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1.
《Journal of pharmaceutical sciences》2023,112(8):2212-2222
For supersaturating formulations of BCS-II compounds, which by definition have high intestinal permeability, a closed USP apparatus does not provide the necessary absorptive conditions during dissolution. To address this, an artificial gut simulator (AGS) has been constructed consisting of a 2.5 mL donor compartment in which a hollow fiber-based absorption module is suspended. Drug from donor diffuses across the hollow fiber membrane to be absorbed by the continuously flowing intraluminal receiver fluid. The membrane surface area and intraluminal fluid flow rate are tuned to obtain the physiologically observed absorption rate constant for a weakly basic, poorly water-soluble model compound, ketoconazole (KTZ). Supersaturated solutions of KTZ were generated in the donor in pH 6.5 phosphate buffer by the pH-shift method in the absence (closed system, control) and presence (open system, biorelevant) of an optimally or suboptimally tuned absorption module. Drug concentrations in the donor and intraluminal fluids were determined by in-line UV spectroscopy. The presence of an absorptive sink reduced the supersaturated solution's crystallization propensity, more so in the case of the optimally tuned AGS. This study demonstrates the significance of simulating absorption of drug at a physiological rate during dissolution studies, especially to predict the performance of formulations of BCS-II drugs. 相似文献
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3.
Qiangsheng He Chongfei Huang Xiwen Qin Yuanyuan Yu Di Tang Junjie Huang Zi Chong Kuo Yuyao Ling Deli Mao Bin Xia Wenjing Li Kuiqing Lu Man Yang Yulong He Wenbo Meng Jinqiu Yuan Yihang Pan 《International journal of cancer. Journal international du cancer》2023,153(5):942-949
Recent epidemiological studies suggested that proton pump inhibitor (PPI) use was associated with an increased risk of biliary tract cancer (BTC), however, confounders were not adequately controlled. Our study aimed to evaluate PPI use and subsequent risk of BTC and its subtypes in three well-established cohorts. We conducted a pooled analysis of the subjects free of cancers in UK Biobank (n = 463 643), Nurses' Health Study (NHS, n = 80 235) and NHS II (n = 95 869). Propensity score weighted Cox models were used to estimate marginal HRs of PPIs use on BTC risk, accounting for potential confounders. We documented 284 BTC cases in UK Biobank (median follow-up: 7.6 years), and 91 cases in NHS and NHS II cohorts (median follow-up: 15.8 years). In UK biobank, PPI users had a 96% higher risk of BTC compared to nonusers in crude model (HR 1.96, 95% CI 1.44-2.66), but the effect was attenuated to null after adjusting for potential confounders (HR 0.95, 95% CI 0.60-1.49). PPI use was not associated with risk of BTC in the pooled analysis of three cohorts (HR 0.93, 95% CI 0.60-1.43). We also observed no associations between PPI use with risk of intrahepatic (HR 1.00, 95% CI 0.49-2.04), extrahepatic bile duct (HR 1.09, 95% CI 0.52-2.27) and gallbladder cancers (HR 0.66, 95% CI 0.26-1.66) in UK Biobank. In summary, regular use of PPIs was not associated with the risk of BTC and its subtypes. 相似文献
4.
Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid of choice for perioperative analgesia. Because deuteration is known to improve the pharmacokinetic, pharmacodynamic and toxicological properties of some drugs, here we characterized the single dose pharmacokinetic properties and post-operative analgesic efficacy of d9-methadone.The pharmacokinetic profiles of d9-methadone and methadone administered intravenously to CD-1 male mice revealed that deuteration leads to a 5.7- and 4.4-fold increase in the area under the time-concentration curve and maximum concentration in plasma, respectively, as well as reduction in clearance (0.9 ± 0.3 L/h/kg vs 4.7 ± 0.8 L/h/kg). The lower brain-to-plasma ratio of d9-methadone compared to that of methadone (0.35 ± 0.12 vs 2.05 ± 0.62) suggested that deuteration decreases the transfer of the drug across the blood-brain barrier. The estimated LD50 value for a single intravenous dose of d9-methadone was 2.1-fold higher than that for methadone. Moreover, d9-methadone outperformed methadone in the efficacy against postoperative pain by primarily activating peripheral opioid receptors. Collectively, these data suggest that the replacement of three hydrogen atoms in three methyl groups of methadone altered its pharmacokinetic properties, improved safety, and enhanced its analgesic efficacy. 相似文献
5.
《Current problems in cardiology》2022,47(9):100902
Genistein, an isoflavone in soybean products has potential cardio-protective effects and is used also as an alternative for estrogen therapy in postmenopausal women. However, results in this regard are inconsistent and also, not all risk factors related to cardiovascular supportive effects have been meta-analyzed. We searched PubMed, Scopus, ISI Web of Science, and Google Scholar from inception up to October 2020. Random-effects meta-analysis was used for data synthesis. The search included studies with information on genistein supplementation and lipid profile [triglycerides (TG), total cholesterol (TC),low-density lipoprotein (LDL-C), and high-density lipoprotein HDL-C)], systolic and diastolic blood pressure (SBP & DBP), body mass index [BMI] and body weight. Pooled results of studies showed that genistein intake significantly reduced TC [95%CI: -0.49(-0.80, -0.18); P=0.002)], LDL-C [95%CI: -0.60(-1.10, -0.10); P=0.018)] and SBP [95%CI: -0.52(-0.90, -0.14); P=0.007)]. DBP, HLD-C, TG, BMI, and body weight showed no meaningful improvement. Subgroup analysis showed that LDL-C and SBP were reduced more effectively in postmenopausal women with metabolic syndrome. Genistein intake more than 6 months showed a greater effect on lowering cholesterol -0.76(-1.27, -0.24), SBP [-0.39(-0.70, -0.08)] and DBP -0.40(-0.81, -0.00) and increasing TG and LDL-C. This meta-analysis provides consistent evidence that genistein intake reduces the CVD risk factors of TC, LDL-C, and SBP significantly. 相似文献
6.
Oxidative stress and inflammation are two possible mechanisms related to nephrotoxicity caused by environmental pollutants. Ellagic acid, a powerful antioxidant phytochemical, may have great relevance in mitigating pollutant-induced nephrotoxicity and preventing the progression of kidney disease. This review discusses the latest findings on the protective effects of ellagic acid, its metabolic derivatives, the urolithins, against kidney toxicity caused by heavy metals, pesticides, mycotoxins, and organic air pollutants. We describe the chelating, antioxidant, anti-inflammatory, antifibrotic, antiautophagic, and antiapoptotic properties of ellagic acid to attenuate nephrotoxicity. Furthermore, we present the molecular targets and signaling pathways that are regulated by these antioxidants, and suggest some others that should be explored. Nevertheless, the number of reports is still limited to establish the efficacy of ellagic acid against kidney damage induced by environmental pollutants. Therefore, additional preclinical studies on this topic are required, as well as the development of well-designed clinical trials. 相似文献
7.
8.
Simultaneous Determination of Six Compounds in Rat Plasma by Ultra‑Performance Liquid Chromatography with Tandem Mass Spectrometry: Application in the Pharmacokinetic Study of Qing Gan‑Shu Yu‑Fang 下载免费PDF全文
Hai Jiang A‑Jiao Hou Yan‑Yan Zhang Wen‑Jing Man Liu Yang Yong‑Hai Meng Xin‑Yue Guo Song Wang Jia‑Xu Zhang Bing‑You Yang Qiu‑Hong Wang Kelvin Chan Hai‑Xue Kuang 《World Journal of Traditional Chinese Medicine》2019,(4)
A rapid and high selective ultra?performance liquid chromatography (UPLC) with tandem mass spectrometry method for simultaneous
determination of six compounds including albiflorin, paeoniflorin, picroside I, picroside II, saikosaponin A, and saikosaponin D in rat plasma
was developed and validated using butyl p-hydroxybenzoate as an internal standard. One-step direct protein precipitation with acetonitrile was
used to extract the compounds from the rat plasma samples. Chromatographic separation was achieved using an ACQUITY UPLC BEH C18
column (100 mm × 2.1 mm, 1.7 µm) at a flow rate of 0.4 mL/min, using gradient mode containing 0.1% formic acid in water and acetonitrile
were used as the Mobile phase A and B. Electrospray ionization in negative ion mode and multiple reaction monitoring were used to identify
and quantify active components. Calibration curves showed good linearity (R2 > 0.9908) over a wide concentration range for all compounds.
The intra- and interday precision (relative standard deviation) ranged 2.4%–7.0% and 2.6%–8.0%, respectively. The accuracy (relative error)
was from ?13.0% to 13.2% at all quality control levels. The recovery ranged from 81.1% to 92.5%. The validated method was successfully
applied to pharmacokinetic study in rats after oral administration of Qing Gan?Shu Yu?Fang. The results show that one can draw a conclusion
that these six active ingredients can be quickly absorbed and play a pharmacodynamic role rapidly in vivo. 相似文献
9.
良性前列腺增生(BPH)是老年男性常见的泌尿系统疾病,其发病与前列腺慢性炎症之间存在显著相关。感染因子、尿液返流、代谢综合征、衰老过程和自身免疫应答在内的几种刺激,通过相应分子途径引起前列腺免疫细胞的组织定位和组成成分发生广泛改变,从而导致免疫系统失调,之后引发的组织损伤和缓慢愈合,导致了BPH发生和进展。本文通过总结良性前列腺增生与前列腺慢性炎症的相关性的临床研究结果,前列腺免疫细胞在病理生理机制层面与前两者之间的内在联系,以及抗炎药物对BPH-LUTS的干预作用,以其为BPH-LUTS的药物研发提供参考。 相似文献
10.
《Biomaterials》2015
The human mutT homologue MTH1, a nucleotide pool sanitizing enzyme, represents a vulnerability factor and an attractive target for anticancer therapy. However, there is currently a lack of selective and effective platforms for the detection and inhibition of MTH1 in cells. Here, we demonstrate for the first time a gold nanoparticle (AuNP) flares-capped mesoporous silica nanoparticle (MSN) nanoplatform that is capable of detecting MTH1 mRNA and simultaneously suppressing MTH1 activity. The AuNP flares are made from AuNPs that are functionalized with a dense shell of MTH1 recognition sequences hybridized to short cyanine (Cy5)-labeled reporter sequences and employed to seal the pores of MSN to prevent the premature MTH1 inhibitors (S-crizotinib) release. Just like the pyrotechnic flares that produce brilliant light when activated, the resulting AuNP flares@MSN (S-crizotinib) undergo a significant burst of red fluorescence enhancement upon MTH1 mRNA binding. This hybridization event subsequently induces the opening of the pores and the release of S-crizotinib in an mRNA-dependent manner, leading to significant cytotoxicity in cancer cells and improved therapeutic response in mouse xenograft models. We anticipate that this nanoplatform may be an important step toward the development of MTH1-targeting theranostics and also be a useful tool for cancer phenotypic lethal anticancer therapy. 相似文献