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2.
Sci Total Environ ; 677: 545-555, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31063896

RESUMO

The release of pharmacologically active compounds (PhACs) into aquatic ecosystems poses an environmental risk resulting in a chronic exposure of non-target organisms. A great variety of PhACs, of generally low concentrations, and the complicated sample preparation, makes circumstantial the accurate detection and quantification. Additionally, there is little information published about the spatiotemporal variation of the PhAC load in a larger catchment area utilised for touristic purposes. In addition to the natural biotic and abiotic changes, the seasonal variation of tourism also has a dramatic impact on water quality and the natural ecosystem in larger catchment areas. Therefore, our aim was to develop a reliable solid-phase extraction (SPE)-supercritical fluid chromatography tandem mass spectrometry (SFC-MS/MS) method for simultaneous multi-residue analysis of drugs to reveal the spatiotemporal changes in the PhAC contaminations in the waters of an important touristic region, the catchment area of the largest shallow lake in Central Europe, Lake Balaton (Hungary). The environmental application of the developed method revealed 69 out of the traced 134 chemical compounds, including 15 PhACs, which were detected from natural waters for the first time. Wastewater treatment plant (WWTP) loads have a major role in the PhAC contamination of the studied area; at the same time, the mass tourism-induced PhAC contamination was also detectable. Furthermore, the impact of tourism was indicated by elevated concentrations of recreational substances (e.g., caffeine and illicit drugs) in the touristic season affecting the water quality of this important summer holiday destination.


Assuntos
Monitoramento Ambiental/métodos , Lagos/análise , Preparações Farmacêuticas/análise , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos , Poluentes Químicos da Água/análise , Férias e Feriados , Hungria , Preparações Farmacêuticas/classificação , Estações do Ano , Análise Espaço-Temporal , Viagem
3.
Arch. Soc. Esp. Oftalmol ; 94(2): 75-80, feb. 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-180368

RESUMO

Antecedentes: El marcado descenso en los niveles de C-LDL producidos por los inhibidores de la proproteína convertasa plasmática subtilisina kexina tipo 9 (iPCSK9) podría asociarse con un mayor riesgo de cataratas. Métodos: Realizamos un metaanálisis que incluyó ensayos clínicos aleatorizados y controlados con iPCSK9, solos o combinados con otros fármacos hipolipidemiantes, que reportaron nuevos casos de cataratas, buscando en PubMed/Medline, bases de datos de EMBASE y Cochrane Clinical Trials. Se utilizó un modelo de efectos fijos y se realizó una metarregresión evaluando la relación entre el C-LDL intratratamiento y el riesgo de desarrollar cataratas. Resultados: Se tomaron en cuenta 5 estudios elegibles con iPCSK9 que incluyeron 83.492 pacientes para el análisis, refiriendo 531 nuevos casos de cataratas en el grupo con iPCSK9 frente a 532 en el grupo placebo. La terapia con iPCSK9 no se asoció con un mayor riesgo de presentar cataratas (OR: 0,96; IC 95%: 0,85-1,08; p = 0,86, I2: 0%]. Asimismo, no se encontró una asociación significativa entre la diferencia de C-LDL intratratamiento entre las ramas de los estudios y el riesgo de cataratas. Conclusión. En nuestro análisis, la utilización de iPCSK9 no se asoció con un mayor riesgo de cataratas


Background: The marked decrease in LDL-C levels produced by the inhibitors of the plasma proprotein convertase subtilisin/kexin type 9 (iPCSK9) could be associated with an increased risk of cataracts. Methods: A meta-analysis was performed that included randomised clinical trials controlled with iPCSK9, alone, or in combination with other lipid-lowering drugs, which reported new cases of cataracts, by searching PubMed/Medline, databases of EMBASE and Cochrane Clinical Trials. A fixed-effect model was used, and a meta-regression was carried out evaluating the relationship between intra-treatment LDL-C and the risk of developing cataracts. Results: Five eligible studies of iPCSK9 including 83,492 patients were taken into account for the analysis, and 531 new cases of cataracts in iPCSK9 group vs. 532 in placebo group were diagnosed. The iPCSK9 therapy was not associated with an increased risk of cataracts [OR: 0.96, 95% CI: 0.85-1.08; P = .86, I2: 0%]. Likewise, no significant association was found between on-treatment LDL-C levels, differences between study arms, and new cases of cataracts. Conclusion: In this analysis, the use of iPCSK9 was not associated with an increased risk of cataracts


Assuntos
Humanos , Oftalmopatias/classificação , Inibidores de Proteases/classificação , Lipoproteínas LDL/classificação , Preparações Farmacêuticas/classificação , Cardiopatias/classificação , Placebos/classificação , Colesterol/classificação , Grupos Controle
4.
Biopharm Drug Dispos ; 40(2): 51-61, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30635908

RESUMO

Solubility and permeability are recognized as key parameters governing drug intestinal absorption and represent the basis for biopharmaceutics drug classification. The Biopharmaceutics Classification System (BCS) is widely accepted and adopted by regulatory agencies. However, currently established low/high permeability and solubility boundaries are the subject of the ongoing scientific discussion. The aim of the present study was to apply data mining analysis on the selected drugs data set in order to develop a human permeability predictive model based on selected molecular descriptors, and to perform data clustering and classification to identify drug subclasses with respect to dose/solubility ratio (D/S) and effective permeability (Peff ). The Peff values predicted for 30 model drugs for which experimental human permeability data are not available were in good agreement with the reported fraction of drug absorbed. The results of clustering and classification analysis indicate the predominant influence of Peff over D/S. Two Peff cut-off values (1 × 10-4 and 2.7 × 10-4  cm/s) have been identified indicating the existence of an intermediate group of drugs with moderate permeability. Advanced computational analysis employed in the present study enabled the recognition of complex relationships and patterns within physicochemical and biopharmaceutical properties associated with drug bioperformance.


Assuntos
Biofarmácia/métodos , Mineração de Dados , Mucosa Intestinal/metabolismo , Modelos Biológicos , Preparações Farmacêuticas/classificação , Humanos , Absorção Intestinal , Permeabilidade , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Solubilidade
5.
Res Vet Sci ; 123: 239-246, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30685649

RESUMO

BACKGROUND: The voltage-gated K+-channel Kv11.1 has a central role in cardiac repolarization. Blockage of Kv11.1 has been linked to severe cardiovascular side effects, such as acquired long QT syndrome (aLQTS), torsade de pointes arrhythmia and sudden cardiac death (SCD). Kv11.1 is susceptible to unspecific drug interactions due to the presence of two aromatic amino acids residing in the inner vestibule of the pore. These aromatic residues are also present in the equine orthologue of Kv11.1. This suggests that equine Kv11.1 may also be prone to high-affinity block by a range of different chemical entities, which potentially could cause severe cardiac side effects and SCD in horses. AIM: To screen a series of commonly used drugs in equine medicine for interaction with Kv11.1. METHODS: High-throughput screening of selected compounds on human Kv11.1 expressed in a mammalian cell line was performed using an automated patch clamp system, the SyncroPatch 384PE (Nanion Technologies, Munich, Germany). Results were validated on equine Kv11.1 expressed in CHO-K1 cells by manual patch clamp. RESULTS: Acepromazine maleat (IC50 = 0.5 µM) trimethoprim (IC50 = 100 µM), diphenhydramine hydrochloride (IC50 = 2 µM) and cyproheptadine hydrochloride (IC50 = 1.84 µM) inhibited equine Kv11.1 current at clinically relevant drug concentrations. CONCLUSION: The results suggest that drug interaction with Kv11.1 can occur in horses and that some drugs potentially may induce repolarization disorders in horses.


Assuntos
Canal de Potássio ERG1/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Cavalos , Preparações Farmacêuticas/classificação , Animais , Células CHO , Cricetinae , Cricetulus , Humanos
6.
J Pharm Biomed Anal ; 166: 222-235, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30660807

RESUMO

In recent years, there has been a very active debate about the stability of drug products especially after exceeding the expiry dates. The regulatory authorities require comprehensive stability data for market approval. The shelf-life obtained determines the expiry date, which is typically between 1 and 5 years and commonly set in a conservative manner. Conducting stability studies is a resource- and time-consuming matter for the pharmaceutical manufacturer. Short shelf-lives of drug products are also a challenge for managers of hospitals, nursing homes, and strategic national stockpile agencies which have to dispose of large quantities of outdated medicines every year. This conflict raises the question whether shelf-lives are often longer than the labeled one. In the past years, the FDA has launched several programs for shelf-life extension in order to defer replacement costs and to prevent drug shortages due to supply disruption. The aim of this review was to bring together the available literature of expired drug products as well as historical pharmaceutical relicts with an age of more than 80 years and to discuss the actual shelf-life with regard to the respective dosage form and the affiliation of the drug class. It seems to be reasonable for a large portion of drugs to extend the expiry dates far beyond five years.


Assuntos
Rotulagem de Medicamentos/normas , Estabilidade de Medicamentos , Preparações Farmacêuticas/normas , Formas de Dosagem , Preparações Farmacêuticas/classificação , Controle de Qualidade , Fatores de Tempo
7.
São Paulo; s.n; s.n; 2019. 105 p. tab, graf.
Tese em Português | LILACS | ID: biblio-996861

RESUMO

Quitosana é um biopolímero encontrado principalmente na parede celular de crustáceos e é obtida pela desacetilação da quitina. Como biopolímero a quitosana é utilizada como excipiente para medicamentos e composição de alimentos. No entanto a quitosana devidamente purificada para uso farmacêutico ou alimentício tem custo financeiro elevado. Outro fator que contribui para o uso limitado é a falta de procedimento padronizado para desacetilação, o que resulta em materiais com diferentes graus de qualidade, dificultando suas aplicações e controle de qualidade de matéria prima e produto. Este trabalho tem como principal objetivo estabelecer procedimento reprodutível para a extração da quitina e da quitosana, por meio da aplicação dos conceitos de Quality by Design e planejamento de experimentos. A quitosana foi obtida pela desacetilação da quitina de crustáceos pelas etapas de desmineralização, desproteinização e despigmentação. O procedimento técnico para purificação da quitosana foi definido a partir de planejamento fatorial com ponto central para as etapas otimizadas, por meio da aplicação dos conceitos de Quality by Design e planejamento de experimentos. O projeto definiu um procedimento padronizado para purificação da quitosana que pode ser empregado em escala industrial, e financeiramente vantajoso para produção de medicamentos ou alimentos


Chitosan is a biopolymer found mainly in the cell wall of crustaceans and is obtained by the deacetylation of chitin. As biopolymer chitosan is used as excipient for medicaments and food composition. However, chitosan duly purified for pharmaceutical or food use has a high financial cost. Another factor that contributes to the limited use is the lack of standardized procedure for deacetylation, which results in materials with different grades of quality, hindering their applications and quality control of raw material and product. This work has as main objective to establish a reproducible procedure for the extraction of chitin and chitosan, through the application of the concepts of Quality by Design and planning of experiments. Chitosan was obtained by the deacetylation of chitin from crustaceans through the demineralization, deproteinization and depigmentation stages. The technical procedure for purification of chitosan was defined from a factorial planning with a central point for the optimized steps, through the application of the concepts of Quality by Design and planning of experiments. The project defined a standard procedure for the purification of chitosan that can be used on industrial scale and financially advantageous for the production of medicines or foods


Assuntos
Preparações Farmacêuticas/classificação , Quitosana/isolamento & purificação , Quitosana/análise , Otimização , Alimentos/classificação , Quitina/isolamento & purificação
8.
São Paulo; s.n; s.n; 2019. 132 p. graf, tab, ilus.
Tese em Português | LILACS | ID: biblio-995087

RESUMO

O controle microbiológico durante a produção de preparações farmacêuticas é de grande importância para garantir a qualidade do produto final, quanto às propriedades terapêuticas e de segurança ao paciente. O monitoramento ambiental é uma valiosa ferramenta como forma de mensurar a efetividade das medidas que integram a estratégia de controle de contaminação microbiana. Neste contexto, pouco destaque tem sido dado à manufatura de produtos farmacêuticos não-estéreis, por representarem as classes cujos riscos de contaminação microbiana são menores, quando comparados aos produtos parenterais. Dessa maneira, este estudo teve como objetivo caracterizar os isolados microbianos de amostras de ar ativo e passivo e de superfícies de áreas produtivas não-estéreis. Ainda, visou-se avaliar estatisticamente os dados de monitoramento ambiental, como base para o desenvolvimento de uma abordagem para determinação de limites de alerta e ação. Os resultados obtidos revelaram que a maioria dos microrganismos encontrados são de origem humana, seguidos por bactérias e fungos provenientes do solo. As diferenças sazonais foram observadas, principalmente, para a ocorrência de fungos, mais prevalentes no período seco. Foi desenvolvida uma abordagem estatística baseada em (1) determinação de subgrupos racionais, (2) avaliação da distribuição estatística e (3) determinação de limites, utilizando, como critério, o índice de capacidade do processo (Cpk). Um melhor entendimento do perfil microbiano das áreas produtivas e a determinação de limites de acordo com a distribuição real dos dados levará à destinação dos recursos necessários a ações que visem a qualidade do produto e a segurança do paciente


The microbiological control during the production of pharmaceutical preparations is of great importance for quality assurance of the final product regarding to therapeutic properties and patient safety. Environmental monitoring is a valuable tool to measure the effectiveness of the actions that integrate the microbial contamination control strategy. In this context, little attention has been given to the manufacture of non-sterile pharmaceutical products, because they represent classes whose microbial contamination risks are lower when compared to parenteral products. Considering this scenario, this study aimed to characterize microbial isolates from surfaces, active and passive air sampling of non-sterile manufacturing areas. Furthermore, it was expected to statistically evaluate the environmental monitoring data, as a basis for the development of an approach for determining alert and action limits. The results showed that most of the microorganisms found are from human source, followed by bacteria and fungi typically found in the soil. The seasonal differences were mainly observed for fungi recovery, which were more prevalent in the dry period. A statistical approach was developed based on (1) the determination of rational subgroups, (2) evaluation of the statistical distribution and (3) limit determination, using the process capacity index (Cpk) as criteria. A better understanding of the typical manufacturing areas microbial profile and the determination of limits according to the actual data distribution will lead to the allocation of the necessary resources to actions focusing on product quality and patient safety


Assuntos
Preparações Farmacêuticas/classificação , Análise Microbiológica , Monitoramento Ambiental/estatística & dados numéricos , Preparações Farmacêuticas/análise , Estatísticas Ambientais , Microbiota/fisiologia
9.
Comput Methods Programs Biomed ; 168: 1-10, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30527128

RESUMO

BACKGROUND AND OBJECTIVE: Due to the synergistic effects of drugs, drug combination is one of the effective approaches for treating complex diseases. However, the identification of drug combinations by dose-response methods is still costly. It is promising to develop supervised learning-based approaches to predict potential drug combinations on a large scale. Nevertheless, these approaches have the inadequate utilization of heterogeneous features, which causes the loss of information useful to classification. Moreover, they have an intrinsic bias, because they assume unknown drug pairs as non-combinations, of which some could be real drug combinations in practice. METHODS: To address above issues, this work first designs a two-layer multiple classifier system (TLMCS) to effectively integrate heterogeneous features involving anatomical therapeutic chemical codes of drugs, drug-drug interactions, drug-target interactions, gene ontology of drug targets, and side effects. To avoid the bias caused by labelling unknown samples as negative, it then utilizes the one-class support vector machines, (which requires no negative instance and only labels approved drug combinations as positive instances), as the member classifiers in TLMCS. Last, both a 10-fold cross validation (10-CV) and a novel prediction are performed to validate the performance of TLMCS. RESULTS: The comparison with three state-of-the-art approaches under 10-CV exhibits the superiority of TLMCS, which achieves the area under the receiver operating characteristic curve = 0.824 and the area under the precision-recall curve = 0.372. Moreover, the experiment under the novel prediction demonstrates its ability, where 9 out of the top-20 predicted combinative drug pairs are validated by checking the published literature. Furthermore, for each of the newly-validated drug combinations, this work analyses the combining mode of the member drugs and investigates their relationship in terms of drug targeting pathways. CONCLUSIONS: The proposed TLMCS provides an effective framework to integrate those heterogeneous features and is trained by only positive samples such that the bias of taking unknown drug pairs as negative samples can be avoided. Furthermore, its results in the novel prediction reveal five types of drug combinations and three types of drug relationships in terms of pathways.


Assuntos
Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos/métodos , Interações de Medicamentos , Preparações Farmacêuticas/química , Preparações Farmacêuticas/classificação , Farmácia/instrumentação , Algoritmos , Biologia Computacional , Simulação por Computador , Bases de Dados Factuais , Humanos , Farmácia/métodos , Curva ROC , Software
10.
An Real Acad Farm ; 84(3): 301-311, jul.-sept. 2018. graf
Artigo em Espanhol | IBECS | ID: ibc-178064

RESUMO

En este trabajo se analizan los documentos conocidos como Recetario de Alba, que comprende la relación de medicamentos expedidos a la Casa de Alba entre los años 1469 y 1470. Dicho análisis ha servido no solo para conocer qué medicinas se usaban en el ámbito de las élites castellanas durante ese periodo, sino también para introducirnos en la práctica médica real y en el papel del boticario y la influencia del galenismo durante la segunda mitad del siglo XV. Para ello, se ha realizado, por un lado, la comprobación de quienes fueron los beneficiarios de los medicamentos, y por otro lado, la clasificación y el análisis de los medicamentos simples y compuestos anotados en dicho recetario, atendiendo a distintos aspectos como su naturaleza, vía de administración y consistencia


This work analyzes a number of documents known as the "Recetario de Alba" which comprises the medicines prescribed for the House of Alba between 1469 and 1470. This study has contributed not only to learn about the medicines used by Castilian social elites in this period, but also to introduce us to the real medical practice, the role of apothecaries and the influence of Galenism during the second half of 15th century. To this aim, the study has firstly checked the identity of the patients who received the treatments and then has carried out the classification and analysis of the simple and compound medicines mentioned in the recipe book have been carried out, according to different aspects like their nature, route of administration and consistency


Assuntos
História do Século XV , Papel Profissional , Uso de Medicamentos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/classificação , Livros de Culinária como Assunto/métodos , Tratamento Farmacológico/métodos
11.
Aquat Toxicol ; 201: 151-161, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29909292

RESUMO

Tetracycline hydrochloride (TH), indomethacin (IM), and bezafibrate (BF) belong to the three different important classes of pharmaceuticals, which are well known for their toxicity and environmental concerns. However, studies are still elusive to highlight the mechanistic toxicity of these pharmaceuticals and rank them using both, the toxicity prediction and confirmation approaches. Therefore, we employed the next generation toxicity testing in 21st century (TOX21) tools and estimated the in vitro/vivo toxic endpoints of mentioned pharmaceuticals, and then confirmed them using in vitro/vivo assays. We found significant resemblance in the results obtained via both approaches, especially in terms of in vivo LC50 s and developmental toxicity that ranked IM as most toxic among the studied pharmaceuticals. However, TH appeared most toxic with the lowest estimated AC50s, the highest experimental IC50s, and DNA damages in vitro. Contrarily, IM was found as congener with priority concern to activate the Pi3k-Akt-mTOR pathway in vitro at concentrations substantially lower than that of TH and BF. Further, IM exposure at lower doses (2.79-13.97 µM) depressed the pharmaceuticals detoxification phase I (CYP450 s), phase II (UGTs, SULTs), and phase III (TPs) pathways in zebrafish, whereas, at relatively higher doses, TH (2.08-33.27 µM) and BF (55.28-884.41 µM) partially activated these pathways, which ultimately caused the developmental toxicity in the following order: IM > TH > BF. In addition, we also ranked these pharmaceuticals in terms of their particular toxicity to myogenesis, hematopoiesis, and hepatogenesis in zebrafish embryos. Our results revealed that IM significantly affected myogenesis, hematopoiesis, and hepatogenesis, while TH and BF induced prominent effects on hematopoiesis via significant downregulation of associated genetic markers, such as drl, mpx, and gata2a. Overall, our findings confirmed that IM has higher toxicity than that of TH and BF, therefore, the consumption of these pharmaceuticals should be regulated in the same manner to ensure human and environmental safety.


Assuntos
Preparações Farmacêuticas/classificação , Testes de Toxicidade/métodos , Toxicogenética , Animais , Biomarcadores/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Células HEK293 , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Transcrição Genética/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/embriologia , Peixe-Zebra/genética
12.
BMC Bioinformatics ; 19(1): 129, 2018 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-29642848

RESUMO

BACKGROUND: Drug repositioning is the process of identifying new uses for existing drugs. Computational drug repositioning methods can reduce the time, costs and risks of drug development by automating the analysis of the relationships in pharmacology networks. Pharmacology networks are large and heterogeneous. Clustering drugs into small groups can simplify large pharmacology networks, these subgroups can also be used as a starting point for repositioning drugs. In this paper, we propose a two-tiered drug-centric unsupervised clustering approach for drug repositioning, integrating heterogeneous drug data profiles: drug-chemical, drug-disease, drug-gene, drug-protein and drug-side effect relationships. RESULTS: The proposed drug repositioning approach is threefold; (i) clustering drugs based on their homogeneous profiles using the Growing Self Organizing Map (GSOM); (ii) clustering drugs based on drug-drug relation matrices based on the previous step, considering three state-of-the-art graph clustering methods; and (iii) inferring drug repositioning candidates and assigning a confidence value for each identified candidate. In this paper, we compare our two-tiered clustering approach against two existing heterogeneous data integration approaches with reference to the Anatomical Therapeutic Chemical (ATC) classification, using GSOM. Our approach yields Normalized Mutual Information (NMI) and Standardized Mutual Information (SMI) of 0.66 and 36.11, respectively, while the two existing methods yield NMI of 0.60 and 0.64 and SMI of 22.26 and 33.59. Moreover, the two existing approaches failed to produce useful cluster separations when using graph clustering algorithms while our approach is able to identify useful clusters for drug repositioning. Furthermore, we provide clinical evidence for four predicted results (Chlorthalidone, Indomethacin, Metformin and Thioridazine) to support that our proposed approach can be reliably used to infer ATC code and drug repositioning. CONCLUSION: The proposed two-tiered unsupervised clustering approach is suitable for drug clustering and enables heterogeneous data integration. It also enables identifying reliable repositioning drug candidates with reference to ATC therapeutic classification. The repositioning drug candidates identified consistently by multiple clustering algorithms and with high confidence have a higher possibility of being effective repositioning candidates.


Assuntos
Reposicionamento de Medicamentos , Estatística como Assunto , Algoritmos , Análise por Conglomerados , Biologia Computacional , Humanos , Preparações Farmacêuticas/classificação
13.
Reprod Toxicol ; 80: 117-125, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29660390

RESUMO

Details of embryo-fetal development (EFD) studies were compiled for all FDA drug approvals in 2016-17. Rats and rabbits were used for 63% of small molecule (SM) drugs. The cynomolgus monkey was used for 47% of biopharmaceuticals. Rodent studies using the clinical mAb or animal homologue replaced monkey studies under some circumstances. EFD studies were not required for anti-cancer drugs when the mode of action was associated with known developmental risk. One quarter of SM non-oncology drugs and all tested SM anti-cancer drugs were teratogenic in at least one species. The rat and rabbit were essentially equally sensitive to developmental toxicity. Eighty-nine percent of SM non-cancer drugs induced maternal or fetal toxicity in at least one species at below 25-times human exposure (proposed maximum exposure in the draft revised ICH S5(R3) guideline). The pregnancy and lactation labeling rule (PLLR) has brought consistency to the presentation of EFD data in drug labels.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Exposição Materna/efeitos adversos , Preparações Farmacêuticas/classificação , Animais , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos , Rotulagem de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Preparações Farmacêuticas/normas , Gravidez , Especificidade da Espécie , Testes de Toxicidade , Estados Unidos , United States Food and Drug Administration
14.
Drug Dev Res ; 79(3): 97-110, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29697151

RESUMO

Preclinical Research & Development An in vitro-in vivo correlation (IVIVC) is as a predictive mathematical model that demonstrates a key role in the development, advancement, evaluation and optimization of extended release, modified release and immediate release pharmaceutical formulations. A validated IVIVC model can serve as a surrogate for bioequivalence studies and subsequently save time, effort and expenditure during pharmaceutical product development. This review discusses about different levels of correlations, general approaches to develop an IVIVC by mathematical modelling, validation, data analysis and various applications. In the current setting, the dearth of success associated with IVIVC is due to complexity of underlying scientific principles as well as the practice of fitting/matching in vivo plasma level-time data with in vitro dissolution profile. Hence, a simple, straightforward practical means to predict plasma drug levels by convolution technique and percentage drug absorbed computed from in vitro dissolution profile based on deconvolution method are illustrated. The bioavailability/bioequivalence assessment and evaluation are frequently validated by the pharmacokinetic parameters such as maximum concentration, time to reach maximum concentration, and area under the curve. The implementation of a quality by design manufacturing based on in vivo bioavailability and clinically relevant dissolution specification are recommended because corresponding design safe space will guarantee that all batches from relevant products are met with sufficient quality and bioperformance. Recently, United States Food and Drug Administration and European Medicines Agency have proposed that in silico/physiologically based pharmacokinetic modelling can be used in decision making during preclinical experiments as well as to recognize the dissolution profiles that can forecast and ensure the desired clinical performance.


Assuntos
Modelos Teóricos , Farmacocinética , Animais , Biofarmácia , Humanos , Preparações Farmacêuticas/química , Preparações Farmacêuticas/classificação , Preparações Farmacêuticas/metabolismo , Estados Unidos , United States Food and Drug Administration
15.
Farm. hosp ; 42(2): 53-61, mar.-abr. 2018. graf, tab
Artigo em Inglês | IBECS | ID: ibc-171662

RESUMO

Objective: The aim of this study was to stratify medications used in hospital care according to their potential risk. Method: The RAND/UCLA Appropriateness Method was used. Anatomical Therapeutic Chemical subgroups were classified according to their potential risk. A literature search, bulletins, and alerts issued by patient safety organizations were used to identify the potential safety risk of these subgroups. Nine experts in patient/medication safety were selected to score the subgroups for their appropriateness in the classification. Two evaluation rounds were conducted: the first by email and the second by a panel meeting. Results: A total of 298 Anatomical Therapeutic Chemical subgroups were evaluated. They were classified into three scenarios (low, medium, and high risk). In the first round, 266 subgroups were classified as appropriate to the assigned scenario, 32 were classified as uncertain, and none were classified as inappropriate. In the second round, all subgroups were classified as appropriate. The most frequent subgroups in the low-risk scenario belonged to group A “Alimentary tract and metabolism” (44%); the most frequent in the medium-risk scenario belonged to group J “Antiinfectives for systemic use” (32%); and the most frequent in the high-risk scenario belonged to group L “Antineoplastic and immunomodulating agents” (29%) and group N “Nervous system” (26%). Conclusions: Based on the RAND/UCLA appropriateness method, Anatomical Therapeutic Chemical subgroups used in hospital care were classified according to their potential risk (low, medium, or high). These lists can be incorporated into a risk-scoring tool for future patient/medication safety studies (AU)


Objetivo: Estratificar los medicamentos utilizados en el ámbito hospitalario según el riesgo de provocar daño al paciente. Método: Se utilizó la metodología RAND/UCLA para clasificar los subgrupos terapéuticos del código Anatómica, Terapéutica, Química según el riesgo de provocar daño al paciente. Para ello se realizó una revisión de la evidencia disponible en publicaciones, boletines y alertas de organismos de seguridad del paciente. A continuación se seleccionaron nueve expertos en seguridad del paciente/medicamento para evaluar la clasificación de los subgrupos terapéuticos: una primera ronda de evaluación por vía telemática y una segunda ronda en una reunión presencial en la que se presentaron y discutieron los resultados de la primera. Resultados: Se evaluaron 298 subgrupos terapéuticos. Se clasificaron en tres escenarios (riesgo bajo, medio y alto). En la primera ronda se clasificaron 266 subgrupos como adecuados al escenario asignado, 32 subgrupos fueron clasificados como inciertos y ninguno fue clasificado como inapropiado. En la segunda ronda, todos los subgrupos fueron clasificados como adecuados. Los subgrupos más frecuentes en el escenario de riesgo bajo pertenecieron al Grupo A: “Tracto alimentario y metabolismo” (44%), en el de riesgo medio al Grupo J: “Antiinfecciosos para uso sistémico” (32%), y en el de riesgo alto al Grupo L: “Agentes antineoplásicos e inmunomoduladores” (29%) y al Grupo N: “Sistema nervioso” (26%). Conclusiones: La metodología RAND/UCLA ha permitido estratificar los subgrupos utilizados en el ámbito hospitalario según el riesgo potencial de provocar daño al paciente. Esta estratificación puede servir como herramienta para futuros estudios de seguridad en la utilización de medicamentos (AU)


Assuntos
Humanos , Preparações Farmacêuticas/classificação , Medição de Risco/métodos , Segurança do Paciente , Erros de Medicação , Gestão de Riscos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Uso de Medicamentos/classificação , Gestão de Riscos/métodos , Tratamento Farmacológico/classificação , Tratamento Farmacológico
16.
Eur J Pharm Sci ; 117: 98-106, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29425862

RESUMO

The aim of this work is to develop a gastrointestinal (GI) drug absorption model based on a reaction limited model of dissolution and consider its impact on the biopharmaceutic classification of drugs. Estimates for the fraction of dose absorbed as a function of dose, solubility, reaction/dissolution rate constant and the stoichiometry of drug-GI fluids reaction/dissolution were derived by numerical solution of the model equations. The undissolved drug dose and the reaction/dissolution rate constant drive the dissolution rate and determine the extent of absorption when high-constant drug permeability throughout the gastrointestinal tract is assumed. Dose is an important element of drug-GI fluids reaction/dissolution while solubility exclusively acts as an upper limit for drug concentrations in the lumen. The 3D plots of fraction of dose absorbed as a function of dose and reaction/dissolution rate constant for highly soluble and low soluble drugs for different "stoichiometries" (0.7, 1.0, 2.0) of the drug-reaction/dissolution with the GI fluids revealed that high extent of absorption was found assuming high drug- reaction/dissolution rate constant and high drug solubility. The model equations were used to simulate in vivo supersaturation and precipitation phenomena. The model developed provides the theoretical basis for the interpretation of the extent of drug's absorption on the basis of the parameters associated with the drug-GI fluids reaction/dissolution. A new paradigm emerges for the biopharmaceutic classification of drugs, namely, a model independent biopharmaceutic classification scheme of four drug categories based on either the fulfillment or not of the current dissolution criteria and the high or low % drug metabolism.


Assuntos
Absorção Intestinal , Modelos Biológicos , Preparações Farmacêuticas/classificação , Preparações Farmacêuticas/metabolismo , Administração Oral , Biofarmácia , Simulação por Computador , Liberação Controlada de Fármacos , Trato Gastrointestinal/metabolismo , Secreções Intestinais/química , Preparações Farmacêuticas/química , Solubilidade
17.
Eur J Pharm Sci ; 117: 193-203, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29452210

RESUMO

A semi-physiological two compartment pharmacokinetic model with two active metabolites (primary (PM) and secondary metabolites (SM)) with saturable and non-saturable pre-systemic efflux transporter, intestinal and hepatic metabolism has been developed. The aim of this work is to explore in several scenarios which analyte (parent drug or any of the metabolites) is the most sensitive to changes in drug product performance (i.e. differences in in vivo dissolution) and to make recommendations based on the simulations outcome. A total of 128 scenarios (2 Biopharmaceutics Classification System (BCS) drug types, 2 levels of KM Pgp, in 4 metabolic scenarios at 2 dose levels in 4 quality levels of the drug product) were simulated for BCS class II and IV drugs. Monte Carlo simulations of all bioequivalence studies were performed in NONMEM 7.3. Results showed the parent drug (PD) was the most sensitive analyte for bioequivalence trials in all the studied scenarios. PM and SM revealed less or the same sensitivity to detect differences in pharmaceutical quality as the PD. Another relevant result is that mean point estimate of Cmax and AUC methodology from Monte Carlo simulations allows to select more accurately the most sensitive analyte compared to the criterion on the percentage of failed or successful BE studies, even for metabolites which frequently show greater variability than PD.


Assuntos
Estudos de Equivalência como Asunto , Mucosa Intestinal/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Farmacocinética , Projetos de Pesquisa , Administração Oral , Área Sob a Curva , Biotransformação , Simulação por Computador , Humanos , Modelos Lineares , Método de Monte Carlo , Dinâmica não Linear , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/classificação , Solubilidade , Equivalência Terapêutica
18.
Curr Drug Deliv ; 15(7): 918-929, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29336263

RESUMO

A great number of new drug candidates identified from the discovery pipeline are poorly water soluble, which is a drawback to bring such candidates into the pharmaceutical market. Formulating these compounds as self-emulsifying/microemulsifying/ nanoemulsifying drug delivery systems (SEDDS/SMEDDS/SNEDDS) within lipid based formulations is of growing interest. Some of the recent studies have resulted in commercial products that provided improved bioavailability and dissolution due to the better dispersion properties of SEDDS/SMEDDS/SNEDDS. An ongoing challenge that the pharmaceutical industry is facing is identifying in vitro tests that are needed in order to predict the behavior of dosage forms in the GI tract. The goal of the current review is to present the various levels of in vitro-in vivo correlations (IVIVCs) and to provide tools on the utilization of the IVIVCs in product development and optimization of SEDDS/SMEDDS/SNEDDS.


Assuntos
Descoberta de Drogas , Modelos Biológicos , Animais , Biofarmácia , Química Farmacêutica , Excipientes/química , Humanos , Lipídeos/química , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Preparações Farmacêuticas/classificação , Solubilidade , Água/química
19.
Eur J Pharm Sci ; 111: 153-157, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28964950

RESUMO

Bioequivalence (BE) is considered one of the key questions in new and generic drug product development and registration worldwide. However, the regulations and jurisdiction vary from country to country and continent to continent. Harmonization of regulatory requirements and criteria for BE determination may avoid unnecessary repetition of BE studies and minimize drug exposure to humans. Harmonization around the globe may be achieved by a better understanding of scientific principles and expectations from different regulatory authorities. To facilitate global harmonization, the Network on Bioavailability and Biopharmaceutics (BABP) under the European Federation for Pharmaceutical Sciences (EUFEPS) launched a Global Bioequivalence Harmonization Initiative (GBHI) several years ago. This international conference was the first in a series of workshops organized by EUFEPS/BABP under GBHI. The workshop provided a forum for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on selected BE issues in the hope of identifying common ground and arriving at a harmonized view on these topics.


Assuntos
Aprovação de Drogas/legislação & jurisprudência , Preparações Farmacêuticas/química , Farmacocinética , Congressos como Assunto , Medicamentos Genéricos/farmacocinética , Excipientes/química , Regulamentação Governamental , Guias como Assunto , Cooperação Internacional , Preparações Farmacêuticas/classificação , Equivalência Terapêutica , Estados Unidos , United States Food and Drug Administration
20.
Expert Rev Gastroenterol Hepatol ; 12(1): 31-38, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28931315

RESUMO

INTRODUCTION: Drug-induced liver injury (DILI) is challenging for drug development, clinical practice and regulation. The Liver Toxicity Knowledge Base (LTKB) provides essential data for DILI study. Areas covered: The LTKB provided various types of data that can be used to assess and predict DILI. Among much information available, several reference drug lists with annotated human DILI risk are of important. The LTKB DILI classification data include DILI severity concern determined by the FDA drug labeling, DILI severity score from the NIH LiverTox database, and other DILI classification schemes from the literature. Overall, ~1000 drugs were annotated with at least one classification scheme, of which around 750 drugs were flagged for some degree of DILI risk. Expert commentary: The LTKB provides a centralized repository of information for DILI study and predictive model development. The DILI classification data in LTKB could be a useful resource for developing biomarkers, predictive models and assessing data from emerging technologies such as in silico, high-throughput and high-content screening methodologies. In coming years, streamlining the prediction process by including DILI predictive models for both DILI severity and types in LTKB would enhance the identification of compounds with the DILI potential earlier in drug development and risk assessment.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Descoberta de Drogas/métodos , Bases de Conhecimento , Fígado/efeitos dos fármacos , Preparações Farmacêuticas/classificação , Toxicologia/métodos , Animais , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Bases de Dados Factuais , Células Hep G2 , Humanos , Incidência , Fígado/metabolismo , Fígado/patologia , Estrutura Molecular , Preparações Farmacêuticas/química , Medição de Risco , Índice de Gravidade de Doença , Relação Estrutura-Atividade , Toxicogenética
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