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1.
Medicine (Baltimore) ; 100(3): e24413, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33546087

RESUMO

BACKGROUND: As a classic prescription for treating knee osteoarthritis, Du-Huo-Ji-Sheng-decoction has been widely recognized for its clinical efficacy. The purpose of this systematic review and meta-analysis is to evaluate the effectiveness and safety of Du-Huo-Ji-Sheng-decoction in the treatment of knee osteoarthritis. METHODS: The following databases will be searched from January 2011 to December 2020: PubMed, Embase, Web of Science, Cochrane Library, Chinese Biomedical Medical Database, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database, and Wanfang Database. Statistical analysis will be processed by RevMan V.5.3 software. RESULTS: This study will provide an assessment of the current state of DHJSD in the treatment of KOA, aiming to show the efficacy and safety of DHJSD. CONCLUSION: This study will provide evidence to judge whether DHJSD is an effective intervention for KOA.


Assuntos
Protocolos Clínicos , Medicamentos de Ervas Chinesas/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/normas , Humanos , Metanálise como Assunto , Revisões Sistemáticas como Assunto
2.
Pharmacoeconomics ; 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33598860

RESUMO

OBJECTIVES: Our objective was to generate a value set for the SF-6Dv2 using time trade-off (TTO) and a discrete-choice experiment with a duration dimension (DCETTO) in China. METHODS: A large representative sample of the Chinese general population was recruited from eight provinces/municipalities in China, stratified by age, sex, education level, and proportion of urban/rural residence. Respondents completed eight TTO tasks and ten DCETTO tasks during face-to-face interviews. Ordinary least squares (OLS), random-effects, fixed-effects, and Tobit models were used for TTO data, and conditional logit and mixed logit models were used for DCETTO. The monotonicity of model coefficients and the consistency of the predicted values according to intraclass correlation coefficient (ICC), mean absolute difference (MAD), and mean squared difference (MSD) were compared between the two approaches. RESULTS: In total, 3320 respondents (50.3% male; range 18-90 years) were recruited. The random-effects model and the conditional logit model were preferred for the TTO and DCETTO, respectively. The TTO values ranged from - 0.277 to 1, with 927 (4.94%) states considered as worse than dead (WTD). The corresponding range for DCETTO was - 0.535 to 1, with a higher WTD of 8.50%. DCETTO presented minor non-monotonicity with the coefficients in two dimensions. Values from the two approaches were highly consistent (ICC 0.9804, MAD 0.0588, MSD 0.0055), albeit those with DCETTO were slightly lower than those with TTO. The value set generated by TTO was preferred given the better monotonicity and the statistical significance of coefficients. CONCLUSIONS: The Chinese value set for the SF-6Dv2 was established based on the TTO approach, but the DCETTO also performed well. Minor issues of non-monotonicity did present for DCETTO.

3.
Eur J Med Chem ; 211: 113063, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33340914

RESUMO

Inspired by our previous efforts to improve the drug-resistance profiles of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP) were designed, synthesized, and evaluated for their anti-HIV potency in TZM-bl and MT-4 cells. Eight compounds exhibited moderate to excellent potencies in inhibiting wild-type (WT) HIV-1 replication with EC50 values ranging from 2.45 nM to 5.36 nM, and 14c (EC50 = 2.45 nM) proved to be the most promising inhibitor. Of note, 14c exhibited potent activity against the single mutant strain E138K (EC50 = 10.6 nM), being comparable with ETR (EC50 = 9.80 nM) and 3.5-fold more potent than that of compound 7 (EC50 = 37.3 nM). Moreover, 14c acted as a classical NNRTI with high affinity for WT HIV-1 RT (IC50 = 0.0589 µM). The detailed structure-activity relationships (SARs) of the representative compounds were also determined, and further supported by molecular dynamics simulation. Overall, we envision that the "dual-site"-binding NNRTIs have significant prospects and pave the way for the next round of rational design of potent anti-HIV-1 agents.

4.
J Med Internet Res ; 22(11): e21099, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33027037

RESUMO

BACKGROUND: Great efforts have been made to prevent the spread of COVID-19, including national initiatives to promote the change of personal behaviors. The lessons learned from the 2003 SARS outbreak indicate that knowledge and attitudes about infectious diseases are related to panic among the population, which may further complicate efforts to prevent the spread of infectious diseases. Misunderstandings may result in behaviors such as underestimation, panic, and taking ineffective measures to avoid infection; these behaviors are likely to cause the epidemic to spread further. OBJECTIVE: The purpose of this study is to assess public health perceptions and misunderstandings about COVID-19 in China, and to propose targeted response measures based on the findings to control the development of the epidemic. METHODS: The study was conducted in April 2020 through an online survey, with participants in 8 provinces in Eastern, Central, and Western China. We designed a questionnaire with a health knowledge section consisting of 5 questions (4 conventional questions and 1 misleading question) on clinical features of and preventive measures against COVID-19. Descriptive statistics, chi-square analysis, binary logistic regression, and Mantel-Haenszel hierarchical analysis were used for statistical analysis. RESULTS: In total, 4788 participants completed the survey and the mean knowledge score was 4.63 (SD 0.67), gained mainly through experts (76.1%), television (60.0%), newspapers (57.9%), and opinions (46.6%) and videos (42.9%) from social media. Compared to those who obtained information from only 1 or 2 channels, people who obtained information from >3 channels had increased health perception and a better ability to identify misleading information. Suggestions from experts were the most positive information source (χ2=41.61), while information on social media was the most misleading. Those aged >60 years (OR 1.52, 95% CI 1.10-2.11), those with a lower or middle income (OR 1.36, 95% CI 1.00-1.83), those not working and not able to work (OR 1.83, 95% CI 1.04-3.21), those with a household income <100,000 RMB (2 suspected symptoms (OR 2.95, 95% CI 1.50-5.80) were more likely to be misled by videos on social media, but the error correction effect of expert advice was limited in these groups. CONCLUSIONS: Multiple information channels can improve public health perception and the identification of misleading information during the COVID-19 pandemic. Videos on social media increased the risk of rumor propagation among vulnerable groups. We suggest the government should strengthen social media regulation and increase experts' influence on the targeted vulnerable populations to reduce the risk of rumors spreading.


Assuntos
Comunicação , Infecções por Coronavirus/psicologia , Educação em Saúde/estatística & dados numéricos , Conhecimentos, Atitudes e Prática em Saúde , Internet , Pneumonia Viral/psicologia , Inquéritos e Questionários , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Criança , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Surtos de Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Saúde Pública , Mídias Sociais , Adulto Jovem
5.
Health Expect ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33022806

RESUMO

BACKGROUND: As the coronavirus disease 2019 (COVID-19) pandemic is sweeping across the globe, there is an urgent need to develop effective vaccines as the most powerful strategy to end the pandemic. This study aimed to examine how factors related to vaccine characteristics, their social normative influence and convenience of vaccination can affect the public's preference for the uptake of the COVID-19 vaccine in China. METHODS: An online discrete choice experiment (DCE) survey was administered to a sample of China's general population. Participants were asked to make a series of hypothetical choices and estimate their preference for different attributes of the vaccine. A mixed logit regression model was used to analyse the DCE data. Willingness to pay for each attribute was also calculated. RESULTS: Data of 1236 participants who provided valid responses were included in the analysis. There was strong public preference for high effectiveness of the vaccine, followed by long protective duration, very few adverse events and being manufactured overseas. Price was the least important attribute affecting the public preference in selecting the COVID-19 vaccine. CONCLUSIONS: The strong public preferences detected in this study should be considered when developing COVID-19 vaccination programme in China. The results provide useful information for policymakers to identify the individual and social values for a good vaccination strategy. PATIENT OR PUBLIC CONTRIBUTION: The design of the experimental choices was fully based on interviews and focus group discussions participated by 26 Chinese people with diverse socio-economic backgrounds. Without their participation, the study would not be possible.

6.
Eur J Med Chem ; 206: 112811, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32977301

RESUMO

To address the intractable issues of drug resistance and poor solubility, a novel series of morpholine-substituted diarylpyrimidines targeting the tolerant region I and tolerant region II of NNIBP were rationally designed by utilizing the available crystallography studies. The biological evaluation results showed that four most promising compounds (14e1, 14g1, 14g2 and 14j2) displayed excellent potency against WT HIV-1 strain with EC50 values ranging from 58 to 87 nM, being far more potent than NVP and comparable to ETV. Besides, some derivatives exhibited moderate activity in inhibiting the mutant HIV-1 strains. More encouragingly, 14d2 (RF = 0.4) possessed higher antiresistance profile than ETV (RF = 6.3) and K-5a2 (RF = 3.0) toward the double mutant strain F227L + V106A. The HIV-1 RT inhibition assay confirmed their binding target. The molecular docking studies were conducted and discussed in detail to rationalize the preliminary SARs. Further test indicated that morpholine could indeed promote the improvement of water solubility. Additionally, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability were investigated to evaluate their drug-like features.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32977538

RESUMO

COVID-19 presents unprecedented challenges to the global public health response. Preventive behaviors and keeping social distance are regarded as compelling ways to prevent COVID-19. This study focused on the sociological and psychological factors associated with proper and excessive preventive behaviors of the COVID-19 outbreak in China. For the sample, we collected the data of 4788 participants who were surveyed between 4 April and 15 April 2020 from eight provinces in China. This study designed a self-filled questionnaire that included demographic information, six components of the Health Belief Model, and target preventive behaviors. Descriptive analysis, Chi-square test, logistic regression analysis, Mantel-Haenszel hierarchical analysis, and propensity score matching were employed in this study. The results showed that 54.7% of the participants had adequate basic prevention, 63.6% of the participants had adequate advanced prevention, and 5.8% of the participants practiced excessive prevention. The elder participants were less likely to engage in proper preventive behaviors. Perceived susceptibility, perceived benefits, perceived barriers, cues to action, and knowledge levels were associated with preventive behaviors. Excessive preventive behaviors in high-risk groups with suspected symptoms were associated with their extreme psychological condition, while the support from the community and family plays an important role in avoiding these behaviors.


Assuntos
Infecções por Coronavirus/prevenção & controle , Comportamentos Relacionados com a Saúde , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Quarentena/psicologia , Idoso , Betacoronavirus , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/psicologia , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/psicologia , Inquéritos e Questionários
8.
Sensors (Basel) ; 20(17)2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32847071

RESUMO

High-dimensional signals, such as image signals and audio signals, usually have a sparse or low-dimensional manifold structure, which can be projected into a low-dimensional subspace to improve the efficiency and effectiveness of data processing. In this paper, we propose a linear dimensionality reduction method-minimum eigenvector collaborative representation discriminant projection-to address high-dimensional feature extraction problems. On the one hand, unlike the existing collaborative representation method, we use the eigenvector corresponding to the smallest non-zero eigenvalue of the sample covariance matrix to reduce the error of collaborative representation. On the other hand, we maintain the collaborative representation relationship of samples in the projection subspace to enhance the discriminability of the extracted features. Also, the between-class scatter of the reconstructed samples is used to improve the robustness of the projection space. The experimental results on the COIL-20 image object database, ORL, and FERET face databases, as well as Isolet database demonstrate the effectiveness of the proposed method, especially in low dimensions and small training sample size.

9.
Artigo em Inglês | MEDLINE | ID: mdl-32605243

RESUMO

BACKGROUND: Due to the household registration system, Chinese elderly migrants have insufficient access to health services and social support. Thus, this study examined the use of health services, the access to social support, and the interaction among the elderly migrating within China. METHODS: Data were obtained from the China Migrant Dynamic Monitoring Survey in 2015, adopting probability proportionate to size as the sampling strategy. Structural equation modeling and mediating effect tests were employed to explore the associations. RESULTS: Approximately 45.9% of elderly migrants did not seek health services when needed. The use of outpatient and inpatient services was more common than free essential public health services. The use of health services was negatively associated with migrating duration and migrating for offspring, while it was positively associated with outer social support. The mediating effects of outer social support were discovered on the relationships between the use of health services and independent variables such as migrating duration and migrating for offspring, respectively. CONCLUSION: Elderly migrants with a longer migrating duration or migrated for offspring seem to obtain less outer social support, resulting in a decreased use of health services. Outer social support was suggested as a key effort to improve the equalization of health services in Chinese elderly migrants.


Assuntos
Serviços de Saúde , Apoio Social , Migrantes , Idoso , China , Estudos Transversais , Feminino , Humanos , Masculino
10.
ACS Infect Dis ; 6(8): 2225-2234, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32619096

RESUMO

Previous efforts in our lab have led to the development of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI) thiophene[3,2-d]pyrimidine compound 1 (K-5a2) with promising activity against wild-type and mutant HIV-1 strains. In this work, a series of novel diarylpyrimidines derivatives carrying a structurally diverse motif at the right wing of the lead K-5a2 was designed and synthesized as potential anti-HIV-1 agents. The results demonstrated that 8a yielded exceptionally potent activity against HIV-1 wild-type (50% effective concentration (EC50) = 3.30 nM) and mutant strain RES056 (EC50 = 22.6 nM) in MT-4 cells; in the reverse transcriptase inhibitory assay, 8a (half maximal inhibitory concentration (IC50) = 0.028 µM) was remarkably superior to that of K-5a2 (IC50 = 0.300 µM) and comparable to that of etravirine (ETR; IC50 = 0.011 µM). Notably, 8a exhibited better druggability than that of K-5a2, including significantly reduced CYP enzymatic inhibitory activity (IC50 > 50 µM), lower human ether-à-go-go related gene (hERG) inhibition (IC50 > 30 µM), and improved metabolic stability (short half-life, T1/2 = 77.5 min) in vitro.

11.
Sensors (Basel) ; 20(11)2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32517316

RESUMO

The nonrigid point set registration is one of the bottlenecks and has the wide applications in computer vision, pattern recognition, image fusion, video processing, and so on. In a nonrigid point set registration problem, finding the point-to-point correspondences is challengeable because of the various image degradations. In this paper, a robust method is proposed to accurately determine the correspondences by fusing the two complementary structural features, including the spatial location of a point and the local structure around it. The former is used to define the absolute distance (AD), and the latter is exploited to define the relative distance (RD). The AD-correspondences and the RD-correspondences can be established based on AD and RD, respectively. The neighboring corresponding consistency is employed to assign the confidence for each RD-correspondence. The proposed heuristic method combines the AD-correspondences and the RD-correspondences to determine the corresponding relationship between two point sets, which can significantly improve the corresponding accuracy. Subsequently, the thin plate spline (TPS) is employed as the transformation function. At each step, the closed-form solutions of the affine and nonaffine parts of TPS can be independently and robustly solved. It facilitates to analyze and control the registration process. Experimental results demonstrate that our method can achieve better performance than several existing state-of-the-art methods.

12.
BMC Health Serv Res ; 20(1): 557, 2020 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-32552752

RESUMO

BACKGROUND: This study aimed to reveal the effects of the connectedness of primary health care (PHC) workers in social networks on their job burnout. METHODS: Cross-sectional survey data of rural PHC workers in China were analyzed. A total of 663 respondents were enrolled. Chi-square and cumulative logistic regression were used to determine the effects of the connectedness of PHC workers in social networks on their job burnout. RESULTS: PHC workers in rural China had high levels of emotional exhaustion (24.1%), depersonalization (15.7%), and lack of personal accomplishment (34.7%). More than half of the participants were in the middle connectedness level in terms of their advisory (70.4%) and friendship (70.3%) networks. The degree of emotional exhaustion seemed to increase when participants had a low connectedness in their friendship networks (ß = 0.769, 95% CI = 0.080-1.458, P = 0.029). Respondents with the middle level of connectedness in advisory networks had higher levels of depersonalization (ß = 0.739, 95% CI = 0.130-1.348, P = 0.017) and lack of personal accomplishment (ß = 0.583, 95% CI = 0.111-1.055, P = 0.015) than those with the high degree of connectedness in advisory networks. CONCLUSIONS: The connectedness of PHC workers in social networks influenced their job burnout. Thus, organizations should establish an informal communication platform and information feedback mechanism, promote and manage friendship networks, and help PHC workers overcome emotional exhaustion. Managers should also encourage individuals with a high level of connectedness in advisory networks play the role of "opinion leader" so that they can help others mitigate burnout.

13.
Acta Pharm Sin B ; 10(5): 878-894, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32528834

RESUMO

In this report, a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead K-5a2. The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound 26 exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC50 ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure-activity relationship and molecular docking were also investigated. Furthermore, 26 exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound 26 holds great promise as a potential drug candidate for the treatment of HIV-1 infection.

14.
Chem Commun (Camb) ; 56(59): 8222-8225, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32555793

RESUMO

A transition-metal-free double addition/double rearrangement domino reaction affording CF3-substituted pyrimidines was developed, which enables the one-pot construction of five new bonds, namely three C-C bonds and two C-N bonds. The keys to achieve this highly efficient reaction include the delicate design of the bis-nucleophiles in situ generated from the dimerization of alkyl nitriles and the use of trifluoroacetimidoyl nitriles containing C[double bond, length as m-dash]N, C[triple bond, length as m-dash]N, and CF3 groups as the reactant. The mechanistic studies by the experiments and DFT calculations reveal that the transformation involves two addition and two unprecedented rearrangement processes.

15.
Thromb Res ; 190: 122-128, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32361051

RESUMO

BACKGROUND: Heart failure (HF) is associated with an increased incidence of thromboembolic events. Antithrombotic treatment could reduce the stroke risk, whereas increase the bleeding risk. Whether antithrombotic treatment should be a routine therapy for HF and sinus rhythm (SR) patients remains unanswered. METHODS: We systematically searched Medline, Embase, Cochrane Library databases, and ClinicalTrials.gov Website for randomized controlled trials (RCTs) studying antithrombotic therapy in HF and SR patients. The primary outcomes of efficacy and safety were defined as stroke and major bleeding, respectively. The network meta-analysis was conducted. The results were expressed as relative risks (RRs) with 95% confidence intervals (95% CIs), and pooled using a random-effects model. The surface under the cumulative ranking curves (SUCRA) was calculated and trade-off analysis of net clinical benefit (NCB) was estimated. RESULTS: Five studies totally involving 9390 patients were included. A significantly decreased risk of stroke was found for patients with HF and SR, when rivaroxaban was compared with placebo (RR: 0.67, 95%CI: 0.47-0.96) and warfarin was compared with antiplatelets (RR: 0.49, 95%CI: 0.33-0.73). Warfarin (RR: 7.96, 95%CI: 1.06-59.88) and rivaroxaban (RR: 1.65, 95%CI: 1.16-2.33) were associated with a significant increase in the risk of major bleeding when compared with placebo. Considering the ranking of each antithrombotic therapy for primary outcomes, warfarin (SUCRA: 78.2) emerged with the highest cumulative ranking probability for stroke, with rivaroxaban (SUCRA: 73.9) and antiplatelet agents (SUCRA: 19.6) ranked behind. In terms of major bleeding, rivaroxaban (SUCRA: 57.6) was the safer intervention compared with antiplatelet agents (SUCRA: 43.5) or warfarin (SUCRA: 2.9). No difference was observed considering all-cause death, MI and hospitalization of HF among all different antithrombotic regimens. Rivaroxaban was considered as a reasonably effective and the safe antithrombotic agent for HF and SR patients. CONCLUSIONS: Rivaroxaban might the optimal antithrombotic regimen balancing stroke and major bleeding for HF patients with SR. The results might support the attempt to anticoagulation on HF and SR patients. However, further specialized designs of RCTs are necessary to draw a robust conclusion.

16.
Malar J ; 19(1): 131, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32228594

RESUMO

BACKGROUND: China launched the National Malaria Elimination Programme (NMEP) in 2010 and set the goal that all health facilities should be able to diagnose malaria. Additionally, hospitals at all levels could treat malaria by 2015. To provide a reference for the control of imported malaria, a study was conducted on the distribution of malaria patients seeking care in different types of health facilities. METHODS: There were two data sources. One was obtained through the Infectious Diseases Information Reporting Management System (IDIRMS), which only contained the name of health facilities and the number of cases. The other was obtained through multistage stratified cluster sampling. Descriptive statistical analysis was used to investigate the distribution of malaria patients attending different types of health facilities (hospitals, township hospitals, and Centers for Disease Control and Prevention), hospital tiers (county-level, prefecture-level, and provincial-level), and hospital levels (primary, secondary, and tertiary). Chi-square test was also used to compare the proportions of patients seeking care outside their current residence region between different types of hospitals. Point maps were drawn to visualize the spatial distribution of hospitals reporting malaria cases, and flow maps were created to show the spatial flow of malaria patients by using the ArcGIS software. RESULTS: The proportions of malaria patients who sought care in hospitals, township hospitals, and Centers for Disease Control and Prevention were 81.7%, 14.7%, and 3.6%, respectively. For those who sought care in hospitals, the percentages of patients who sought care in provincial-level, prefecture-level and county-level hospitals were 17.4%, 60.5% and 22.1%, correspondingly; the proportions of patients who sought care in tertiary hospitals, secondary hospitals, and primary hospitals were 59.8%, 39.9%, and 0.3%, respectively. Moreover, the proportions of patients seeking care in hospitals within county and prefectural administrative areas were 18.2%, 63.4%, respectively. CONCLUSION: During the implementation of NMEP, malaria patients tended to seek care in tertiary hospitals and prefecture-level hospitals, and more than half of patients could be treated in hospitals in prefecture-level areas. In the current phase, it is necessary to establish referral system from county-level hospitals to higher-level hospitals for malaria treatment.


Assuntos
Assistência à Saúde/normas , Instalações de Saúde/estatística & dados numéricos , Malária/prevenção & controle , Programas Nacionais de Saúde , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , China , Erradicação de Doenças/organização & administração , Humanos
17.
J Med Chem ; 63(9): 4837-4848, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32293182

RESUMO

The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Tiofenos/farmacologia , Animais , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacocinética , Linhagem Celular Tumoral , Ensaios Enzimáticos , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Mutação , Ligação Proteica , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacocinética , Tiofenos/metabolismo , Tiofenos/farmacocinética
18.
J Glob Health ; 10(1): 010807, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32257170

RESUMO

Background: The concept of healthy aging has become a global health strategy in response to the population aging. In China, old-aged migrants are facing serious health care challenges due to the obstacles in the utilization of health services, social integration and ignored public policies. We aimed to examine the old-aged migrants' utilization of the essential public health services and its underlying factors on account of change of residence, and social support. Methods: Data came from the senior sample (aged over 65 years, n = 11 161) of the 2015 National Migrant Dynamic Monitoring Survey in China that employed Probability Proportionate to Size method as a sampling strategy. χ2 tests and binary multilevel model were conducted to analyze the difference and the underlying factors of the utilization of essential health services among old-aged migrants. Results: Approximately 66.2% of old-aged migrants did not receive free physician examination services from health institutions in the past year, and 34.6% of old-aged migrants with chronic disease have been followed up by doctors. There were significant differences in the utilization of essential public health services among old-aged migrants across different individuals and families. It showed that exercise time, migrating range, migrating reason, physical health condition, chronic disease, local friends, health insurance, household expenditure, and income were significantly associated with the elderly migrants' utilization of essential public health services. Conclusions: The utilization of essential public health services among old-aged migrants was insufficient in comparison with the general population. The government should launch targeted policies such as production and work-related injuries for the floating population. The supply side should promote the equalization of essential public health services for migrants. Social organizations and community should undertake the responsibility in social support for old-aged migrants.


Assuntos
Serviços de Saúde Comunitária/estatística & dados numéricos , Assistência à Saúde/organização & administração , Acesso aos Serviços de Saúde , Seguro Saúde/estatística & dados numéricos , Migrantes , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , China/epidemiologia , Emprego , Feminino , Humanos , Renda , Masculino , Pessoa de Meia-Idade , Características de Residência , População Rural , Apoio Social , População Urbana
19.
Eur J Med Chem ; 193: 112237, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32200201

RESUMO

HIV-1 RT has been considered as one of the most important targets for the development of anti-HIV-1 drugs for their well-solved three-dimensional structure and well-known mechanism of action. In this study, with HIV-1 RT as target, we used miniaturized parallel click chemistry synthesis via CuAAC reaction followed by in situ biological screening to discover novel potent HIV-1 NNRTIs. A 156 triazole-containing inhibitor library was assembled in microtiter plates and in millimolar scale. The enzyme inhibition screening results showed that 22 compounds exhibited improved inhibitory activity. Anti-HIV-1 activity results demonstrated that A3N19 effected the most potent activity against HIV-1 IIIB (EC50 = 3.28 nM) and mutant strain RES056 (EC50 = 481 nM). The molecular simulation analysis suggested that the hydrogen bonding interactions of A3N19 with the main chain of Lys101 and Lys104 was responsible for its potency. Overall, the results indicated the in situ click chemistry-based strategy was rational and might be amenable for the future discovery of more potent HIV-1 NNRTIs.


Assuntos
Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Triazóis/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Sítios de Ligação/efeitos dos fármacos , Química Click , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
20.
J Med Chem ; 63(3): 1298-1312, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31935327

RESUMO

Our previous efforts have led to the development of two potent NNRTIs, K-5a2 and 25a, exhibiting effective anti-HIV-1 potency and resistance profiles compared with etravirine. However, both inhibitors suffered from potent hERG inhibition and short half-life. In this article, with K-5a2 and etravirine as leads, series of novel fluorine-substituted diarylpyrimidine derivatives were designed via molecular hybridization and bioisosterism strategies. The results indicated 24b was the most active inhibitor, exhibiting broad-spectrum activity (EC50 = 3.60-21.5 nM) against resistant strains, significantly lower cytotoxicity (CC50= 155 µM), and reduced hERG inhibition (IC50 > 30 µM). Crystallographic studies confirmed the binding of 24b and the role of the fluorine atom, as well as optimal contacts of a nitrile group with the main-chain carbonyl group of H235. Furthermore, 24b showed longer half-life and favorable safety properties. All the results demonstrated that 24b has significant promise in circumventing drug resistance as an anti-HIV-1 candidate.


Assuntos
Fármacos Anti-HIV/farmacologia , Canal de Potássio ERG1/metabolismo , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Tiofenos/farmacologia , Animais , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/toxicidade , Linhagem Celular , Cristalografia por Raios X , Descoberta de Drogas , Feminino , Flúor/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ligação Proteica , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/toxicidade , Ratos Wistar , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/toxicidade , Relação Estrutura-Atividade , Tiofenos/metabolismo , Tiofenos/farmacocinética , Tiofenos/toxicidade
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