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2.
Molecules ; 26(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205704

RESUMO

The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that could be utilized as an effective safe treatment for COVID-19. The anti-inflammatory activity of NSAIDs is also advantageous in the treatment of COVID-19, as it was found that SARS-CoV-2 is responsible for provoking inflammatory cytokine storms resulting in lung damage. In this study, 40 FDA-approved NSAIDs were evaluated through molecular docking against the main protease of SARS-CoV-2. Among the tested compounds, sulfinpyrazone 2, indomethacin 3, and auranofin 4 were proposed as potential antagonists of COVID-19 main protease. Molecular dynamics simulations were also carried out for the most promising members of the screened NSAID candidates (2, 3, and 4) to unravel the dynamic properties of NSAIDs at the target receptor. The conducted quantum mechanical study revealed that the hybrid functional B3PW91 provides a good description of the spatial parameters of auranofin 4. Interestingly, a promising structure-activity relationship (SAR) was concluded from our study that could help in the future design of potential SARS-CoV-2 main protease inhibitors with expected anti-inflammatory effects as well. NSAIDs may be used by medicinal chemists as lead compounds for the development of potent SARS-CoV-2 (Mpro) inhibitors. In addition, some NSAIDs can be selectively designated for treatment of inflammation resulting from COVID-19.


Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Anti-Inflamatórios não Esteroides/metabolismo , Antivirais/química , Antivirais/farmacologia , Auranofina/química , Auranofina/farmacologia , Sítios de Ligação , COVID-19/complicações , Biologia Computacional , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Bases de Dados de Compostos Químicos , Humanos , Indometacina/química , Indometacina/farmacologia , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ligação Proteica , SARS-CoV-2/química , SARS-CoV-2/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfimpirazona/química , Sulfimpirazona/farmacologia , Estados Unidos , United States Food and Drug Administration
3.
Trials ; 22(1): 375, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074329

RESUMO

Clinical trial transparency forms the foundation of evidence-based medicine, and trial sponsors, especially publicly funded institutions such as universities, have an ethical and scientific responsibility to make the results of clinical trials publicly available in a timely fashion. We assessed whether the thirty UK universities receiving the most Medical Research Council funding in 2017-2018 complied with World Health Organization best practices for clinical trial reporting on the US Clinical Trial Registry ( ClinicalTrials.gov ). Firstly, we developed and evaluated a novel automated tracking tool ( clinical-trials-tracker.com ) for clinical trials registered on ClinicalTrials.gov . This tracker identifies the number of due trials (whose completion lies more than 395 days in the past) that have not reported results on the registry and can now be used for all sponsors. Secondly, we used the tracker to determine the number of due clinical trials sponsored by the selected UK universities in October 2020. Thirdly, using the FDAAA Trials Tracker, we identified trials sponsored by these universities that are not complying with reporting requirements under the Food and Drug Administration Amendments Act 2007. Finally, we quantified the average and median number of days between primary completion date and results posting. In October 2020, the universities included in our study were sponsoring 1634 due trials, only 1.6% (n = 26) of which had reported results within a year of completion. 89.8% (n = 1468) of trials remained unreported, and 8.6% (n = 140) of trials reported results late. We also identified 687 trials that contained inconsistent data, suggesting that UK universities often fail to update their data adequately on ClinicalTrials.gov . The mean reporting delay after primary completion for trials that posted results was 981 days, the median 728 days. Only four trials by UK universities violated the FDAAA 2007. We suggest a number of reasons for the poor reporting performance of UK universities on ClinicalTrials.gov : (i) efforts to improve clinical trial reporting in the UK have to date focused on the European clinical trial registry (EU CTR), (ii) the absence of a tracking tool for timely reporting on ClinicalTrials.gov has limited the visibility of institutions' reporting performance on the US registry and (iii) there is currently a lack of repercussions for UK sponsors who fail to report results on ClinicalTrials.gov which should be addressed in the future.


Assuntos
Relatório de Pesquisa , Universidades , Humanos , Sistema de Registros , Reino Unido , Estados Unidos , United States Food and Drug Administration
6.
Health Aff (Millwood) ; 40(6): 989-999, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34097520

RESUMO

Biologic drugs account for a disproportionate share of the increase in pharmaceutical spending in the US and worldwide. Against this backdrop, many look to the expanding market for biosimilars-follow-on products to biologic drugs-as a vehicle for controlling pharmaceutical spending. This study explores the early years of entry of biosimilars and related follow-on products in the US. Using monthly sales data from the period 2005-19 for ten drug classes, we examine how quickly biosimilars/follow-on products gained market share and the subsequent trajectory of prevailing (national average invoice) prices. Our analysis suggests that although uptake has been slower than what is typically seen in generic drug markets, the most recent entrants have captured market share more rapidly than comparable earlier biosimilars/follow-on products. We also document that from biosimilar/follow-on products' time of entry, their lower prices help offset the overall trend in average annual reference-product price increases. Our findings can provide insight into future policy reforms aimed at increasing competition and use of biosimilars, leading to expanded patient access and significant cost savings.


Assuntos
Medicamentos Biossimilares , Comércio , Redução de Custos , Medicamentos Genéricos , Humanos , Estados Unidos , United States Food and Drug Administration
8.
Drugs Today (Barc) ; 57(6): 387-399, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34151905

RESUMO

In May of 2019, the adeno-associated virus (AAV)-based gene therapy onasemnogene abeparvovec-xioi (Zolgensma) became the second Food and Drug Administration (FDA)-approved gene therapy with designated use for infants diagnosed with spinal muscular atrophy (SMA). The decision came nearly 10 years after results of the first preclinical models were initially reported. While the journey was an arduous one, the approval was an indication of the remarkable success of the first in-human clinical trials. According to the traditional classification system of autosomal recessive SMA, of which there are multiple types with phenotypic variability, SMA type 1 is the most common and most severe and represents 45% of the SMA patient population. Children with SMA type 1 cannot lift their heads without assistance and do not live past their second birthday. With Zolgensma, the first treated children with SMA type 1 have reached 5 years of age and some of them achieved the ability to sit unassisted or even walk. In this article, we review the work that led to FDA approval with emphasis on the development of preclinical and clinical studies.


Assuntos
Atrofia Muscular Espinal , Atrofias Musculares Espinais da Infância , Produtos Biológicos , Criança , Terapia Genética , Humanos , Lactente , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Proteínas Recombinantes de Fusão , Atrofias Musculares Espinais da Infância/terapia , Estados Unidos , United States Food and Drug Administration
13.
Paediatr Drugs ; 23(4): 381-394, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34173206

RESUMO

Regulatory changes have been enacted in the United States (US) and European Union (EU) to encourage the development of new treatments for pediatric cancer. Here, we review some of the factors that have hampered the development of pediatric cancer treatments and provide a comparison of the US and EU regulations implemented to address this clinical need. We then provide some recommendations for each stage of the oncology drug development pathway to help researchers maximize their chance of successful drug development while complying with regulations. A key recommendation is the engagement of key stakeholders such as regulatory authorities, pediatric oncologists, academic researchers, patient advocacy groups, and a Pediatric Expert Group early in the drug development process. During drug target selection, sponsors are encouraged to consult the Food and Drug Administration (FDA), European Medicines Agency (EMA), and the FDA target list, in addition to relevant US and European consortia that have been established to characterize and prioritize oncology drug targets. Sponsors also need to carefully consider the resourcing requirements for preclinical testing, which include ensuring appropriate access to the most relevant databases, clinical samples, and preclinical models (cell lines and animal models). During clinical development, sponsors can account for the pharmacodynamic (PD)/pharmacokinetic (PK) considerations specific to a pediatric population by developing pediatric formulations, selecting suitable PD endpoints, and employing sparse PK sampling or modeling/simulation of drug exposures where appropriate. Additional clinical considerations include the specific design of the clinical trial, the potential inclusion of children in adult trials, and the value of cooperative group trials.


Assuntos
Antineoplásicos/uso terapêutico , Desenvolvimento de Medicamentos/legislação & jurisprudência , Prova Pericial/legislação & jurisprudência , Oncologia/legislação & jurisprudência , Neoplasias/tratamento farmacológico , Antineoplásicos/síntese química , Criança , Ensaios Clínicos como Assunto/legislação & jurisprudência , Ensaios Clínicos como Assunto/métodos , Sistemas de Liberação de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , União Europeia , Prova Pericial/métodos , Humanos , Oncologia/métodos , Neoplasias/epidemiologia , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudência
15.
J Law Health ; 34(2): 215-251, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34185974

RESUMO

Systemic discrimination in healthcare plagues marginalized groups. Physicians incorrectly view people of color as having high pain tolerance, leading to undertreatment. Women with disabilities are often undiagnosed because their symptoms are dismissed. Low-income patients have less access to appropriate treatment. These patterns, and others, reflect long-standing disparities that have become engrained in U.S. health systems. As the healthcare industry adopts artificial intelligence and algorithminformed (AI) tools, it is vital that regulators address healthcare discrimination. AI tools are increasingly used to make both clinical and administrative decisions by hospitals, physicians, and insurers--yet there is no framework that specifically places nondiscrimination obligations on AI users. The Food and Drug Administration has limited authority to regulate AI and has not sought to incorporate anti-discrimination principles in its guidance. Section 1557 of the Affordable Care Act has not been used to enforce nondiscrimination in healthcare AI and is under-utilized by the Office of Civil Rights. State level protections by medical licensing boards or malpractice liability are similarly untested and have not yet extended nondiscrimination obligations to AI. This Article discusses the role of each legal obligation on healthcare AI and the ways in which each system can improve to address discrimination. It highlights the ways in which industries can self-regulate to set nondiscrimination standards and concludes by recommending standards and creating a super-regulator to address disparate impact by AI. As the world moves towards automation, it is imperative that ongoing concerns about systemic discrimination are removed to prevent further marginalization in healthcare.


Assuntos
Inteligência Artificial/normas , Sistemas de Apoio a Decisões Clínicas/normas , Atenção à Saúde/normas , Setor de Assistência à Saúde/normas , Disparidades em Assistência à Saúde , Discriminação Social , Inteligência Artificial/legislação & jurisprudência , Sistemas de Apoio a Decisões Clínicas/legislação & jurisprudência , Atenção à Saúde/legislação & jurisprudência , Setor de Assistência à Saúde/legislação & jurisprudência , Humanos , Patient Protection and Affordable Care Act , Políticas Públicas de não Discriminação , Estados Unidos , United States Food and Drug Administration
16.
Zhongguo Yi Liao Qi Xie Za Zhi ; 45(3): 315-320, 2021 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-34096244

RESUMO

OBJECTIVE: Discuss the working ideas of the dynamic adjustment mechanism of medical device classification in the United States, and provide reference for the construction of medical device related mechanisms in China. METHODS: Collect and interpret the documents of regulatory background, procedures and orders of the dynamic adjustment mechanism of the medical device classification in the United States, and summarize the overall situation and specific cases of the medical device classification adjustment under this mechanism in recent years. RESULTS: The US work idea of the medical device classification dynamic adjustment mechanism is based on the latest valid scientific evidence, conducting risk analysis and identification, and determining the corresponding measures. CONCLUSIONS: During the adjustment process, industry stakeholders have repeatedly discussed and achieved final agreement. Its procedures and working ideas can be used as a reference for China's work.


Assuntos
United States Food and Drug Administration , China , Estados Unidos
17.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071627

RESUMO

Acute myeloid leukemia (AML) is a heterogenous hematopoietic neoplasm with various genetic abnormalities in myeloid stem cells leading to differentiation arrest and accumulation of leukemic cells in bone marrow (BM). The multiple genetic alterations identified in leukemic cells at diagnosis are the mainstay of World Health Organization classification for AML and have important prognostic implications. Recently, understanding of heterogeneous and complicated molecular abnormalities of the disease could lead to the development of novel targeted therapeutic agents. In the past years, gemtuzumab ozogamicin, BCL-2 inhibitors (venetovlax), IDH 1/2 inhibitors (ivosidenib and enasidenib) FLT3 inhibitors (midostaurin, gilteritinib, and enasidenib), and hedgehog signaling pathway inhibitors (gladegib) have received US Food and Drug Administration (FDA) approval for the treatment of AML. Especially, AML patients with elderly age and/or significant comorbidities are not currently suitable for intensive chemotherapy. Thus, novel therapeutic planning including the abovementioned target therapies could lead to improve clinical outcomes in the patients. In the review, we will present various important and frequent molecular abnormalities of AML and introduce the targeted agents of AML that received FDA approval based on the previous studies.


Assuntos
Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Leucemia Mieloide/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Transdução de Sinais/efeitos dos fármacos , Doença Aguda , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/uso terapêutico , Estados Unidos , United States Food and Drug Administration
18.
Chin Med J (Engl) ; 134(12): 1471-1476, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074841

RESUMO

BACKGROUND: Taxanes are an essential class of antineoplastic agents used to treat various cancers and are a fundamental cause of hypersensitivity reactions. In addition, other adverse events, such as bone marrow toxicity and peripheral neuropathy, can lead to chemotherapy discontinuation. This study aimed to evaluate the safety of taxanes in the real world. METHODS: Taxane-associated adverse events were identified by the Medical Dictionary for Regulatory Activities Preferred Terms and analyzed and compared by mining the US Food and Drug Administration Adverse Event Reporting System pharmacovigilance database from January 2004 to December 2019. Reported adverse events, such as hypersensitivity reaction, bone marrow toxicity, and peripheral neuropathy, were analyzed with the following signal detection algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), multi-item gamma Poisson shrinker (MGPS), Bayesian confidence propagation neural network (BCPNN), and logistic regression methods. Adverse outcome events and death outcome rates were compared between different taxane groups using Pearson's χ2 test, whereas significance was determined at P < 0.05 with a 95% confidence interval (CI). RESULTS: A total of 966 reports of hypersensitivity reactions, 1109 reports of bone marrow toxicity, and 1374 reports of peripheral neuropathy were analyzed. Compared with paclitaxel and docetaxel, bone marrow toxicity following the use of nab-paclitaxel had the highest ROR of 6.45 (95% two-sided CI, 6.05-6.88), PRR of 5.66, (χ2 = 4342.98), information component of 2.50 (95% one-sided CI = 2.34), and empirical Bayes geometric mean of 5.64 (95% one-sided CI = 5.34). Peripheral neuropathy following the use of nab-paclitaxel showed a higher ROR of 12.78 (95% two-sided CI, 11.55-14.14), PRR of 12.16 (χ2 = 4060.88), information component of 3.59 (95% one-sided CI = 3.25), and empirical Bayes geometric mean of 12.07 (95% one-sided CI = 11.09). CONCLUSIONS: The results showed that bone marrow toxicity and peripheral neuropathy were the major adverse events induced by taxanes. Nab-paclitaxel exhibited the highest potential for taxane-associated adverse events. Further research in the future is warranted to explain taxane-associated adverse effects in real-world circumstances.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Taxoides , Teorema de Bayes , Hidrocarbonetos Aromáticos com Pontes , Taxoides/efeitos adversos , Estados Unidos , United States Food and Drug Administration
19.
Molecules ; 26(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063139

RESUMO

The concurrent use of oral encorafenib (Braftovi, ENF) and binimetinib (Mektovi, BNB) is a combination anticancer therapy approved by the United States Food and Drug Administration (USFDA) for patients with BRAFV600E/V600K mutations suffering from metastatic or unresectable melanoma. Metabolism is considered one of the main pathways of drug elimination from the body (responsible for elimination of about 75% of known drugs), it is important to understand and study drug metabolic stability. Metabolically unstable compounds are not good as they required repetitive dosages during therapy, while very stable drugs may result in increasing the risk of adverse drug reactions. Metabolic stability of compounds could be examined using in vitro or in silico experiments. First, in silico metabolic vulnerability for ENF and BNB was investigated using the StarDrop WhichP450 module to confirm the lability of the drugs under study to liver metabolism. Second, we established an LC-MS/MS method for the simultaneous quantification of ENF and BNB applied to metabolic stability assessment. Third, in silico toxicity assessment of ENF and BNB was performed using the StarDrop DEREK module. Chromatographic separation of ENF, BNB, and avitinib (an internal standard) was achieved using an isocratic mobile phase on a Hypersil BDS C18 column. The linear range for ENF and BNB in the human liver microsome (HLM) matrix was 5-500 ng/mL (R2 ≥ 0.999). The metabolic stabilities were calculated using intrinsic clearance and in vitro half-life. Furthermore, ENF and BNB did not significantly influence each other's metabolic stability or metabolic disposition when used concurrently. These results indicate that ENF and BNB will slowly bioaccumulate after multiple doses.


Assuntos
Antineoplásicos/análise , Benzimidazóis/análise , Benzimidazóis/metabolismo , Carbamatos/análise , Carbamatos/metabolismo , Aprovação de Drogas , Sulfonamidas/análise , Sulfonamidas/metabolismo , Espectrometria de Massas em Tandem , Benzimidazóis/química , Calibragem , Carbamatos/química , Cromatografia Líquida , Simulação por Computador , Estabilidade de Medicamentos , Humanos , Microssomos Hepáticos/metabolismo , Controle de Qualidade , Reprodutibilidade dos Testes , Sulfonamidas/química , Estados Unidos , United States Food and Drug Administration
20.
Orphanet J Rare Dis ; 16(1): 265, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107994

RESUMO

BACKGROUND: Orphan drug designations are a useful proxy to investigate trends in rare disease drug development. Drug developers must receive a designation before they are eligible for the economic incentives of the Orphan Drug Act in the United States. We created a database of all orphan drugs designated between 1983 and 2019 that included numerous drug characteristics, including therapeutic area. In addition, we constructed a "broad disease" categorization of designations as an alternative to therapeutic area, based on disease etiology and age of onset rather than organ system. By looking at the pattern of orphan drug designations over the past four decades, this analysis studied the impact of the evolving rare disease drug development landscape and considers the future of rare disease therapies over the coming decades. RESULTS: Between 1983 and 2019, a total of 5099 drugs and biologics received orphan drug designation. Designations more than doubled between the 1980s and 1990s, almost doubled between the 1990s and 2000s, and almost tripled in number between the 2000s and 2010s. The top three therapeutic areas represented in the orphan drug designations were: oncology (1910, 37%), neurology (674, 13%), and infectious diseases (436, 9%). The broad disease categorization found that the proportion of designations for pediatric-onset diseases has increased in the most recent decade to 27%. CONCLUSIONS: Analysis of the last four decades of orphan drug designation indicates seismic shifts have occurred in the rare disease drug development space. The number of designations granted more than quadrupled between the 1990s and 2010s. While these substantial increases led to growth in the absolute number of designations within all therapeutic areas (bar one) and broad disease categories, the relative proportions have seen considerable change over time. In the most recent decade, there have been notable increases in the proportion of drugs in oncology, pediatric-onset diseases, and neurologic disorders. The dramatic rise in overall orphan designations over the past four decades suggests we may continue to see an upward trajectory in designations leading to an increased number of approvals for drugs and biologics designed specifically for diagnosing, preventing, and treating rare diseases in the coming decades.


Assuntos
Produção de Droga sem Interesse Comercial , Preparações Farmacêuticas , Criança , Aprovação de Drogas , Humanos , Doenças Raras , Estados Unidos , United States Food and Drug Administration
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