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1.
BMC Med Res Methodol ; 21(1): 246, 2021 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-34773983

RESUMO

BACKGROUND: Although discontinuation is common in clinical trials, no study has been conducted to analyse the current situation and reasons for the suspension or discontinuation of drug clinical trials in China. This study aims to analyse the general characteristics and reasons for the discontinuation of registered clinical trials in mainland China and to identify the associated factors. METHODS: We conducted a cross-sectional observational study of discontinued trials registered in the Drug Trial Registration and Information Publication Platform before March 31, 2020. All trials with a status of terminated or stopped recorded in the platform were classified as discontinued trials and included in the analysis. The basic characteristics of the discontinued trials were recorded, reasons for trial discontinuation were recorded and divided into 4 categories as drug development strategy, trial planning, trial conduct and studied drug. Pearson's chi-square test and fisher's exact test were used to compare the differences in reasons for discontinuation between neoplasm trials and non-neoplasm trials, and to examine the associations of trial characteristics with different reasons related to trials discontinuation. RESULTS: Three hundred twelve discontinued trials were included in this study. The studied drugs were mainly chemical drugs [229 (73.4%)], and indications of the studied drugs were mainly neoplasms [77 (24.7%)]. Geographical location of the discontinued trials were mostly in northern [114 (36.5%)] and eastern [96 (30.8%)] China. Study type of the included trials was mainly bioequivalence studies [97 (31.1%)]. The most common reason for trial discontinuation was commercial or strategic decision [84 (26.9%)], followed by futility/lack of efficacy [70 (22.4%)]. The number of trial centers, sample size and whether participants had been enrolled were significantly associated with trial discontinuation (P <  0.05). Multiple center trials showed a higher rate of trial discontinuation due to trial conduct related reasons than single center trials (P <  0.05), trials with sample size > 500 showed a higher rate of trial discontinuation due to studied drug related reasons (P < 0.05), and trials enrolled participants showed a lower rate of trial discontinuation due to commercial or strategic decision and a higher rate of trial discontinuation due to studied drug related reasons than trials without enrolled participants (P < 0.05). Besides, neoplasm trials showed a higher rate of trial discontinuation due to poor recruitment and safety comparing with non-neoplasm trials (P < 0.05). CONCLUSIONS: Trial discontinuation in China mainly occurred because of commercial or strategic decision and futility/lack of efficacy of the studied drug. Clinical trials with multiple centers and a large sample size may more likely be discontinued due to trial conduct related reasons such as good clinical practice. Discontinuation due to drug safety and lack of efficacy in multiple center trials with a large sample size deserves more attention to avoid resources wastes. Full communication with regulatory authorities such as Center for Drug Evaluation and research institutes to develop a feasible protocol is important for sponsors to avoid trial discontinuation due to protocol issues.


Assuntos
Preparações Farmacêuticas , Projetos de Pesquisa , Estudos Transversais , Avaliação de Medicamentos , Humanos , Tamanho da Amostra
2.
JAMA Netw Open ; 4(11): e2132540, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34726743

RESUMO

Importance: Continuous assessment of the effectiveness and safety of the US Food and Drug Administration-authorized SARS-CoV-2 vaccines is critical to amplify transparency, build public trust, and ultimately improve overall health outcomes. Objective: To evaluate the effectiveness of the Johnson & Johnson Ad26.COV2.S vaccine for preventing SARS-CoV-2 infection. Design, Setting, and Participants: This comparative effectiveness research study used large-scale longitudinal curation of electronic health records from the multistate Mayo Clinic Health System (Minnesota, Arizona, Florida, Wisconsin, and Iowa) to identify vaccinated and unvaccinated adults between February 27 and July 22, 2021. The unvaccinated cohort was matched on a propensity score derived from age, sex, zip code, race, ethnicity, and previous number of SARS-CoV-2 polymerase chain reaction tests. The final study cohort consisted of 8889 patients in the vaccinated group and 88 898 unvaccinated matched patients. Exposure: Single dose of the Ad26.COV2.S vaccine. Main Outcomes and Measures: The incidence rate ratio of SARS-CoV-2 infection in the vaccinated vs unvaccinated control cohorts, measured by SARS-CoV-2 polymerase chain reaction testing. Results: The study was composed of 8889 vaccinated patients (4491 men [50.5%]; mean [SD] age, 52.4 [16.9] years) and 88 898 unvaccinated patients (44 748 men [50.3%]; mean [SD] age, 51.7 [16.7] years). The incidence rate ratio of SARS-CoV-2 infection in the vaccinated vs unvaccinated control cohorts was 0.26 (95% CI, 0.20-0.34) (60 of 8889 vaccinated patients vs 2236 of 88 898 unvaccinated individuals), which corresponds to an effectiveness of 73.6% (95% CI, 65.9%-79.9%) and a 3.73-fold reduction in SARS-CoV-2 infections. Conclusions and Relevance: This study's findings are consistent with the clinical trial-reported efficacy of Ad26.COV2.S and the first retrospective analysis, suggesting that the vaccine is effective at reducing SARS-CoV-2 infection, even with the spread of variants such as Alpha or Delta that were not present in the original studies, and reaffirm the urgent need to continue mass vaccination efforts globally.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Adolescente , Adulto , Idoso , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/imunologia , Teste de Ácido Nucleico para COVID-19 , Vacinas contra COVID-19/administração & dosagem , Avaliação de Medicamentos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pandemias , Pontuação de Propensão , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , Fatores de Tempo , Estados Unidos/epidemiologia , Vacinação/estatística & dados numéricos , Adulto Jovem
3.
Comput Intell Neurosci ; 2021: 2794588, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34567098

RESUMO

Incidence rate of mental illness is increasing year by year with the development of city. The amount of modern medical data is huge and complex. In many cases, it is difficult to realize the rational allocation of resources, which puts forward an urgent demand for the artificial intelligence of modern medicine and brings great pressure to the development of the medical industry. The purpose of this study is to develop and construct a grey correlation analysis and related drug evaluation system of mental diseases based on deep convolution neural network. The establishment of the system can effectively improve the automation and intelligence of modern psychiatric treatment process. In this article, the grey correlation analysis of patient data is carried out, and then, the optimized deep convolution neural network is constructed. Combined with the medical knowledge base, the analysis of disease results is realized, and on this basis, the efficacy of related drugs in the treatment of mental diseases is evaluated. The results show that the advantage of the deep convolution neural network system is to effectively improve the induction rate. What's more, compared with other algorithms, this algorithm has higher accuracy and efficiency. It improves the comprehensiveness and informatization of disease screening methods, improves the accuracy of screening, reduces the consumption of doctors' human resources, and provides a theoretical basis for the digitization of the medical industry in the future.


Assuntos
Inteligência Artificial , Redes Neurais de Computação , Algoritmos , Avaliação de Medicamentos , Humanos
4.
J Endocrinol ; 251(1): 111-123, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34370682

RESUMO

Supplementation with precursors of NAD has been shown to prevent and reverse insulin resistance, mitochondrial dysfunction, and liver damage in mouse models of diet-induced obesity. We asked whether the beneficial effects of supplementation with the NAD precursor nicotinamide riboside (NR) are dependent on mouse strain. We compared the effects of NR supplementation on whole-body energy metabolism and mitochondrial function in mildly obese C57BL/6N and C57BL/6J mice, two commonly used strains to investigate metabolism. Male C57BL/6N and C57BL/6J mice were fed a high-fat diet (HFD) or standard chow with or without NR supplementation for 8 weeks. Body and organ weights, glucose tolerance, and metabolic parameters as well as mitochondrial O2 flux in liver and muscle fibers were assessed. We found that NR supplementation had no influence on body or organ weight, glucose metabolism or hepatic lipid accumulation, energy expenditure, or metabolic flexibility but increased mitochondrial respiration in soleus muscle in both mouse strains. Strain-dependent differences were detected for body and fat depot weight, fasting blood glucose, hepatic lipid accumulation, and energy expenditure. We conclude that, in mild obesity, NR supplementation does not alter metabolic phenotype in two commonly used laboratory mouse strains.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Niacinamida/análogos & derivados , Obesidade/tratamento farmacológico , Compostos de Piridínio/uso terapêutico , Animais , Respiração Celular/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Avaliação de Medicamentos , Intolerância à Glucose/prevenção & controle , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Niacinamida/uso terapêutico , Obesidade/metabolismo
5.
PLoS One ; 16(7): e0255336, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34329365

RESUMO

Yearly, about 1.5 million people become chronically infected with hepatitis C virus (HCV) and for the 71 million with chronic HCV infection about 400,000 die from related morbidities, including liver cirrhosis and cancer. Effective treatments exist, but challenges including cost-of-treatment and wide-spread undiagnosed infection, necessitates the development of vaccines. Vaccines should induce neutralizing antibodies (NAbs) against the HCV envelope (E) transmembrane glycoprotein 2, E2, which partly depends on its interaction partner, E1, for folding. Here, we generated three soluble HCV envelope protein antigens with the transmembrane regions deleted (i.e., fused peptide backbones), termed sE1E2 (E1 followed by E2), sE2E1 (E2 followed by E1), and sE21E (E2 followed by inverted E1). The E1 inversion for sE21E positions C-terminal residues of E1 near C-terminal residues of E2, which is in analogy to how they likely interact in native E1/E2 complexes. Probing conformational E2 epitope binding using HCV patient-derived human monoclonal antibodies, we show that sE21E was superior to sE2E1, which was consistently superior to sE1E2. This correlated with improved induction of NAbs by sE21E compared with sE2E1 and especially compared with sE1E2 in female BALB/c mouse immunizations. The deletion of the 27 N-terminal amino acids of E2, termed hypervariable region 1 (HVR1), conferred slight increases in antigenicity for sE2E1 and sE21E, but severely impaired induction of antibodies able to neutralize in vitro viruses retaining HVR1. Finally, comparing sE21E with sE2 in mouse immunizations, we show similar induction of heterologous NAbs. In summary, we find that C-terminal E2 fusion of E1 or 1E is superior to N-terminal fusion, both in terms of antigenicity and the induction of heterologous NAbs. This has relevance when designing HCV E1E2 vaccine antigens.


Assuntos
Antígenos Virais , Hepacivirus , Anticorpos Anti-Hepatite C/imunologia , Proteínas do Envelope Viral , Vacinas contra Hepatite Viral , Animais , Antígenos Virais/genética , Antígenos Virais/imunologia , Antígenos Virais/farmacologia , Avaliação de Medicamentos , Feminino , Células HEK293 , Hepacivirus/genética , Hepacivirus/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Solubilidade , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/farmacologia , Vacinas contra Hepatite Viral/genética , Vacinas contra Hepatite Viral/imunologia , Vacinas contra Hepatite Viral/farmacologia
6.
Ann Hematol ; 100(11): 2755-2761, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34331562

RESUMO

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare plasma cell dyscrasia without standard front-line treatment. Merely, few studies have reported the responses and outcomes of bortezomib plus dexamethasone (BDex) in POEMS syndrome. In this study, a total of 69 patients (40 males) treated with front-line BDex were included. The median age at diagnosis was 50 years (range, 30-78 years). After a median of 9 cycles BDex (range 1-9), fifty-two (88.1%), thirty-two (46.4%), and forty-seven (71.2%) patients achieved the best neurologic response, hematological complete response, and serum vascular endothelial growth factor (VEGF) response, respectively. The extravascular overload, pulmonary hypertension, and renal impairment also substantially improved. No treatment-related death occurred. Two patients developed grade-1 bortezomib-induced peripheral neuropathy and were reversible after drug withdrawal. After a median follow-up of 22.5 months, the estimated 2-year overall survival and time to next treatment were 95.7% and 65.6%, respectively. In conclusion, the combination of bortezomib and dexamethasone is effective, with a high response rate and safety profile for patients with newly diagnosed POEMS syndrome.


Assuntos
Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Síndrome POEMS/tratamento farmacológico , Adulto , Idoso , Biomarcadores , Bortezomib/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Dexametasona/efeitos adversos , Diarreia/induzido quimicamente , Avaliação de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Síndrome POEMS/sangue , Paraproteínas/análise , Parestesia/induzido quimicamente , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular/sangue
7.
Sci Rep ; 11(1): 14623, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272419

RESUMO

To evaluate the long-term outcomes of ranibizumab (RBZ) vs. aflibercept (AFL) in treatment-naïve eyes with typical neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV). This multicenter, retrospective, matched-cohort analysis was conducted on data  up to 4 years of follow-ups. The primary outcome was the visual acuity (VA) change from baseline. The secondary outcomes included the number of injections, proportion of eyes without a yearly injection, and the number of eyes with treatment switching. Subgroup analyses were performed for typical nAMD and PCV. Typical nAMD was defined as nAMD other than PCV. We included VA-matched 215 eyes of 209 patients (131 and 84 eyes with RBZ and AFL, respectively). The crude mean VA changes from baseline were + 6.7 vs. + 2.6, + 2.1 vs. - 0.4, - 1.3 vs. - 1.8, and - 2.2 vs. - 5.0 letters in the RBZ and AFL groups, at 1, 2, 3, and 4 years, respectively (p > 0.05). The adjusted predicted VA by linear mixed model, proportion of eyes stratified by VA, and the survival curve for significant vision loss were comparable during the 4-year follow-up (p > 0.05). The mean number of injections were similar between the RBZ and AFL groups (2.9 vs. 3.0, respectively, p = 0.692). The subgroup analysis for typical nAMD and PCV showed similar results between the groups. The visual outcomes did not differ between RBZ and AFL during 4 years with comparable numbers of injections. Our study reflects the long-term, real-world clinical practice and treatment pattern of two treatments for typical nAMD and PCV.


Assuntos
Doenças da Coroide/tratamento farmacológico , Degeneração Macular/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Pólipos/tratamento farmacológico , Ranibizumab/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Corioide/irrigação sanguínea , Avaliação de Medicamentos , Oftalmopatias/tratamento farmacológico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia , Estudos Retrospectivos , Fatores de Tempo , Tomografia de Coerência Óptica , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual/efeitos dos fármacos
8.
Molecules ; 26(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208408

RESUMO

Essential oils have been widely used as an active ingredient in mosquito repellent products. However, essential oils are highly unstable and prone to degradation when exposed to the environment during storage. Microencapsulation techniques help to maintain the stability of molecules in essential oils that are sensitive to environmental stress, and therefore improve shelf life. In this study, the physical stability and efficacy of a repellent formulation consisting of encapsulated Citrus grandis essential oil (CGEO) were evaluated under different storage conditions over a 12-month period by comparing the formulation with a non-encapsulated formulation. The formulations were both stored under two different storage conditions, i.e., 25 ± 2 °C/60% ± 5% relative humidity (RH) and 40 ± 2 °C/75% RH ± 5%, for 12 months. Droplet size, zeta potential, and pH value were measured after 1, 6, and 12 months of storage to determine their stability. For the study of efficacy, each formulation was tested against Aedes aegypti under laboratory conditions. We found that the microencapsulated formulation's physical characteristics showed insignificant changes as compared with the non-encapsulated formulation during storage. The microencapsulated formulation demonstrated better repellent effects, sustaining high protection (>80%) for 4 more hours of exposure after 12 months of storage as compared with the non-encapsulated formulation that demonstrated high protection for only an hour post application. Microencapsulation helped to preserve the stability of the formulation, which resulted in high protection being maintained for over 12 months of storage.


Assuntos
Aedes/efeitos dos fármacos , Citrus/química , Repelentes de Insetos/química , Óleos Voláteis/química , Aedes/fisiologia , Animais , Composição de Medicamentos , Avaliação de Medicamentos , Estabilidade de Medicamentos
9.
Molecules ; 26(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202191

RESUMO

Twenty-two novel, variously substituted nitroazetidines were designed as both sulfonamide and urethane vinylogs possibly endowed with antimicrobial activity. The compounds under study were obtained following a general procedure recently developed, starting from 4-nitropentadienoates deriving from a common ß-nitrothiophenic precursor. While being devoid of any activity against fungi and Gram-negative bacteria, most of the title compounds performed as potent antibacterial agents on Gram-positive bacteria (E. faecalis and three strains of S. aureus), with the most potent congener being the 1-(4-chlorobenzyl)-3-nitro-4-(p-tolyl)azetidine 22, which displayed potency close to that of norfloxacin, the reference antibiotic (minimum inhibitory concentration values 4 and 1-2 µg/mL, respectively). Since 22 combines a relatively efficient activity against Gram-positive bacteria and a cytotoxicity on eucharyotic cells only at 4-times higher concentrations (inhibiting concentration on 50% of the cultured eukaryotic cells: 36 ± 10 µM, MIC: 8.6 µM), it may be considered as a promising hit compound for the development of a new series of antibacterials selectively active on Gram-positive pathogens. The relatively concise synthetic route described herein, based on widely available starting materials, could feed further structure-activity relationship studies, thus allowing for the fine investigation and optimization of the toxico-pharmacological profile.


Assuntos
Antibacterianos , Azetidinas , Enterococcus faecalis/crescimento & desenvolvimento , Staphylococcus aureus/crescimento & desenvolvimento , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Azetidinas/síntese química , Azetidinas/química , Azetidinas/farmacologia , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Células Hep G2 , Humanos , Relação Estrutura-Atividade
10.
Multimedia | Recursos Multimídia | ID: multimedia-9006

RESUMO

Com o objetivo de ampliar a divulgação de notícias sobre Covid-19 para pessoas com deficiências auditivas, a Coordenação de Comunicação Social (CCS/Fiocruz) lançou um programa semanal que reúne as principais notícias publicadas na Agência Fiocruz de Notícias (AFN) traduzidas para a Língua Brasileira de Sinais (Libras) e com áudio em português.


Assuntos
Insumos Farmacêuticos , Vacinas/provisão & distribuição , Avaliação de Medicamentos , Síndrome Respiratória Aguda Grave , Pesquisa Científica e Desenvolvimento Tecnológico , Mídias Sociais , Notícias , e-Acessibilidade
11.
Sci Rep ; 11(1): 12020, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103637

RESUMO

Bemisia tabaci is one of the most notorious agricultural pests in the world. A vicious circle among insect resistance, dose increased, environment and human body impaired as the overuse of synthetic pesticides are becoming increasingly evident. Entomopathogenic Beauveria sp. is known as an effective natural enemy to control B. tabaci. Therefore, this study aimed to purify and identify the biological compounds from Beauveria sp. LY2 via extensive chromatographic techniques, NMR and MS and evaluated for their insecticidal activities against B. tabaci via contact and feeding assay. The outcome identified that one new cerebroside, cerebroside F (1), nine known compounds, cerebroside B (2), bassiatin (3), methyl 1,4-dihydro-4-oxo-2-quinolinecarboxylate (4), cerevisterol (5), 9-hydroxycerevisterol (6), 6-dehydrocerevisterol (7), (22E,24R)-ergosta-8(14),22-diene-3ß,5α,6ß,7α-tetrol (8), melithasterol B (9) and ergosterol peroxide (10) were isolated. Among the known compounds, methyl 1,4-dihydro-4-oxo- 2-quinolinecarboxylate (4) was isolated from natural origin for the first time. It is demonstrable from the results that compounds 3, 4 and 7 strongly featured insecticidal activities against B. tabaci, being the LC50 value as 10.59, 19.05, 26.59 µg/mL respectively in contact as well as 11.42, 5.66, 5.65 µg/mL respectively in feeding experiment. Moreover, no adverse effect on plant growth/height or phytotoxicity was observed on pepper, cucumber, tomato and cotton. The data from the current study has provided the foundation for the use of newly purified compounds against Bemisia tabaci as an alternative to synthetic chemical compounds.


Assuntos
Beauveria/química , Hemípteros/crescimento & desenvolvimento , Inseticidas , Compostos Fitoquímicos , Animais , Avaliação de Medicamentos , Inseticidas/química , Inseticidas/isolamento & purificação , Inseticidas/farmacologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia
13.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073595

RESUMO

Urolithins (hydroxylated 6H-benzo[c]chromen-6-ones) are the main bioavailable metabolites of ellagic acid (EA), which was shown to be a cognitive enhancer in the treatment of neurodegenerative diseases. As part of this research, a series of alkoxylated 6H-benzo[c]chromen-6-one derivatives were designed and synthesized. Furthermore, their biological activities were evaluated as potential PDE2 inhibitors, and the alkoxylated 6H-benzo[c]chromen-6-one derivative 1f was found to have the optimal inhibitory potential (IC50: 3.67 ± 0.47 µM). It also exhibited comparable activity in comparison to that of BAY 60-7550 in vitro cell level studies.


Assuntos
Benzopiranos , Desenho de Fármacos , Inibidores Enzimáticos , Exonucleases/antagonistas & inibidores , Benzopiranos/síntese química , Benzopiranos/química , Benzopiranos/farmacologia , Linhagem Celular , Avaliação de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Exonucleases/metabolismo , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
14.
JAMA Netw Open ; 4(4): e217063, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33877309

RESUMO

Importance: Adequate representation of demographic subgroups in premarketing and postmarketing clinical studies is necessary for understanding the safety and efficacy associated with novel cancer therapeutics. Objective: To characterize and compare the reporting of demographic data and the representation of individuals by sex, age, and race in premarketing and postmarketing studies used by the Food and Drug Administration (FDA) to evaluate novel cancer therapeutics. Design, Setting, and Participants: In this cross-sectional study, premarketing and postmarketing studies for novel cancer therapeutics approved by the FDA from 2012 through 2016 were identified. Study demographic information was abstracted from publicly available sources, and US cancer population demographic data was abstracted from US Cancer Statistics. Analyses were conducted from February 25 through September 21, 2020. Main Outcomes and Measures: The percentages of trials reporting sex, age, and race/ethnicity were calculated, and participation to prevalence ratios (PPRs) were calculated by dividing the percentage of study participants in each demographic group by the percentage of the US cancer population in each group. PPRs were constructed for premarketing and postmarketing studies and by cancer type. Underrepresentation was defined as PPR less than 0.8. Results: From 2012 through 2016, the FDA approved 45 cancer therapeutics. The study sample included 77 premarketing studies and 56 postmarketing studies. Postmarketing studies, compared with premarketing studies, were less likely to report patient sex (42 studies reporting [75.0%] vs 77 studies reporting [100%]; P < .001) and race (27 studies reporting [48.2%] vs 62 studies reporting [80.5%]; P < .001). Women were adequately represented in premarketing studies (mean [SD] PPR, 0.91; 95% CI, 0.90-0.91) and postmarketing studies (mean PPR, 1.00; 95% CI, 1.00-1.01). Although older adults and Black patients were underrepresented in premarketing studies (older adults: mean PPR, 0.73; 95% CI, 0.72-0.74; Black patients: mean PPR, 0.32; 95% CI, 0.31-0.32), these groups continued to be underrepresented in postmarketing studies (older adults: mean PPR, 0.75; 95% CI, 0.75-0.76; Black patients: mean PPR, 0.21; 95% CI, 0.21-0.21). Conclusions and Relevance: This study found that older adults and Black patients were underrepresented in postmarketing studies of novel cancer therapeutics to a similar degree that they were underrepresented in premarketing studies. These findings suggest that postmarketing studies are not associated with improvements to gaps in demographic representation present at the time of FDA approval.


Assuntos
Afro-Americanos/estatística & dados numéricos , Antineoplásicos/uso terapêutico , Americanos Asiáticos/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Neoplasias/tratamento farmacológico , Sujeitos da Pesquisa/estatística & dados numéricos , Adulto , Distribuição por Idade , Idoso , Estudos Transversais , Avaliação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Vigilância de Produtos Comercializados , Distribuição por Sexo , Estados Unidos/epidemiologia , United States Food and Drug Administration
15.
Virol Sin ; 36(5): 890-900, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33835389

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating pandemic worldwide. Vaccines and antiviral drugs are the most promising candidates for combating this global epidemic, and scientists all over the world have made great efforts to this end. However, manipulation of the SARS-CoV-2 should be performed in the biosafety level 3 laboratory. This makes experiments complicated and time-consuming. Therefore, a safer system for working with this virus is urgently needed. Here, we report the construction of plasmid-based, non-infectious SARS-CoV-2 replicons with turbo-green fluorescent protein and/or firefly luciferase reporters by reverse genetics using transformation-associated recombination cloning in Saccharomyces cerevisiae. Replication of these replicons was achieved simply by direct transfection of cells with the replicon plasmids as evident by the expression of reporter genes. Using SARS-CoV-2 replicons, the inhibitory effects of E64-D and remdesivir on SARS-CoV-2 replication were confirmed, and the half-maximal effective concentration (EC50) value of remdesivir and E64-D was estimated by different quantification methods respectively, indicating that these SARS-CoV-2 replicons are useful tools for antiviral drug evaluation.


Assuntos
COVID-19 , SARS-CoV-2 , Antivirais/farmacologia , Avaliação de Medicamentos , Humanos , Replicon , Replicação Viral
16.
Molecules ; 26(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808667

RESUMO

Novel α-aminoamide derivatives containing different benzoheterocyclics moiety were synthesized and evaluated as voltage-gated sodium ion channels blocks the treatment of pain. Compounds 6a, 6e, and 6f containing the benzofuran group displayed more potent in vivo analgesic activity than ralfinamide in both the formalin test and the writhing assay. Interestingly, they also exhibited potent in vitro anti-Nav1.7 and anti-Nav1.8 activity in the patch-clamp electrophysiology assay. Therefore, compounds 6a, 6e, and 6f, which have inhibitory potency for two pain-related Nav targets, could serve as new leads for the development of analgesic medicines.


Assuntos
Amidas , Analgésicos , Dor/tratamento farmacológico , Bloqueadores dos Canais de Sódio , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Avaliação de Medicamentos , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Dor/induzido quimicamente , Dor/metabolismo , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia
17.
Front Immunol ; 12: 669339, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912196

RESUMO

The world has entered the second wave of the COVID-19 pandemic, and its intensity is significantly higher than that of the first wave of early 2020. Many countries or regions have been forced to start the second round of lockdowns. To respond rapidly to this global pandemic, dozens of COVID-19 vaccine candidates have been developed and many are undergoing clinical testing. Evaluating and defining effective vaccine candidates for human use is crucial for prioritizing vaccination programs against COVID-19. In this review, we have summarized and analyzed the efficacy, immunogenicity and safety data from clinical reports on different COVID-19 vaccines. We discuss the various guidelines laid out for the development of vaccines and the importance of biological standards for comparing the performance of vaccines. Lastly, we highlight the key remaining challenges, possible strategies for addressing them and the expected improvements in the next generation of COVID-19 vaccines.


Assuntos
Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/normas , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , COVID-19/epidemiologia , COVID-19/virologia , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/classificação , Desenvolvimento de Medicamentos/normas , Desenvolvimento de Medicamentos/tendências , Avaliação de Medicamentos/normas , Humanos , Imunização/tendências , Imunogenicidade da Vacina , Padrões de Referência , SARS-CoV-2/genética
20.
J Biochem Mol Toxicol ; 35(6): 1-9, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33704864

RESUMO

In this study, preparation, as well as investigation of α-glycosidase and cholinesterase (ChE) enzyme inhibition activities of furan-2-ylmethoxy-substituted compounds 1-7, are reported. Peripherally, tetra-substituted copper and manganese phthalocyanines (5 and 6) were synthesized for the first time. The substitution of furan-2-ylmethoxy groups provides remarkable solubility to the complex and redshift of the phthalocyanines Q-band. Besides, the inhibitory effects of these compounds on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase (α-Gly) enzymes have been investigated. The AChE was inhibited by these compounds (1-7) in low micromolar levels, and K i values were recorded between 11.17 ± 1.03 and 83.28 ± 11.08 µM. Against the BChE, the compounds demonstrated K i values from 7.55 ± 0.98 to 81.35 ± 12.80 µM. Also, these compounds (1-7) effectively inhibited α-glycosidase, with K i values in the range of 744.87 ± 67.33 to 1094.38 ± 88.91 µM. For α-glycosidase, the most effective K i values of phthalocyanines 3 and 6 were with K i values of 744.87 ± 67.33 and 880.36 ± 56.77 µM, respectively. Moreover, the studied metal complexes were docked with target proteins PDB ID: 4PQE, 1P0I, and 3WY1. Pharmacokinetic parameters and secondary chemical interactions that play an active role in interaction were predicted with docking simulation results. Overall, furan-2-ylmethoxy-substituted phthalocyanines can be considered as potential agents for the treatment of Alzheimer's diseases and diabetes mellitus.


Assuntos
Acetilcolinesterase , Inibidores da Colinesterase , Complexos de Coordenação , Inibidores de Glicosídeo Hidrolases , Indóis , Simulação de Acoplamento Molecular , alfa-Glucosidases/química , Acetilcolinesterase/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Avaliação de Medicamentos , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/química , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Humanos , Indóis/síntese química , Indóis/química
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