[Access to orphan drugs for the treatment of spinal muscular atrophy in Spain]. / Acceso a medicamentos huérfanos para el tratamiento de la atrofia muscular espinal en España.

INTRODUCTION: Spinal muscular atrophy (SMA) is a rare disease whose diagnosis and treatment are complex. In Spain, there are two orphan medicines that are currently financed by the state, nusinersen and onasemnogene abeparvovec and, a third in process, risdiplam. The objective was to detect possible causes of inequity in the diagnosis and treatment of SMA in Spain. MATERIALS AND METHOD: Descriptive study realized in two phases: a first phase of bibliographic revision and a second phase of semi-structured interviews with clinical experts in SMA in Andalusia, Castilla-La Mancha, Catalonia and Murcia. RESULTS: The number of centers, services or units of reference, the availability of regional autonomous plans for rare diseases and pilot programs of neonatal screenings can regulate access to treatments. The number of new patients diagnosed per year is estimated between one and six in the four autonomous communities (ACs) of Spain studied. Differences were not found in logistical resources. Two of the four ACs studied have regional autonomous plans for rare diseases, however, their utility has only had relevance in one of two of the ACs. CONCLUSIONS: Important differences in access to nusinersen were not identified in the studied ACs The diagnosis of SMA requires clinical specialized experts and specialized centers for early intervention of disease-modifying therapies.

TITLE: Acceso a medicamentos huérfanos para el tratamiento de la atrofia muscular espinal en España.Introducción. La atrofia muscular espinal (AME) es una enfermedad rara cuyo diagnóstico y tratamiento es complejo. En España hay dos medicamentos huérfanos financiados por el Sistema Nacional de Salud, nusinersén y onasemnogén abeparvovec, y un tercero, risdiplam, pendiente. El objetivo fue analizar el acceso a los fármacos modificadores de la AME y detectar posibles causas de inequidad. Materiales y método. Estudio descriptivo realizado en dos fases: revisión bibliográfica y entrevistas semiestructuradas a expertos clínicos en AME de las comunidades autónomas (CC. AA.) de Andalucía, Castilla-La Mancha, Cataluña y Murcia. Resultados. El número de centros, servicios o unidades de referencia, la disponibilidad de planes autonómicos para enfermedades raras y los programas piloto de cribado neonatal pueden modular el acceso a los nuevos tratamientos farmacológicos. El número de nuevos pacientes diagnosticados al año se estimó entre uno y seis en cada una de las CC. AA. estudiadas. Dos de las cuatro CC. AA. estaban participando en ensayos clínicos. El tiempo desde la prescripción a la administración de nusinersén estaba entre siete y 60 días. Sólo Cataluña comunicó experiencia con onasemnogén abeparvovec a 30 de junio de 2022. Dos CC. AA. de las cuatro estudiadas disponen de plan autonómico para enfermedades raras; no obstante, se identificó como relevante para el tratamiento de la AME sólo en una de ellas. Conclusiones. No se identificaron diferencias importantes en el acceso al nusinersén en las CC. AA. estudiadas. El diagnóstico de la AME requiere personal clínico experto y centros especializados para iniciar precozmente los tratamientos modificadores de la enfermedad.

Assessment of the quality of patient information sheets and informed consent forms for clinical trials at a hospital neurology service.

BACKGROUND AND PURPOSE: Clinical trials (CTs) aimed at vulnerable groups, such as patients with mental disorders, create ethical complexity. The patient information sheet (PIS) should provide all of the information about the CT that is relevant to the subject's decision to participate. After being informed, the subject will decide freely whether to take part in the CT and will read and sign the informed consent form (ICF). The objective was to assess the quality of PISs/ICFs from a hospital neurology service. The assessment was made using validated and reliable checklists of the information included in the PISs/ICFs of CTs with medicinal products. METHODS: The study comprised analyses of compliance with the checklists of 21 PISs and ICFs reviewed/approved during 2016-2017 by a medicinal research ethics committee. RESULTS: All PISs/ICFs were from multicenter CTs sponsored by pharmaceutical companies in different therapeutic areas, mainly Parkinson's (52.4%) and Alzheimer's (38.1%) diseases. The PISs from the neurology service demonstrated good compliance (≥80%) with the checklist, whereas ICFs should be improved. Sponsors omitted some relevant information, such as the study title or that the participant be informed of any information arising from the research that may be relevant to the subject's health, although this information may be in the PIS. CONCLUSIONS: The PISs/ICFs of CTs of medicinal products that are currently used need improvement. PISs and ICFs should be separate documents for each CT. In particular, the PISs/ICFs should consider the criteria related to the decision of participants, protect their rights and ensure that the information received is complete.

Pharmacokinetic disposition of triclabendazole in cattle and sheep; discrimination of the order and the rate of the absorption process of its active metabolite triclabendazole sulfoxide.

A comparative pharmacokinetic study was conducted to determine the order and the rate of absorption of triclabendazole (TCBZ) in cattle and sheep. A commercial suspension of TCBZ (Biofasiolex, Biogénesis S.A., Argentina) was administered at a dose rate of 10 mg/kg by the oral route to six Holstein female calves and six Corriedale female sheep. The plasma concentration profiles of the metabolites triclabendazole sulfoxide (TCBZ-SO) and triclabendazole sulfone (TCBZ-SO(2)) were analysed by means of the non-compartmental method. The order of the absorption process of the active metabolite, TCBZ-SO, was determined by construction of curves of cumulative absorbed fraction of the drug by means of the Wagner-Nelson method. The appearance of TCBZ-SO in plasma of cattle and sheep resembles the entry of a constant quantity of drug into the organism per unit time. This is explained by the reservoir effect of the rumen, which acts as a biological slow-release system for TCBZ-SO and its precursor TCBZ to the posterior digestive tract where they are absorbed. The plasma concentration profiles of TCBZ-SO in both species were well described by a one-compartment open model with zero-order process of absorption and first-order process of elimination. The values of AUC(0-infinity) and C(max) of TCBZ-SO did not differ between species, while other kinetic parameters except for lambda(z) had higher values in calves than in sheep. In the case of TCBZ-SO(2), t(max) was the only parameter that did not differ between species, while other kinetic parameters except for lambda(z) had higher values in calves than in sheep.

[Development and validation of laboratory methods for antiretroviral quantitation using HPLC]. / Desarrollo y validación de métodos analíticos para la cuantificacion de antirretrovirales por HPLC.

OBJECTIVE: Development, validation and error characterization of three analytical methods, by high performance liquid chromatography (HPLC), for the quantitative analysis of ritonavir, saquinavir and abacavir in human plasma. METHOD: Reagents and instrumentation used, preparation of different standards, sample extraction procedure from biologic matrix, and analytical conditions assayed were detailed to set up three analytical methods. In addition, the validation and the determination of analytical error were also described. RESULTS: The analytical methods developed for ritonavir, saquinavir and abacavir in human plasma were selective, linear (r2>0.99), precise (coefficients of variation<15%) and accurate (relative errors<15%) over the concentration range selected. The recovery was more than 95% in all methods. Antiretroviral drugs were stable in the storage conditions assayed according to the routine laboratory. The error function discriminated for each analytical method validated was linear in saquinavir (SD=4.84+7.14.10(-2)C) and abacavir (SD=-1.072+3.70.10(-2)C), and non-linear in ritonavir (SD=39.98+2.40.10(-5)C2). CONCLUSIONS: Three analytical methods were developed and subsequently validated, with validation parameters being within the specifications and attributes of quality established. The error function characterized for each validated method can be used as a heteroscedastic weighting method in the parameter estimation by non-linear regression analysis in clinical pharmacokinetic studies of antiretroviral drugs assayed.

Two reproducible and sensitive liquid chromatographic methods to quantify atenolol and propranolol in human plasma and determination of their associated analytical error functions.

Two liquid chromatography (LC) methods with fluorimetric detection have been developed to measure atenolol and propranolol in human plasma. The same 5 microm Nucleosil RP-18 column, extraction procedure and mobile phase (containing acetonitrile, water, triethylamine and phosphoric acid, pH 3) were used. The linearity ranges were 25-800 ng/ml for atenolol and 3.13-100 ng/ml for propranolol. The coefficients of variation for validation assays were lower than 15% at the concentration assayed. The functions of the analytical error were linear: SD (ng/ml)=7.698+0.037C for atenolol and SD (ng/ml)=0.126+0.036C for propranolol.

A comparative in vitro study of percutaneous penetration of beta-blockers in human skin.

In vitro diffusion experiments with propranolol, oxprenolol, metoprolol and atenolol were carried out using excised human abdominal skin. The main permeation parameters (permeability coefficient, flow and lag time) were calculated and compared as measurement of intrinsic permeability across human skin. A long lag time and a low steady-state flow were found for all drugs assayed. Skin permeability predicted at steady state did not reach therapeutic concentrations, which indicated the need for appropriate chemical penetration enhancers or vehicles to overcome limiting factors. The results, including those of celiprolol and bisoprolol reported previously, correlated with physicochemical properties, especially with lipophilicity, one of the main factors in drug permeability prediction through human skin.

Determination of celiprolol and oxprenolol in human plasma by high-performance liquid chromatography and the analytical error function.

Two reversed-phase HPLC methods with UV detection to quantify celiprolol and oxprenolol in human plasma are described. The analytical methods for the determination of both drugs used the same reversed-phase HPLC column, mobile phase and extraction procedure. Linearity was obtained in the ranges 15.63-1000 and 25-800 ng/ml for celiprolol and oxprenolol, respectively. Intra-day and inter-day variation was lower than 14%. After validation of the methods, analytical error functions were established as S.D. (ng/ml)=3.096+0.041C for celiprolol and S.D. (ng/ml)=8.906+8.075x10(-8)C3 for oxprenolol.

Error structure for the HPLC analysis for atenolol, metoprolol and propranolol: a useful weighting method in parameter estimation.

Three reversed-phase high performance liquid chromatography (HPLC) methods with UV detection were developed and fully validated for the quantification of three beta-blockers: atenolol, metoprolol and propranolol. After validation, error structures for the HPLC analysis were established using a convenient and practical procedure. The mean percentage of relative standard deviation (RSD) of the experimental concentrations (C), were less than 4.29% for proportionality and less than 3.68% for precision for any of the drugs, which allowed the quantitation of beta-blockers assayed at concentrations in the range 25-0.78 micrograms.ml-1. The error structures for the HPLC analysis were: SD (micrograms.ml-1) = 5.02 x 10(-2) C for atenolol, SD (micrograms.ml-1) = 4.55 x 10(-2) + 0.63 x 10(-2) C - 7.58 x 10(-6) C3 for metoprolol and SD (micrograms.ml-1) = 2.73 x 10(-2) C - 3.49 x 10(-4) C2 for propranolol. The reciprocal of the square of the SD of the drug concentrations measured within the calibration curve could be used as weighting methods in parameter estimation by non-linear regression.

Determination of analytical error function for beta-blockers as a possible weighting method for the estimation of the regression parameters.

Three analytical methods have been developed and validated for the quantification of beta-blockers (celiprolol, bisoprolol and oxprenolol) using high performance liquid chromatography (HPLC) with UV detection. The methods were determined to be linear, precise and accurate (RSDs were lower than 5%), which allowed the quantitation of beta-blockers assayed at concentrations in the range 25-0.78 micrograms ml-1. After validation of reversed-phase HPLC methods, their analytical error functions were established by a rapid, simple and economical procedure. The discrimination of the best function for each active principle was performed by an appropriate polynomial statistical analysis, yielding SD (microgram ml-1) = 0.0295 + 0.0124C - 3.88 x 10(-4)C2 for celiprolol, 0.0199 + 0.011C - 1.27 x 10(-5)C3 for bisoprolol; and 0.0183 + 0.0089C - 9.68 x 10(-6)C3 for oxprenolol. These analytical error functions are an alternative to the weighting methods used in parameter estimation of beta-blockers.

Stability of an oral midazolam solution for premedication in paediatric patients.

The objectives of this study were to assess the stability of a 1 mg/ml oral midazolam solution elaborated by our Hospital Pharmacy Service, and to confirm its clinical effect in presurgical paediatric patients. The solution's stability was tested by determining its pH and its UV-visible absorption spectrum at room temperature for up to 60 days. A high performance liquid chromatography method was used to confirm it. There was no significant change in pH value of either the test or a control solution. No loss of midazolam could be detected during the test. The Anaesthesiology Service assessed the sedation quality (very good, good, bad) and the venous puncture response, 20 minutes after the administration of 0.3 mg/kg of an oral midazolam solution. Twenty children were examined (age: 4-7 years). In addition, the haemodynamic and ventilatory functions were evaluated.