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European journal of pharmaceutical sciences
Elsevier
European journal of pharmaceutical sciences

Elsevier

0928-0987

European journal of pharmaceutical sciences/Journal European journal of pharmaceutical sciencesSCIICCCRISTP
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    The gut microbiota contributes to the modulation of intestinal CYP3A1 and P-gp in streptozotocin-induced type 1 diabetic rats

    Hu, NanLiu, XiangMu, QinfengYu, Miaomei...
    12页
    查看更多>>摘要：Hepatic and intestinal CYP3A and P-gp in diabetic rats exhibit opposite expression patterns. However, the underlying mechanisms remain unclear. In this study, CYP3A1 and P-gp protein and mRNA expression levels in liver and different intestinal segments (duodenum, jejunum, ileum and colon) were compared between diabetic and normal rats. The microbiota in the ileum and colon contents was analyzed via 16S rRNA high-throughput sequencing technology. Caco-2 cells were incubated with serum or culture supernatant of colon contents from diabetic and normal rats, and CYP3A4 and ABCB1 mRNA levels were measured. Compared with that in normal rats, hepatic CYP3A1 and P-gp protein expression in diabetic rats was increased. CYP3A1 and P-gp protein was not changed in the duodenum and jejunum but significantly decreased by 29-41% in the ileum and colon of diabetic rats. Cyp3a1 and Abcb1a mRNA expression results were similar to the protein expression results. The composition of some bacteria changed significantly in the ileum and colon of diabetic rats compared with normal rats. CYP3A1 and P-gp protein expression was positively correlated with Lachnoclostridium and unclassified_f_Ruminococcaceae but negatively correlated with Clostridium_sensu_stricto_1, Turicibacter, Ruminococcaceae_UCG005 and several genera belonging to the family Prevotellaceae. In addition, in vitro cell culture experiments showed that serum from diabetic rats significantly induced CYP3A4 and ABCB1 mRNA expression, while the supernatant of colon contents of diabetic rats significantly reduced CYP3A4 and ABCB1 mRNA expression by 45% and 86% respectively in Caco-2 cells. In conclusion, diabetes exhibited synchronous and regional effects on CYP3A and P-gp expression in the intestinal tract, in which gut microbiota dysbiosis might play an important role.
      原文链接:
    • NSTL
    • Elsevier

    Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review

    Vinarov, ZahariAbdallah, MohammadAgundez, Jose A. G.Allegaert, Karel...
    33页
    查看更多>>摘要：The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age-and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area.
      原文链接:
    • NSTL
    • Elsevier

    1-MT grafted carboxymethyl chitosan and its nanoparticles: Preparation, characterization and evaluation

    Qiu, TongZhang, XueqiongLi, JiamingHan, Lei...
    12页
    查看更多>>摘要：This work aims to synthesize two novel 1-MT (1-Methyl-DL-tryptophan) grafted CMCS (carboxymethyl chitosan) polymer prodrugs CMCS-amido-1-MT and CMCS-ester-1-MT, and to further manufacture their nanoparticles for potential biomedical applications. The polymeric prodrugs are prepared by three-step chemical synthesis. The chemical structure of drugs is confirmed by FTIR and 1H-NMR. The drug loadings of the CMCS-amido-1-MT NPs and CMCS-ester-1-MT NPs are 11.43% and 10.18%, respectively. The surface morphology of the nanoparticles is spherical or nearly spherical, while the surface is smooth and the size distribution is uniform. The average particle size is both about 200 nm, while the polydispersity index is both about 0.15. The nanoparticles have a negative charge on the surface. The particle size and its distribution change little, when the two nanoparticles are tested in the simulated blood pH environment for 7 days. However, only the CMCS-ester-1-MT nanoparticles are pH-sensitive. The cell toxicity of the CMCS-ester-1-MT nanoparticles and the original drug are both in a dose- and time-dependent manner, while the nanoparticles enter cells by endocytosis. In ECA109 cells, the CMCS-ester-1MT nanoparticles and the original drug both induce the apoptosis. CMCS-ester-1-MT NPs can activate the ATF4/ CHOP pathway in endoplasmic reticulum stress, and achieve cancer suppression through mitochondrial-related apoptosis.
      原文链接:
    • NSTL
    • Elsevier

    Nifuroxazide as JAK2 inhibitor: A binding mode proposal and Hel cell proliferation assay

    da Costa, Marcela Oliveira LegramantiPavani, Thais Fernanda AmorimScott, Ana LigiaRamos, Debora Felicia Vieira...
    11页
    查看更多>>摘要：Nifuroxazide has been employed as an anti-diarrheic agent since 1966, but in the last decade has brought to the research spotlight again due to its recently described antitumoral activity through the JAK2 inhibitory potential. Since 2008, more than 70 papers have been published about the issue and more are expected to the following years. Herein we discuss the findings of molecular modelling studies which were performed to elucidate the potential binding mode of this drug into the JAK2 ATP recognition site and also into the allosteric region near the catalytic site. Molecular modelling followed by dynamics simulations indicated the NFZ could bind at both sites, such as a Type II kinase inhibitor since residues from both ATP and modulatory site would exhibit contacts with the drug when in a stable complex. Synthesis of NFZ and its sulfur bioisosteric analogue GPQF-63 were performed and experimental assays against HEL cells indicate the potential of NFZ and, mainly of its analogue GPQF-63 in acting as inhibitors of cell growth. HEL-cells present the JAK2 V617F mutation which leads to an enhanced JAK/STAT pathway and they have never been tested by the NFZ activity before. A mechanistic approach was also performed and revealed that both compounds induce cell apoptosis.Taken together, both the theoretical and experimental approaches point out the N-acylhydrazones as good starting points in the search for JAK2 modulatory small molecules which could then, be studied as promising leads toward new alternatives to control the JAK-STAT pathway related pathologies. This is the first study, as far as we have known, to propose a potential binding mode for NFZ as well as reporting the activity of this drug against HEL cells, which are a usual cellular model to human erythroleukemia and other myeloproliferative diseases.
      原文链接:
    • NSTL
    • Elsevier

    Is Riparin III a promising drug in the treatment for depression

    Vasconcelos Mallmann, Auriana SerraChaves, Raquell de Castrode Oliveira, Natalia FerreiraMaia Oliveira, Iris Cristina...
    10页
    查看更多>>摘要：Stress is crucially related to the pathophysiology of mood disorders, including depression. Since the effectiveness and number of the current pharmacological options still presents significant limitations, research on new substances is paramount. In rodents, several findings have indicated that corticosterone administration induces the manifestation of behavioral and neurochemical aspects of depression. Recently, riparin III has shown antidepressant-like properties in trials performed on animal models. Thus, our goal was to investigate the effects of riparin III on behavioral tests, monoamines levels, oxidative stress and cytokines levels in chronic corticosterone-induced model of depression. To do this, female swiss mice were treated with subcutaneous administration of corticosterone for 22 days. In addition, for the last 10 days, riparin III or fluvoxamine were also administered per os in specific test groups. Control groups received subcutaneous saline injections or distilled water per os. At the end of the timeline, the animals were killed and their hippocampi, prefrontal cortex, and striatum dissected for neurochemical analysis. Brain changes following corticosterone administration were confirmed, and riparin III could reversed the most abnormal behavioral and neurochemical corticosteroneinduced alterations. These results suggest the potential antioxidant, anti-inflammatory and antidepressant effects of riparin III after a chronic stress exposure.
      原文链接:
    • NSTL
    • Elsevier

    Evaluation of the pharmacokinetic effects of itraconazole on alflutinib (AST2818): an open-label, single-center, single-sequence, two-period randomized study in healthy volunteers

    Heng, JianfuTang, QiChen, XueBao, Jingjing...
    8页
    查看更多>>摘要：Alflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor for the treatment of lung cancer patients with T790M-resistant mutations. It is metabolized mainly by the CYP3A4 enzyme. At the same time, it has the potential to induce CYP3A4. In this study, we aimed to estimate the effect of itraconazole (a strong inhibitor of CYP3A4) on the pharmacokinetics of alflutinib. For this aim, a single-center, open-label, single-sequence, two-period trial was designed. The pharmacokinetic parameters of AST2818 and its active metabolite AST5902 were established from blood concentration measurements, and adverse events (AEs) of two periods of treatment were documented. For AST2818, the Cmax, AUC0-t, and AUC0-infinity in period II (coadministration of itraconazole) increased by 6.5 ng/mL, 1263.0 h*ng/mL, and 1067.0 h*ng/mL, respectively. And the corresponding 90% CIs were 1.23 (1.14-1.32), 2.41 (2.29-2.54), and 2.22 (2.11-2.34), respectively. The Cmax, AUC0-t, and AUC0-infinity of AST5902 in period II decreased by 4.849 ng/mL, 415.60 h*ng/mL, and 391.4 h*ng/mL, respectively. Moreover, the corresponding 90% CIs were 0.09 (0.08-0.10), 0.18 (0.17-0.19), and 0.14 (0.13-0.15), respectively. Nonetheless, in period II, plasma concentrations of total active components (AST2818 and AST5902) changed marginally. The AUC0-infinity of total active components increased 60%, and the corresponding Cmax increased 8%. Possible treatment-related AEs assessed by investigators were fewer in period II (23.3% vs 36.7%). In conclusion, the total exposure of AST2818 and active metabolite AST5902 increased following the coadministration of itraconazole, but it was still safe and well-tolerated.
      原文链接:
    • NSTL
    • Elsevier

    Prolonged activity of a recombinant manganese superoxide dismutase through a formulation of polymeric multi-layer nanoassemblies targeting cancer cells

    Russo, GiacomoIaccarino, GiuliaPiccolo, MarialuisaFerraro, Maria Grazia...
    10页
    查看更多>>摘要：A new isoform of human manganese superoxide dismutase (SOD) has been recently isolated and obtained in a synthetic recombinant form and termed rMnSOD. As compared to other SODs, this isoform exhibits a dramatically improved cellular uptake and an intense antioxidant and antitumoral activity. Unfortunately, its use is severely hampered as this active pharmaceutical ingredient (API) in solution suffers from remarkable instability, which realizes as an interplay of unfolding and aggregation phenomena. This leads the API to be ineffective after three weeks only when stored at 4 degrees C.
      原文链接:
    • NSTL
    • Elsevier

    Cross-linked valerolactone copolymer implants with tailorable biodegradation, loading and in vitro release of paclitaxel

    Bufton, JackJung, SungminEvans, James C.Bao, Zeqing...
    13页
    查看更多>>摘要：Implantable drug delivery systems, formed from degradable and non-degradable polymers, can offer several advantages over traditional dosage forms for sustained drug delivery. The majority of degradable implant systems developed to date are composed of poly(lactide-co-glycolide) (PLGA). However, PLGA-based systems are not suitable for the delivery of all drugs. Each drug is unique in terms of physico-chemical properties, and polymer-drug compatibility plays a significant role in determining a drug formulation's performance. In this study, two novel cross-linkable delta-valerolactone-based copolymers were synthesized and used to prepare crosslinked disc-shaped implants. The manipulation of the composition of the discs and conditions used during drug loading were found to influence various aspects of the delivery system performance including the degree of swelling, degradation, drug-loading and in vitro release. The polymeric discs resulted in no adverse effects following subcutaneous implantation in naive rats. These studies support further development of cross-linkable valerolactone matrices as implantable formulations for sustained drug delivery.
      原文链接:
    • NSTL
    • Elsevier

    Targeting breast cancer using pirarubicin-loaded vasoactive intestinal peptide grafted sterically stabilized micelles

    Eskandari, ZahraBahadori, FatemehYapaoz, Melda AltikatogluYenigun, Vildan Betul...
    13页
    查看更多>>摘要：In this study the chemotherapeutic agent Pirarubicin (PRB) which is known for its serious side effects was actively targeted to the breast cancer cells by uploading it to the biocompatible and biodegradable Sterically Stabilized Micelles (SSMs) made of 1,2-Distearoyl-sn-glycero-3 phosphoethanolamine-N-methoxy-polyethylene glycol 2000 (DSPE-PEG(2000)) to enhance efficacy and reduce toxicity. Vasoactive intestinal peptide (VIP), the receptors of which are overexpressed on the breast cancer cells, was grafted on the surface of the micelles. To the best of our knowledge this is the first report on active targeting of PRB to tumor site.
      原文链接:
    • NSTL
    • Elsevier

    Drug solubilization during simulated pediatric gastro-intestinal digestion

    Kofoed-Djursner, CarolineJamil, AliSelen, ArzuMullertz, Anette...
    8页
    查看更多>>摘要：To increase the understanding of how drugs behave following oral administration to the pediatric population, the aim of the present study was to investigate the solubilization of fluconazole and ibuprofen during simulated gastro-intestinal (GI) digestion, using an immediate transfer model mimicking pediatric GI digestion. The effects of infant formula and digestion, on the drug solubilization, were studied using simulated fasted and fed state digestion media in the presence and absence of digestive enzymes. Additionally, the effect of digestion media viscosity on the solubilization process was investigated. It was found that the solubilization of fluconazole was unaffected by all tested parameters, as the entire estimated dose equivalent was solubilized in the aqueous phase throughout all digestion studies. In contrast, the solubilization of ibuprofen was affected by all the tested parameters, i.e. in the fasted state, the solubilization of ibuprofen was limited by its solubility in the aqueous phase of the simulated GI digestion media, whereas the solubilization in the fed state was affected by drug partitioning between the lipid and the aqueous phases, and therefore by the digestion of the lipid phase. Adding Nestle ' Thicken UpTM, containing xanthan gum as a thickening agent, to the digestion medium increased its viscosity, which in turn resulted in a reduced initial digestion rate, increased pH fluctuations, as well as high variability in all drug solubilization data as evident in large standard deviations. Furthermore, the increased digestion medium viscosity decreased the drug recovery from the combined pellet and aqueous phase. The observed viscosity effects might translate into a more variable and lower oral bioavailability.
      原文链接:
    • NSTL
    • Elsevier