Abstract The concern about the risks of viral infections transmission through blood transfusion has led into a search for improvements on screening tests used for the selection of blood donors. Molecular biology techniques applied in researches of viral genomes, known as Nucleic Acid-amplification-Test (NAT), represent a technology capable of increasing transfusion safety by shortening the diagnostic window period. In Brazil, the implementation of this technology for the detection of HIV, HCV and HBV occurred due to the implantation of the NAT Kit – produced by Immunobiological Technology Institute (Biomanguinhos-FIOCRUZ), in the Brazilian blood centers. The National Health Surveillance Agency attaches great importance to validation, since it standardizes, disciplines and regulates criteria for the registration of health products. This work aims to establish a protocol of performance validation by real-time PCR method, taking as the object of study the Bio-Manguinhos NAT Kit, in order to update the product registration or to meet any future needs to ensure all regulatory requirements for the performance validation of the real-time PCR diagnostic kit. The protocol developed followed the ICH recommendations. The results revealed that the adopted methodology contemplates the necessary requirements for compliance with the Brazilian legislation, as well as the established validation parameters.

Abstract Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the latest class of drugs approved to treat type 2 DM (T2DM). Although adverse effects are often caused by a metabolite rather than the drug itself, only the safety assessment of disproportionate drug metabolites is usually performed, which is of particular concern for drugs of chronic use, such as SGLT2i. Bearing this in mind, in silico tools are efficient strategies to reveal the risk assessment of metabolites, being endorsed by many regulatory agencies. Thereby, the goal of this study was to apply in silico methods to provide the metabolites toxicity assessment of the SGLT2i. Toxicological assessment from SGLT2i metabolites retrieved from the literature was estimated using the structure and/or statistical-based alert implemented in DataWarrior and ADMET predictorTM softwares. The drugs and their metabolites displayed no mutagenic, tumorigenic or cardiotoxic risks. Still, M1-2 and M3-1 were recognized as potential hepatotoxic compounds and M1-2, M1-3, M3-1, M3-2, M3-3 and M4-3, were estimated to have very toxic LD50 values in rats. All SGLT2i and the metabolites M3-4, M4-1 and M4-2, were predicted to have reproductive toxicity. These results support the awareness that metabolites may be potential mediators of drug-induced toxicities of the therapeutic agents.

Abstract Sildenafil is a potent selective inhibitor of phosphosdiesterase-5 previously used in erectile dysfunction and subsequently approved in 2005 for pulmonary arterial hypertension treatment. Since oral administration of sildenafil shows pharmacokinetic problems with mean absolute bioavailability of 41%, the goal of this work was to develop a novel sildenafil self-emulsifying drug delivery system (SEDDS) for oral absorption improvement and management of dosage. One pharmaceutical solution and four SEDDS containing sildenafil were successfully obtained and SEDDS formed O/W nanoemulsion with droplet size less than 300 nm. The stability studies evidenced that the SEDDS containing 3.3% w/w of sildenafil yielded the best results. The safety of 2-pyrrolidone/isobutanol in oral formulations was assessed in mice and no lethality was achieved in the placebo groups with LD50 of 490 mg/Kg for SEDDS II-3.3, suggesting it as a safe excipient for humans. Therewithal, in silico studies using PBPK models provided the pharmacokinetic profile of sildenafil SEDDS. Subsequently, in silico evaluation indicated that the sildenafil SEDDS droplet size influenced its bioavailability, enhancing absorption, assuring a good pharmacokinetic profile. These findings suggest that the formulations developed here presented the potential to enhance drug oral absorption with the possibility to control drug dosage as they are liquid pharmaceutical formulations.

RESUMO Objetivo: Analisar relatos espontâneos de suspeitas de Reação Adversa a Medicamento (RAM) em crianças de 0 a 12 anos notificadas pela Agência Nacional de Vigilância Sanitária entre 2008 e 2013. Métodos: Um estudo transversal a partir de notificações de suspeitas de RAM relacionadas a medicamentos e produtos para a saúde em crianças foi realizado por um período de seis anos (2008-2013). O ano da notificação, a origem do relato por estado brasileiro, sexo, idade, o medicamento suspeito, a descrição da reação adversa e a gravidade foram incluídos na análise, bem como o número de leitos nos serviços de saúde e dados global da VigiBase. Resultados: Um total de 3330 reações adversas foram relatadas em crianças no Brasil no período investigado (54% em meninos). Cerca de 28% dos relatos de suspeitas de RAM envolveram crianças de 0 a 1 ano de idade. Quase 40% dos relatos vieram da região Sudeste. Aproximadamente 60% foram classificados como eventos graves. Houve ocorrência de morte em 75 casos. Quase 30% das mortes envolveram o uso off-label dos medicamentos. Um total de 3875 medicamentos (465 substâncias ativas) foram considerados fármacos suspeitos. Medicamentos anti-infecciosos (vancomicina, ceftriaxona, oxacilina e anfotericina), com ação no sistema nervoso (dipirona) e no trato digestivo foram os mais frequentemente notificados. Conclusões: As notificações de suspeitas de RAM por sexo e faixa etária corresponderam ao perfil de crianças hospitalizadas no Brasil. Os dados sobre gravidade e medicamentos relatados podem ser úteis para encorajar ações reguladoras e melhorar o uso seguro de medicamentos em crianças.

ABSTRACT Objective: To assess spontaneous reports of suspected adverse drug reactions in children aged 0-12 years from the Brazilian Health Regulatory Agency between 2008 and 2013. Methods: A cross-sectional study on suspected adverse drug reactions reports related to medicines and health products in children was carried out for a six-year period (2008-2013). Year of report, origin of report by Brazilian state, gender, age, suspected drug, adverse reaction description and seriousness were included in the analysis. The data obtained was compared to the number of pediatric beds in health services and to global data from the VigiBase (World Health Organization). Results: A total of 3330 adverse drug reactions were reported in children in Brazil in the investigated period (54% were in boys). About 28% of suspected adverse drug reactions reports involved 0 to 1-year-old children. Almost 40% of reports came from the Southeast region. Approximately 60% were classified as serious events. There was death in 75 cases. Nearly 30% of deaths involved off-label use; 3875 medicines (465 active substances) were considered suspected drugs. Anti-infective (vancomycin, ceftriaxone, oxacillin, and amphotericin), nervous system (metamizole) and alimentary tract and metabolism medicines were more frequent in reports. Conclusions: The distribution of suspected adverse drug reactions reports by sex and age group corresponded to the profile of children hospitalized in Brazil. Data about seriousness and medicines reported may be useful to encourage regulatory actions and improve the safe use of medicines in children.

Abstract Dietary supplements in many countries such as the USA do not require registration prior to commercialization. The Agência Nacional de Vigilância Sanitária (ANVISA) registers substances with functional properties as foods. Lutein is a carotenoid with antioxidant activity available on the market. However, no regulatory mandates exist to govern the design of quality control tests, which are necessary to ensure formulation effectiveness. Therefore, in the present study, tablet and dosage formulations from different manufacturers were tested following general methods outlined in the Brazilian and American Pharmacopeias. The averageweight, disintegration, content and dose uniformity assays were performed for all tablets and capsules, whereas hardness assays were only performed on tablets. None of the 10 formulations studied were found to be of satisfactory quality. Of all tablets tested, two had no-significant available lutein content, which may indicate adulteration. The capsules displayed adequate amounts of lutein, however had alarmingly negative disintegration and dissolution test results, which may contribute to non-bioavailability of lutein. All formulations analyzed are currently being marketed in the Brazilian and American markets. The low physicochemical performance in these formulations can be explained by the lack of specific regulations, which are necessary to ensure the quality of lutein-containing products on the market.

A nanotecnologia está relacionada às estruturas, propriedades e processos envolvendo materiais com dimensões numa escala nanométrica. O conceito de nanotecnologia em aplicações farmacêuticas, mais especificamente na liberação de fármacos, está baseado na produção de nanopartículas que contêm moléculas do fármaco a serem depositadas exclusivamente no órgão ou tecido alvo com a vantagem de serem inativas. Neste contexto, o presente trabalho busca estudar a utilização de uma organoargila, previamente modificada com octadecilamina, viscogel B8, como matriz de liberação controlada de fármacos por meio da reação de intercalação desta argila com PEG 6000 e MEG, comparando-se os resultados obtidos com um derivado previamente obtido da intercalação desta argila com PVP K-30. Estes materiais têm como diferencial a reunião de diferentes aspectos de funcionalidade, possibilitando se obter excipientes de liberação modificada de propriedades mistas.

Nanotechnology is related to structures, properties and processes involving materials in a nanometer dimension. This is widely used for pharmaceutical applications, more specifically in drugs' release. In this context, the present work studies the use of organophilic montmorillonite (OMMT), viscogel B8, as matrix of controlled release of drugs. New polymer-layered silicate nanocomposites (PLN) of MEG, PEG 6000 and OMMT were prepared and compared with PVP K-30-OMMT.