Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
2.
Trends Biotechnol ; 39(5): 425-427, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33568314

RESUMO

The role of the 'file drawer' problem in nanomedicine, which partly drives the current limited clinical success of therapeutic nanoparticles, has been poorly investigated. We propose an integrated functioning of all stakeholders as the only effective way to address the file drawer problem in an efficient and timely manner.


Assuntos
Nanomedicina , Publicações Periódicas como Assunto , Nanomedicina/normas , Nanomedicina/tendências , Pesquisa/normas
3.
J Chromatogr A ; 1635: 461767, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33310281

RESUMO

Asymmetric-flow field-flow fractionation (AF4) has been recognized as an invaluable tool for the characterisation of particle size, polydispersity, drug loading and stability of nanopharmaceuticals. However, the application of robust and high quality standard operating procedures (SOPs) is critical for accurate measurements, especially as these complex drug nanoformulations are most often inherently polydisperse. In this review we describe a unique international collaboration that lead to the development of a robust SOP for the measurement of physical-chemical properties of nanopharmaceuticals by multi-detector AF4 (MD-AF4) involving two state of the art infrastructures in the field of nanomedicine, the European Union Nanomedicine Characterization Laboratory (EUNCL) and the National Cancer Institute-Nanotechnology Characterisation Laboratory (NCI-NCL). We present examples of how MD-AF4 has been used for the analysis of key quality attributes, such as particle size, shape, drug loading and stability of complex nanomedicine formulations. The results highlight that MD-AF4 is a very versatile analytical technique to obtain critical information on a material particle size distribution, polydispersity and qualitative information on drug loading. The ability to conduct analysis in complex physiological matrices is an additional very important advantage of MD-AF4 over many other analytical techniques used in the field for stability studies. Overall, the joint NCI-NCL/EUNCL experience demonstrates the ability to implement a powerful and highly complex analytical technique such as MD-AF4 to the demanding quality standards set by the regulatory authorities for the pre-clinical safety characterization of nanomedicines.


Assuntos
Fracionamento por Campo e Fluxo , Nanomedicina/métodos , Tamanho da Partícula , Composição de Medicamentos/normas , União Europeia , Humanos , Laboratórios/normas , Nanomedicina/normas , Nanotecnologia , National Cancer Institute (U.S.) , Preparações Farmacêuticas/normas , Estados Unidos
5.
Small ; 16(36): e2000673, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32406992

RESUMO

The rate of translational effort of nanomedicine requires strategic planning of nanosafety research in order to enable clinical trials and safe use of nanomedicine in patients. Herein, the experiences that have emerged based on the safety data of classic liposomal formulations in the space of oncology are discussed, along with a description of the new challenges that need to be addressed according to the rapid expansion of nanomedicine platform beyond liposomes. It is valuable to consider the combined use of predictive toxicological assessment supported by deliberate investigation on aspects such as absorption, distribution, metabolism, and excretion (ADME) and toxicokinetic profiles, the risk that may be introduced during nanomanufacture, unique nanomaterials properties, and nonobvious nanosafety endpoints, for example. These efforts will allow the generation of investigational new drug-enabling safety data that can be incorporated into a rational infrastructure for regulatory decision-making. Since the safety assessment relates to nanomaterials, the investigation should cover the important physicochemical properties of the material that may lead to hazards when the nanomedicine product is utilized in humans.


Assuntos
Nanomedicina , Neoplasias , Toxicologia , Antineoplásicos/toxicidade , Controle de Medicamentos e Entorpecentes , Humanos , Nanomedicina/normas , Nanoestruturas/toxicidade , Neoplasias/terapia , Toxicologia/métodos , Toxicologia/normas , Toxicologia/tendências
6.
Artigo em Inglês | MEDLINE | ID: mdl-32266791

RESUMO

Various nanomedicinal products (NMPs) have been reported to induce an adverse immune response, which may be related to their tendency to accumulate in or target cells of the immune system. Therefore, before their market authorization, NMPs should be thoroughly evaluated for their immunotoxic potential. Nonclinical regulatory immunotoxicity testing of nonbiological medicinal products, including NMPs, is currently performed by following the guideline S8 "Immunotoxicity Studies for Human Pharmaceuticals" of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). However, this guideline does not cover all the immunotoxicity endpoints reported for NMPs in the literature, such as complement activation related pseudo allergy, hypersensitivity and immunosuppression. In addition, ICH-S8 does not provide any nanospecific testing considerations, which is important given their tendency to interfere with many commonly used toxicity assays. We therefore propose a nonclinical regulatory immunotoxicity assessment strategy, which considers the immunotoxicity endpoints currently missing in the ICH-S8. We also list the known pitfalls related to the testing of NMPs and how to tackle them. Next to defining the relevant physicochemical and pharmacokinetic properties of the NMP and its intended use, the proposed strategy includes an in vitro assay battery addressing various relevant immunotoxicity endpoints. A weight of evidence evaluation of this information can be used to shape the type and design of further in vivo investigations. The final outcome of the immunotoxicity assessment can be included in the overall risk assessment of the NMP and provide alerts for relevant endpoints to address during clinical investigation. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.


Assuntos
Sistema Imunitário , Nanomedicina , Nanoestruturas , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Nanomedicina/legislação & jurisprudência , Nanomedicina/normas , Nanoestruturas/efeitos adversos , Nanoestruturas/normas , Nanoestruturas/toxicidade , Medição de Risco , Testes de Toxicidade , Toxicologia
7.
Int J Pharm ; 582: 119266, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32251694

RESUMO

Nanomedicines are well recognised for their ability to improve therapeutic outcomes. Yet, due to their complexity, nanomedicines are challenging and costly to produce using traditional manufacturing methods. For nanomedicines to be widely exploited, new manufacturing technologies must be adopted to reduce development costs and provide a consistent product. Within this study, we investigate microfluidic manufacture of nanomedicines. Using protein-loaded liposomes as a case study, we manufacture liposomes with tightly defined physico-chemical attributes (size, PDI, protein loading and release) from small-scale (1 mL) through to GMP volume production (200 mL/min). To achieve this, we investigate two different laminar flow microfluidic cartridge designs (based on a staggered herringbone design and a novel toroidal mixer design); for the first time we demonstrate the use of a new microfluidic cartridge design which delivers seamless scale-up production from bench-scale (12 mL/min) through GMP production requirements of over 20 L/h using the same standardised normal operating parameters. We also outline the application of tangential flow filtration for down-stream processing and high product yield. This work confirms that defined liposome products can be manufactured rapidly and reproducibly using a scale-independent production process, thereby de-risking the journey from bench to approved product.


Assuntos
Doxorrubicina/química , Lipídeos/química , Microfluídica , Nanomedicina , Nanopartículas , Ovalbumina/química , Doxorrubicina/administração & dosagem , Doxorrubicina/normas , Composição de Medicamentos , Liberação Controlada de Fármacos , Lipídeos/normas , Lipossomos , Microfluídica/instrumentação , Microfluídica/normas , Nanomedicina/instrumentação , Nanomedicina/normas , Ovalbumina/administração & dosagem , Ovalbumina/normas , Tamanho da Partícula , Controle de Qualidade , Solubilidade
8.
Annu Rev Anal Chem (Palo Alto Calif) ; 13(1): 431-452, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32084321

RESUMO

Development and application of nanotechnology-enabled medical products, including drugs, devices, and in vitro diagnostics, are rapidly expanding in the global marketplace. In this review, the focus is on providing the reader with an introduction to the landscape of commercially available nanotechnology-enabled medical products as well as an overview of the international documentary standards and reference materials that support and facilitate efficient regulatory evaluation and reliable manufacturing of this diverse group of medical products. We describe the materials, test methods, and standards development needs for emerging medical products. Scientific and measurement challenges involved in the development and application of innovative nanoenabled medical products motivate discussion throughout this review.


Assuntos
Produtos Biológicos/análise , Nanomedicina/normas , Nanotecnologia/normas
9.
AMA J Ethics ; 21(4): E347-355, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31012422

RESUMO

The US Food and Drug Administration (FDA) oversees safety and efficacy of a broad spectrum of medical products (ie, drugs, biologics, and devices) under the auspices of federal legislation and agency regulations and policy. Complex and emerging nanoscale products challenge this regulatory framework and illuminate its shortcomings for combination products that integrate multiple mechanisms of therapeutic action. This article surveys current FDA regulatory structures and nanotechnology-specific guidance, discusses relevant nanomedicine products, and identifies regulatory challenges.


Assuntos
Guias como Assunto , Nanomedicina/normas , Nanopartículas/normas , Nanopartículas/uso terapêutico , United States Food and Drug Administration/normas , Humanos , Estados Unidos
10.
AMA J Ethics ; 21(4): E356-362, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31012423

RESUMO

Many employers now offer workers wearable or implantable devices that can monitor their health, productivity, and wellness. Nanotechnology enables even more powerful and functional monitoring capacity for these devices. A history of workplace monitoring programs suggests that, despite nanosensors' potential benefits to employers and employees, they can only be successful and sustainable when a company's motivations for offering them are acceptable and transparent to workers. This article describes 5 best practices for motivating nano-enabled worker monitoring programs that are acceptable, effective, and ethical.


Assuntos
Monitorização Fisiológica/ética , Monitorização Fisiológica/normas , Nanomedicina/ética , Nanomedicina/normas , Saúde do Trabalhador/ética , Saúde do Trabalhador/normas , Local de Trabalho/normas , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
AMA J Ethics ; 21(4): E363-369, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31012424

RESUMO

A central ethical and policy issue regarding minimizing and managing risks of engineered nanomaterials (ENMs) is whether existing legal frameworks sufficiently protect public health and the environment. This article argues that policymakers should (1) use existing laws to regulate ENMs and the best available evidence to inform appropriate levels of regulation and (2) support additional research on risks of ENMs. Were they to do so, public health and environmental risks of ENMs could be minimized and managed without sacrificing their potential clinical, social, and economic benefits.


Assuntos
Saúde Ambiental/ética , Saúde Ambiental/normas , Monitorização Fisiológica/ética , Monitorização Fisiológica/normas , Nanomedicina/ética , Nanomedicina/normas , Saúde Pública/ética , Saúde Pública/normas , Humanos
12.
Artigo em Inglês | MEDLINE | ID: mdl-30556649

RESUMO

As nanomedicines have the potential to address many currently unmet medical needs, the early identification of regulatory requirements that could hamper a smooth translation of nanomedicines from the laboratory environment to clinical applications is of utmost importance. The blood system is especially relevant as many nanomedicinal products that are currently under development are designed for intravenous administration and cells of the blood system will be among the first biological systems exposed to the injected nanomedicine. This review collects and summarizes the current knowledge related to the blood compatibility of nanomedicines and nanomaterials with a potential use in biomedical applications. Different types of nanomedicines were analyzed for their toxicity to the blood system, and the role of their physicochemical properties was further elucidated. Trends were identified related to: (a) the nature of the most frequently occurring blood incompatibilities such as thrombogenicity and complement activation, (b) the contribution of physicochemical properties to these blood incompatibilities, and (c) the similarities between data retrieved from in vivo and in vitro studies. Finally, we provide an overview of available standards that allow evaluating the compatibility of a material with the blood system. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Therapeutic Approaches and Drug Discovery > Emerging Technologies Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.


Assuntos
Células Sanguíneas , Sistemas de Liberação de Medicamentos/efeitos adversos , Nanomedicina/normas , Nanoestruturas , Animais , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/fisiologia , Hemólise/efeitos dos fármacos , Humanos , Nanoestruturas/efeitos adversos , Nanoestruturas/toxicidade , Trombose/induzido quimicamente , Testes de Toxicidade
13.
Artigo em Inglês | MEDLINE | ID: mdl-29923692

RESUMO

Appropriate documentary standards and reference materials are crucial building blocks for the development of innovative products. In order to support the emerging sector of nanomedicine, relevant standards must be identified and/or developed before the products will enter into the regulatory approval process. The anticipation of standardization needs requires a good understanding on the regulatory information requirements that can be triggered by the particularities of nanomedicines. However, robust datasets allowing firm conclusions on regulatory demands are not yet available due to a lack of regulatory experience with innovative products. Such a catch-22 situation can only be advanced in an iterative process by monitoring continuously the scientific evidence and by promoting intensive knowledge exchange between all involved stakeholders. In this study, we have compiled information requirements released by regulatory scientists so far and mapped it against available standards that could be of relevance for nanomedicines. Our gap analysis clearly demonstrated that for some endpoints such as drug release/loading and the interaction of nanomedicines with the immune system no standards are available so far. The emerging nanomedicine sector could benefit from cross-sector collaboration and review the suitability of standards that have been developed for nanomaterials used for other industrial applications. Only a concerted action of all parties can lead to a smooth translation of nanomedicines to clinical application and to the market. This is in particular important because nanotechnology-based drug delivery systems are key for the development and implementation of personalized medicine. This article is characterized under: Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.


Assuntos
Nanomedicina/legislação & jurisprudência , Nanomedicina/normas , Controle Social Formal , Animais , Aprovação de Drogas , Liberação Controlada de Fármacos , Humanos , Padrões de Referência
14.
Cardiovasc Res ; 114(13): 1714-1727, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30165574

RESUMO

Cardiovascular diseases (CVD) account for nearly half of all deaths in Europe and almost 30% of global deaths. Despite the improved clinical management, cardiovascular mortality is predicted to rise in the next decades due to the increasing impact of aging, obesity, and diabetes. The goal of emerging cardiovascular nanomedicine is to reduce the burden of CVD using nanoscale medical products and devices. However, the development of novel multicomponent nano-sized products poses multiple technical, ethical, and regulatory challenges, which often obstruct their road to successful approval and use in clinical practice. This review discusses the rational design of nanoparticles, including safety considerations and regulatory issues, and highlights the steps needed to achieve efficient clinical translation of promising nanomedicinal products for cardiovascular applications.


Assuntos
Cardiologia/normas , Doenças Cardiovasculares/terapia , Nanomedicina/normas , Guias de Prática Clínica como Assunto/normas , Pesquisa Médica Translacional/normas , Animais , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Modelos Animais de Doenças , Humanos , Segurança do Paciente , Medição de Risco , Testes de Toxicidade/normas
15.
AAPS J ; 20(5): 92, 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-30128758

RESUMO

The US Food and Drug Administration (FDA) recently released a draft guidance for industry titled "Drug Products, Including Biological Products, that Contain Nanomaterials." The FDA's attention to the unique safety and efficacy aspects of drugs containing nanomaterials is commendable. This Draft Guidance succeeds in acknowledging the complexity of these products, as well as the challenges associated with approving safe and therapeutically equivalent complex generic versions. However, the challenge posed by the manufacturing process for drugs containing nanomaterials is insufficiently addressed. The critical quality attributes of such products cannot be properly defined, and therefore it is not possible to design informative comparative physicochemical assessments for equivalence. As a consequence, the 505(j) Abbreviated New Drug Application (ANDA) pathway, currently advised as the standard from the FDA, is not suitable for the approval of complex generic products. Drawing from the successful story of biologics, we propose instead a stepwise totality-of-evidence approach, demonstrating similarity and including clinical studies when deemed necessary, as an appropriate alternative to the 505(j) ANDA pathway.


Assuntos
Produtos Biológicos/uso terapêutico , Aprovação de Drogas , Indústria Farmacêutica/normas , Guias como Assunto/normas , Nanomedicina/normas , Nanopartículas/uso terapêutico , Segurança do Paciente/normas , United States Food and Drug Administration/normas , Produtos Biológicos/efeitos adversos , Aprovação de Drogas/legislação & jurisprudência , Indústria Farmacêutica/legislação & jurisprudência , Humanos , Nanomedicina/legislação & jurisprudência , Nanopartículas/efeitos adversos , Segurança do Paciente/legislação & jurisprudência , Formulação de Políticas , Medição de Risco , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudência
16.
Crit Rev Oncol Hematol ; 125: 89-101, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29650282

RESUMO

A major challenge in the management of breast cancer disease has been the development of metastases. Finding new molecular targets and the design of targeted therapeutic approaches to improve the overall survival and quality of life of these patients is, therefore, of great importance. Nucleolin, which is overexpressed in cancer cells and tumor-associated blood vessels, have been implicated in various processes supporting tumorigenesis and angiogenesis. Additionally, its overexpression has been demonstrated in a variety of human neoplasias as an unfavorable prognostic factor, associated with a high risk of relapse and low overall survival. Hence, nucleolin has emerged as a relevant target for therapeutic intervention in cancer malignancy, including breast cancer. This review focus on the contribution of nucleolin for cancer disease and on the development of therapeutic strategies targeting this protein. In this respect, it also provides a critical analysis about the potential and pitfalls of nanomedicine for cancer therapy.


Assuntos
Neoplasias da Mama/terapia , DNA Helicases/fisiologia , Necessidades e Demandas de Serviços de Saúde , Terapia de Alvo Molecular , Fosfoproteínas/fisiologia , Proteínas de Ligação a RNA/fisiologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Carcinogênese/genética , Feminino , Humanos , Oncologia/métodos , Oncologia/normas , Oncologia/tendências , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/normas , Terapia de Alvo Molecular/tendências , Nanomedicina/normas , Nanomedicina/tendências , Medicina de Precisão/métodos , Medicina de Precisão/normas , Medicina de Precisão/tendências , Qualidade de Vida
17.
J Appl Toxicol ; 38(1): 3-24, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28589558

RESUMO

With the rapid development of nanotechnology, potential applications of nanomaterials in medicine have been widely researched in recent years. Nanomaterials themselves can be used as image agents or therapeutic drugs, and for drug and gene delivery, biological devices, nanoelectronic biosensors or molecular nanotechnology. As the composition, morphology, chemical properties, implant sites as well as potential applications become more and more complex, human biosafety of nanomaterials for clinical use has become a major concern. If nanoparticles accumulate in the human body or interact with the body molecules or chemical components, health risks may also occur. Accordingly, the unique chemical and physical properties, potential applications in medical fields, as well as human biosafety in clinical trials are reviewed in this study. Finally, this article tries to give some suggestions for future work in nanomedicine research. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Contenção de Riscos Biológicos/normas , Nanomedicina/normas , Nanoestruturas , Técnicas Biossensoriais , Humanos , Nanoestruturas/efeitos adversos , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Tamanho da Partícula , Propriedades de Superfície
18.
Ann N Y Acad Sci ; 1407(1): 39-49, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28445611

RESUMO

Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified.


Assuntos
Produtos Biológicos/uso terapêutico , Aprovação de Drogas , Medicamentos Genéricos/uso terapêutico , United States Food and Drug Administration/normas , Europa (Continente) , Humanos , Nanomedicina/métodos , Nanomedicina/normas , Equivalência Terapêutica , Estados Unidos , Organização Mundial da Saúde
19.
Nanotoxicology ; 11(2): 147-149, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28055261

RESUMO

Nanotechnology has transformed materials engineering. However, despite much excitement in the scientific community, translation of nanotechnology-based developments has suffered from significant translational gaps, particularly in the field of biomedicine. Of the many concepts investigated, very few have entered routine clinical application. Safety concerns and associated socioeconomic uncertainties, together with the lack of incentives for technology transfer, are undoubtedly imposing significant hurdles to effective clinical translation of potentially game-changing developments. Commercialisation aspects are only rarely considered in the early stages and in many cases, the market is not identified early on in the process, hence precluding market-oriented development. However, methodologies and in-depth understanding of mechanistic processes existing in the environmental, health and safety (EHS) community could be leveraged to accelerate translation. Here, we discuss the most important stepping stones for (nano)medicine development along with a number of suggestions to facilitate future translation.


Assuntos
Medicina Clínica , Nanomedicina , Nanotecnologia/métodos , Pesquisa Biomédica , Medicina Clínica/economia , Medicina Clínica/métodos , Medicina Clínica/normas , Saúde Ambiental , Humanos , Nanomedicina/economia , Nanomedicina/métodos , Nanomedicina/normas , Segurança
20.
Adv Drug Deliv Rev ; 106(Pt B): 381-401, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27544694

RESUMO

The fascinating properties of nanomaterials opened new frontiers in medicine. Nanocarriers are useful systems in transporting drugs to site-specific targets. The unique physico-chemical characteristics making nanocarriers promising devices to treat diseases may also be responsible for potential adverse effects. In order to develop functional nano-based drug delivery systems, efficacy and safety should be carefully evaluated. To date, no common testing strategy to address nanomaterial toxicological challenges has been generated. Different cell culture models are currently used to evaluate nanocarrier safety using conventional in vitro assays, but overall they have generated a huge amount of conflicting data. In this review we describe state-of-the-art approaches for in vitro testing of orally administered nanocarriers, highlighting the importance of developing harmonized and validated standard operating procedures. These procedures should be applied in a safe-by-design context with the aim to reduce and/or eliminate the uncertainties and risks associated with nanomedicine development.


Assuntos
Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/toxicidade , Técnicas In Vitro/métodos , Nanomedicina/métodos , Nanomedicina/normas , Nanoestruturas/administração & dosagem , Nanoestruturas/toxicidade , Animais , Técnicas de Cultura de Células/métodos , Portadores de Fármacos/efeitos adversos , Humanos , Nanoestruturas/efeitos adversos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...