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Medicine Nov 2023We compared the efficacy and safety of low-intensity atorvastatin and ezetimibe combination therapy with moderate-intensity atorvastatin monotherapy in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
Effectiveness of low-intensity atorvastatin 5 mg and ezetimibe 10 mg combination therapy compared with moderate-intensity atorvastatin 10 mg monotherapy: A randomized, double-blinded, multi-center, phase III study.
BACKGROUND
We compared the efficacy and safety of low-intensity atorvastatin and ezetimibe combination therapy with moderate-intensity atorvastatin monotherapy in patients requiring cholesterol-lowering therapy.
METHODS
At 19 centers in Korea, 290 patients were randomized to 4 groups: atorvastatin 5 mg and ezetimibe 10 mg (A5E), ezetimibe 10 mg (E), atorvastatin 5 mg (A5), and atorvastatin 10 mg (A10). Clinical and laboratory examinations were performed at baseline, and at 4-week and 8-week follow-ups. The primary endpoint was percentage change from baseline in low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up. Secondary endpoints included percentage changes from baseline in additional lipid parameters.
RESULTS
Baseline characteristics were similar among the study groups. At the 8-week follow-up, percentage changes in LDL cholesterol levels were significantly greater in the A5E group (49.2%) than in the E (18.7%), A5 (27.9%), and A10 (36.4%) groups. Similar findings were observed regarding the percentage changes in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B levels. Triglyceride levels were also significantly decreased in the A5E group than in the E group, whereas high-density lipoprotein levels substantially increased in the A5E group than in the E group. In patients with low- and intermediate-cardiovascular risk, 93.3% achieved the target LDL cholesterol levels in the A5E group, 40.0% in the E group, 66.7% in the A5 group, and 92.9% in the A10 group. In addition, 31.4% of patients in the A5E group, 8.1% in E, 9.7% in A5, and 7.3% in the A10 group reached the target levels of both LDL cholesterol < 70 mg/dL and reduction of LDL ≥ 50% from baseline.
CONCLUSIONS
The addition of ezetimibe to low-intensity atorvastatin had a greater effect on lowering LDL cholesterol than moderate-intensity atorvastatin alone, offering an effective treatment option for cholesterol management, especially in patients with low and intermediate risks.
Topics: Humans; Atorvastatin; Anticholesteremic Agents; Cholesterol, LDL; Hypercholesterolemia; Azetidines; Heptanoic Acids; Pyrroles; Drug Therapy, Combination; Ezetimibe; Cholesterol; Treatment Outcome; Double-Blind Method; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 38013289
DOI: 10.1097/MD.0000000000036122 -
Cancer Biotherapy & Radiopharmaceuticals Aug 2018Recently, the direct intratumoral (i.t.) injection of anticancer agents has been investigated. A newly synthesized Antineoplaston A10 analog...
Improved Targeting and Tumor Retention of a Newly Synthesized Antineoplaston A10 Derivative by Intratumoral Administration: Molecular Docking, Technetium 99m Radiolabeling, and In Vivo Biodistribution Studies.
BACKGROUND
Recently, the direct intratumoral (i.t.) injection of anticancer agents has been investigated. A newly synthesized Antineoplaston A10 analog 3-(4-methoxybenzoylamino)-2,6-piperidinedione (MPD) showed an antitumor activity in human breast cancer cell line. Unfortunately, MPD suffered from poor water solubility.
MATERIALS AND METHODS
Pseudoternary phase diagram of oil (isopropyl myristate), surfactant (Tween 80), cosurfactant (ethanol), and water was plotted. MPD microemulsion (MPDME) was developed and characterized for particle size (PS), polydispersity index (PDI), zeta potential (ZP), and morphology (transmission electron microscopy). MPDME and MPD solution (MPDS) were radiolabeled with technetium 99m (Tc) using stannous chloride dihydrate (SnCl.2HO). Molecular docking of MPD and Tc-MPD was performed to study the interaction with DNA.
RESULTS
The impacts of intravenous (i.v.) and i.t. injections of Tc-MPDME and Tc-MPDS on biodistribution were studied. The developed MPDME showed spherical droplets with mean PS (74.00 ± 5.69 nm), PDI (0.25 ± 0.03), and ZP (33.90 ± 0.90 mV). Labeling yield of Tc-MPDME and Tc-MPDS was 97.00% ± 0.60% and 92.02% ± 0.45%, respectively. MPD and Tc-MPD showed almost same binding affinity with DNA binding site. Biodistribution results showed that i.t. injection of Tc-MPDME significantly enhanced tumor retention compared to i.v. route.
CONCLUSIONS
Herein, the authors concluded that microemulsion could be used as i.t. injectable delivery vehicle to improve targeting and tumor retention of MPD.
Topics: Animals; Antineoplastic Agents; Benzeneacetamides; Breast Neoplasms; Cell Line, Tumor; Drug Delivery Systems; Drug Screening Assays, Antitumor; Emulsions; Female; Humans; Injections, Intralesional; Injections, Intravenous; Mice; Molecular Docking Simulation; Particle Size; Piperidones; Technetium; Tissue Distribution; Xenograft Model Antitumor Assays
PubMed: 29894210
DOI: 10.1089/cbr.2017.2431 -
Journal of Clinical Virology : the... Sep 2023Coxsackievirus A10 (CA10) is one of the etiological agents associated with hand, foot and mouth disease (HFMD).
BACKGROUND
Coxsackievirus A10 (CA10) is one of the etiological agents associated with hand, foot and mouth disease (HFMD).
OBJECTIVES
We aimed to perform a retrospective analysis of the molecular epidemiological characteristics and genetic features of HFMD associated with CA10 infections in Zhejiang Province from 2017 to 2022.
STUDY DESIGN
Epidemiologic features were summarized. Throat swab specimens were collected and tested. The VP1 regions were sequenced for genotyping. CA10 positive samples were isolated. Whole genomes of CA10 isolations were sequenced. Nucleotide and amino acid changes were characterized. Phylogenetic trees were constructed.
RESULTS
The number of HFMD cases fluctuated from 2017 to 2022. Children aged below 3 years accounted for the majority (66.29%) and boys were more frequently affected than girls. Cases peaked in June. The positivity rate of HEV was 62.69%. A total of 90 strains of CA10 were isolated and 53 genomes were obtained. All CA10 in this study could be assigned to two genogroups, C (C2) and F (F1 and F3).
CONCLUSION
The clinical manifestations of HFMD associated with HEV are complex and diverse. CA10 infection may be emerging as a new and major cause of HFMD because an upward trend was observed in the proportion of CA10 cases after the use of EV71 vaccines. Different genogroups of CA10 had different geographic distribution patterns. Surveillance should be strengthened and further comprehensive studies should be continued to provide a scientific basis for HFMD prevention and control.
Topics: Child; Male; Female; Humans; Infant; Hand, Foot and Mouth Disease; Phylogeny; Retrospective Studies; China; Genomics; Enterovirus; Enterovirus A, Human
PubMed: 37523938
DOI: 10.1016/j.jcv.2023.105552 -
Virologica Sinica Aug 2022Coxsackievirus A10 (CV-A10) is one of the etiological agents associated with hand, foot and mouth disease (HFMD) and also causes a variety of illnesses in humans,...
Coxsackievirus A10 (CV-A10) is one of the etiological agents associated with hand, foot and mouth disease (HFMD) and also causes a variety of illnesses in humans, including pneumonia, and myocarditis. Different people, particularly young children, may have different immunological responses to infection. Current CV-A10 infection animal models provide only a rudimentary understanding of the pathogenesis and effects of this virus. The characteristics of CV-A10 infection, replication, and shedding in humans remain unknown. In this study, rhesus macaques were infected by CV-A10 via respiratory or digestive route to mimic the HFMD in humans. The clinical symptoms, viral shedding, inflammatory response and pathologic changes were investigated in acute infection (1-11 day post infection) and recovery period (12-180 day post infection). All infected rhesus macaques during acute infection showed obvious viremia and clinical symptoms which were comparable to those observed in humans. Substantial inflammatory pathological damages were observed in multi-organs, including the lung, heart, liver, and kidney. During the acute period, all rhesus macaques displayed clinical signs, viral shedding, normalization of serum cytokines, and increased serum neutralizing antibodies, whereas inflammatory factors caused some animals to develop severe hyperglycemia during the recovery period. In addition, there were no significant differences between respiratory and digestive tract infected animals. Overall, all data presented suggest that the rhesus macaques provide the first non-human primate animal model for investigating CV-A10 pathophysiology and assessing the development of potential human therapies.
Topics: Animals; Antibodies, Neutralizing; Benzeneacetamides; Child, Preschool; Enterovirus A, Human; Hand, Foot and Mouth Disease; Humans; Macaca mulatta; Piperidones
PubMed: 35777657
DOI: 10.1016/j.virs.2022.06.007 -
International Journal of Pharmaceutics Jul 2018A10, (3-phenylacetylamino-2,6-piperidinedione), is a natural peptide with broad antineoplastic activity. Recently, in vitro antitumor effect of a new A10 analog...
Design and development of microemulsion systems of a new antineoplaston A10 analog for enhanced intravenous antitumor activity: In vitro characterization, molecular docking, I-radiolabeling and in vivo biodistribution studies.
A10, (3-phenylacetylamino-2,6-piperidinedione), is a natural peptide with broad antineoplastic activity. Recently, in vitro antitumor effect of a new A10 analog [3-(4-methoxybenzoylamino)-2,6-piperidinedione] (MPD) has been verified. However, poor aqueous solubility represents an obstacle towards intravenous formulation of MPD and impedes successful in vivo antitumor activity. To surmount such limitation, MPD microemulsion (MPDME) was developed. A 32 full factorial design using Design-Expert® software was adopted to study the influence of different parameters and select the optimum formulation (MPDME1). Transmission electron microscopy (TEM) displayed spherical droplets of MPDME1. The cytotoxicity of MPDME1 in Michigan Cancer Foundation 7 (MCF-7) breast cancer cell line exceeded that of MPD solution (MPDS) and tamoxifen. Compatibility with injectable diluents, in vitro hemolytic studies and in vivo histopathological examination confirmed the safety of parenteral application of MPDME1. Molecular docking results showed almost same binding affinity of A10, MPD and I-MPD with histone deacetylase 8 (HDAC8) receptor. Accordingly, radioiodination of MPDME1 and MPDS was done via direct electrophilic substitution reaction. Biodistribution of I-MPDME1 and I-MPDS in normal and tumor (ascites and solid) bearing mice showed high accumulation of I-MPDME1 in tumor tissues. Overall, the results proved that MPDME represents promising parenteral delivery system capable of improving antineoplastic activity of MPD.
Topics: Animals; Antineoplastic Agents; Benzeneacetamides; Breast Neoplasms; Carcinoma, Ehrlich Tumor; Drug Compounding; Emulsions; Ethanol; Female; Histone Deacetylases; Humans; Injections, Intravenous; Iodine Radioisotopes; MCF-7 Cells; Male; Microscopy, Electron, Transmission; Molecular Docking Simulation; Piperidones; Polysorbates; Rabbits; Repressor Proteins; Technology, Pharmaceutical; Tissue Distribution
PubMed: 29733973
DOI: 10.1016/j.ijpharm.2018.05.010 -
Virology Journal Jul 2022Coxsackievirus A10 (CV-A10), the causative agent of hand, foot, and mouth disease (HFMD), caused a series of outbreaks in recent years and often leads to neurological...
Coxsackievirus A10 (CV-A10), the causative agent of hand, foot, and mouth disease (HFMD), caused a series of outbreaks in recent years and often leads to neurological impairment, but a clear understanding of the disease pathogenesis and host response remains elusive. Cellular microRNAs (miRNAs), a large family of non-coding RNA molecules, have been reported to be key regulators in viral pathogenesis and virus-host interactions. However, the role of host cellular miRNAs defensing against CV-A10 infection is still obscure. To address this issue, we systematically analyzed miRNA expression profiles in CV-A10-infected 16HBE cells by high-throughput sequencing methods in this study. It allowed us to successfully identify 312 and 278 miRNAs with differential expression at 12 h and 24 h post-CV-A10 infection, respectively. Among these, 4 miRNAs and their target genes were analyzed by RT-qPCR, which confirmed the sequencing data. Gene target prediction and enrichment analysis revealed that the predicted targets of these miRNAs were significantly enriched in numerous cellular processes, especially in regulation of basic physical process, host immune response and neurological impairment. And the integrated network was built to further indicate the regulatory roles of miRNAs in host-CV-A10 interactions. Consequently, our findings could provide a beneficial basis for further studies on the regulatory roles of miRNAs relevant to the host immune responses and neuropathogenesis caused by CV-A10 infection.
Topics: Benzeneacetamides; Enterovirus A, Human; Epithelial Cells; Hand, Foot and Mouth Disease; Humans; MicroRNAs; Piperidones
PubMed: 35864512
DOI: 10.1186/s12985-022-01852-9 -
PeerJ 2023PFI-3 is a small-molecule inhibitor that targets the bromodomains (BRDs) of Brahma-related gene 1 (BRG1). This monomeric compound, which has high selectivity and potent...
BACKGROUND
PFI-3 is a small-molecule inhibitor that targets the bromodomains (BRDs) of Brahma-related gene 1 (BRG1). This monomeric compound, which has high selectivity and potent cellular effects, has recently been developed. Although PFI-3 has been reported as a potential therapeutic agent targeting thrombomodulin, its role in the regulation of vascular function remains unknown. Therefore, we aimed to investigate the impact of PFI-3 on arterial vessel tone.
METHODS
A microvascular tension measurement device (DMT) was utilized to identify alterations in vascular tension within the mesenteric artery. To detect variations in cytosolic [Ca], a Fluo-3/AM fluorescent probe and fluorescence microscope were employed. Additionally, whole-cell patch clamp techniques were utilized to evaluate the activity of L-type voltage-dependent calcium channels (VDCCs) in cultured arterial smooth muscle cells (A10 cells).
RESULTS
PFI-3 exerted a dose-dependent relaxation effect on rat mesenteric arteries with both intact and denuded endothelium after phenylephrine (PE)- and high-K-induced constriction. PFI-3-induced vasorelaxation was not affected by the presence of L-NAME/ODQ or K channel blockers (Gli/TEA). PFI-3 abolished Ca-induced contraction on endothelium-denuded mesenteric arteries preincubated by PE in Ca-free solution. Incubation with TG had no impact on PFI-3-induced vasorelaxation pre-contracted by PE. PFI-3 reduced Ca-induced contraction on endothelium-denuded mesenteric arteries pre-incubated by KCl (60 mM) in Ca-free solution. PFI-3 declined extracellular calcium influx in A10 cells detected by Fluo-3/AM fluorescent probe and fluorescence microscope. Furthermore, we observed that PFI-3 decreased the current densities of L-type VDCC by whole-cell patch clamp techniques.
CONCLUSIONS
PFI-3 blunted PE and high K-induced vasoconstriction independent of endothelium on rat mesenteric artery. The vasodilatory effect of PFI-3 may be attributed to its inhibition of VDCCs and receptor-operated calcium channels (ROCCs) on vascular smooth muscle cells (VSMCs).
Topics: Animals; Rats; Calcium; Calcium Channels, L-Type; Fluorescent Dyes; Mesenteric Arteries
PubMed: 37250720
DOI: 10.7717/peerj.15407 -
International Journal of Molecular... Jun 2023Naringenin is a 5,7,4'-trihydroxyflavanone naturally occurring mainly in citrus fruits, characterized by a wide spectrum of biological activity. Chemical modifications...
Naringenin is a 5,7,4'-trihydroxyflavanone naturally occurring mainly in citrus fruits, characterized by a wide spectrum of biological activity. Chemical modifications based on alkylation and oximation in most cases increase its bioactivity. The aim of our research was to evaluate the antiproliferative activity and influence on selected representatives of the human gut microbiota of new synthesized -alkyl derivatives (-) and their oximes (-), which contain hexyl, heptyl, octyl, nonyl and undecyl chains attached to the C-7 or to both the C-7 and C-4' positions in naringenin. To the best of our knowledge, compounds , , , - and - have not been described in the scientific literature previously. The anticancer activity was tested on human colon cancer cell line HT-29 and mouse embryo fibroblasts 3T3-L1 using the sulforhodamine B (SRB) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays. We also determined the impacts of all compounds on the growth of Gram-positive and Gram-negative bacterial strains, such as , and . The antimicrobial activity was expressed in terms of minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) values. For 7,4'-di--hexylnaringenin (), 7--undecylnaringenin () and their oximes (, ), which were safe for microbiota (MIC > 512 µg/mL) and almost all characterized by high cytotoxicity against the HT-29 cell line (: IC > 100 µg/mL; : IC = 17.85 ± 0.65 µg/mL; : IC = 49.76 ± 1.63 µg/mL; : IC = 11.42 ± 1.17 µg/mL), apoptosis assays were performed to elucidate their mechanisms of action. Based on our results, new compound induced an apoptotic process via caspase 3/7 activation, which proved its potential as an anticancer agent.
Topics: Animals; Mice; Humans; Oximes; Gastrointestinal Microbiome; Cell Proliferation; Microbial Sensitivity Tests; Anti-Bacterial Agents
PubMed: 37373004
DOI: 10.3390/ijms24129856 -
Bioorganic Chemistry Jan 2023Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), three series of novel 1,3,5-triazine or pyrimidine derivatives...
Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), design, synthesis and biological evaluation of novel PI3Kα selective inhibitors.
Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), three series of novel 1,3,5-triazine or pyrimidine derivatives containing semicarbazones have been designed and synthesized to obtain new potent and selective PI3Kα inhibitors. Their inhibitory activities in vitro were evaluated against PI3Kα and three tumor-derived cell lines (U87-MG, MCF-7, and PC-3). We also tested promising compounds (A4, A6, A10, and B1) for other PI3K class I subtype (PI3Kβ, PI3Kδ, and PI3Kγ) activity. The representative compound A10 exhibited an IC value of 0.32 nM against PI3Kα, and demonstrated extraordinary subtype selectivity. Furthermore, compound A10 obviously inhibited proliferation of MCF-7 cell lines, induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells, and arrested G2 phase in a dose-dependent manner. Additionally, compound A10 induced significant tumor regressions in a xenograft mouse model of U87-MG cell line without an obvious sign of toxicity upon 20 mg/kg oral administration. Compound A10 may serve as a PI3Kα-selective inhibitor and provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family.
Topics: Humans; Mice; Animals; Phosphoinositide-3 Kinase Inhibitors; Structure-Activity Relationship; Cell Proliferation; Antineoplastic Agents; Triazines; Cell Line, Tumor; Benzimidazoles; Drug Design; Drug Screening Assays, Antitumor
PubMed: 36343598
DOI: 10.1016/j.bioorg.2022.106211 -
Plant Disease Sep 2022
Topics: Benzeneacetamides; Biological Control Agents; Oomycetes; Piperidones; Streptomyces
PubMed: 35895328
DOI: 10.1094/PDIS-11-21-2561-A