hospital, así como de los pacientes y sus familiares, sobre los problemas derivados del manejo inapropiado de la farmacoterapia en EP (AU)

Patients with Parkinson’s disease (PD) are admitted to hospital more frequently and for a longer time than other patients from the same age group. The reason they are hospitalised is often different from their underlying baseline disease and they are usually attended in services with little knowledge of the disease. Both the errors made when administering levodopa and the inappropriate use of pharmacological agents with a central antidopaminergic action are relatively common during their stay in hospital. This study reports on an analysis of the literature available on the challenges and complications that patients with PD have to deal with when they are admitted to hospital, especially those that have to do with pharmacotherapy. Likewise, the authors also propose a series of strategies that lead to better care of the patients during the time they are in hospital, including aspects such as controlling the supplies of antiparkinsonian medication and establishing protocols for the therapeutic exchange of antiparkinsonian agents, as well as protocols for a suitable management of comorbidities in this kind of patients. Other strategies involve encouraging self-management of the antiparkinsonian treatment by the hospitalised patients, conducting follow-up studies to monitor inappropriate prescriptions or creating the figure of ‘specialist in PD’. To do so, it will be necessary to raise the awareness of the healthcare staff at the hospital, as well as that of both patients and their relatives, about the problems derived from an inappropriate management of pharmacotherapy in PD (AU)

A novel gene therapy vector based on hyaluronic acid and solid lipid nanoparticles for ocular diseases.

The introduction of therapeutic genes in target tissues is considered as a novel tool for the treatment of several diseases. We have developed nanoparticles consisting on SLNs, protamine (P) and hyaluronic acid (HA) as carrier for gene therapy. Stable complexes positively charged and with a particle size ranging from 240 nm to 340 nm were obtained. Transfection studies in ARPE-19 and HEK-293 cells showed the versatility of vectors to efficiently transfect cells with different division rate, widening the potential applications of SLN-based vectors. In ARPE 19cells, the incorporation of P and HA induced almost a 7-fold increase in the transfection capacity of SLNs. The CD44 inhibition studies suggested the participation of this receptor in the internalization of the vectors in this cell line. The intracellular disposition of DNA showed that the HA is able to modulate the high degree of condensation of DNA due to the protamine inside the cells; an important fact, if the vector is uptaken via non-degradative endocytosis. Besides, the therapeutic plasmid which encodes the protein retinoschisin was employed achieving a positive transfection in ARPE-19 cells, showing a promising application of this new non-viral system for the treatment of X-linked juvenile retinoschisis by gene therapy.

In vivo pharmacokinetic-pharmacodynamic relationship and in vitro equivalence of two oral furosemide tablet formulations.

A randomized, cross-over, open study of bioequivalence between two different furosemide (CAS 54-31-9) formulations was performed; simultaneously, diuretic effects (urine output, sodium, potassium and chloride excretion) were also compared. Both products meet the British Pharmacopoeia specification and the results of a previous in vitro comparative study ensure equivalence of the two dissolution curves. Twenty-four healthy volunteers (male/female) participated in the bioequivalence study. Each treatment was given as a single 40-mg tablet following an overnight fast. Furosemide concentrations in plasma (measured by HPLC) and electrolyte amounts in urine were determined up to 12 h after treatment. The pharmacokinetic parameters AUC0-infinity, Cmax and Cmax/AUC0-infinity were tested for bioequivalence after ln-transformation of data and ratios of tmax were evaluated nonparametrically. The parametric analysis revealed the following test/reference ratios and their 90% confidence intervals (90% CI): 1.06 (0.94-1.19) for AUC0-infinity, 1.12 (0.96-1.31) for Cmax, and 1.06 (0.97-1.16) for Cmax/AUC0-infinity. The 90% CI for tmax was 0.55-1.00. Bioequivalence between both formulations was concluded for all parameters except for tmax. No significant diuretic differences between both formulations (test and reference) were observed after drug administration in relation to the baseline period. Systolic and diastolic blood pressure and heart rate showed a similar time-course after the drug administration and there were no differences between both formulations. Both products were well tolerated. It can be concluded that both formulations are equivalent in vitro and in vivo.

Release of salbutamol sulphate and ketoprofen enantiomers from matrices containing HPMC and cellulose derivatives.

We studied the release of salbutamol and ketoprofen enantiomers from HPMC K100M matrices containing two types of cellulose derivatives: cellulose tris (3,5-dimethylphenylcarbamate) and cellulose tris (2,3-dichlorophenylcarbamate), chiral excipients used as stationary phases for liquid chromatography. These matrices provided an extended release of both drugs. Ketoprofen release from formulations elaborated with cellulose tris (2,3-dichlorophenylcarbamate) was by anomalous transport, because the value of n (release exponent of the diffusion equation) ranged between 0.60-0.68, whereas for all other formulations the value of exponent n ranged from 0.50-0.54. The drug thus diffuses through the matrix and is released following a quasi-Fickian diffusion mechanism (stereoselective process). The matrices preferentially retained R-salbutamol and S-ketoprofen and cellulose tris (3,5-dimethylphenylcarbamate) showed more capacity of chiral discrimination for both drugs than cellulose tris (2,3-dichlorophenylcarbamate). Moreover, we observed that stereoselectivity is dependent on the amount of chiral excipient in the formulation. Diffusion tests confirmed the chiral interaction between drugs and cellulose derivatives observed in the dissolution assays except for matrices elaborated with ketoprofen and cellulose tris (2,3-dichlorophenylcarbamate), where the low stereoselectivity observed with the matrices is due to the presence of HPMC K100M. We conclude that the inclusion of these cellulose derivatives in HPMC matrices does not result in a relevant stereoselectivity with respect to the two drugs studied.