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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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    Mucolytic self-emulsifying drug delivery systems (SEDDS) containing a hydrophobic ion-pair of proteinase

    Hung Thanh LamNguyet-Minh Nguyen LeThi Nhu Quynh PhanBernkop-Schnuerch, Andreas...
    8页
    查看更多>>摘要：Aim: The aim of this study was to form hydrophobic ion-pairs of proteinase with cationic surfactants and to incorporate them into self-emulsifying drug delivery systems (SEDDS) to improve their mucus permeating properties. Methods: Proteinase was ion-paired with benzalkonium chloride (BAK), hexadecylpyridinium chloride (HDP), alkyltrimethylammonium bromide (ATA) and hexadecyltrimethylammonium bromide (HDT) at pH 8.5-9.0, and subsequently incorporated into SEDDS consisting of Cremophor EL, propylene glycol, and Capmul 808-G (40/ 20/40). Mucus permeation of SEDDS containing proteinase complexes was evaluated via rotating tube technique and cell-free Transwell (R) insert system. Additionally, enzymatic activity of proteinase complexes as well as their potential cytotoxicity was evaluated.
      原文链接:
    • NSTL
    • Elsevier

    Gold(III) complexes with thiosemicarbazonate ligands as potential anticancer agents: Cytotoxicity and interactions with biomolecular targets

    Possato, BrunaDalmolin, Luciana FalccoPereira, Luiz MiguelAlves, Jacqueline Querino...
    11页
    查看更多>>摘要：Gold(III) complexes have been studied for the past years due to their anticancer properties and great affinity to biotargets, such as enzymes and proteins, which support their pharmacological applications. Within this scope, in this work the antiproliferative activities of two Au(III)-thiosemicarbazonate complexes, [AuClL1] (1, L1: (E,Z)-Nethyl-N'-(3-nitroso-kN)butan-2-ylidene)carbamohydrazonothioato-k2N2,S) and [Au(Hdamp)L2]Cl (2, L2: N-(N", N"-diethylaminothiocarbonyl)-N'(N"', N"'-dimethylcarbothioamide)benzamidineto-kN,k2S and Hdamp: 2-(N, N-dimethylaminomethyl)-phenyl-C1), and their affinities to possible biological targets were investigated. Three different tumor cell lines were used to perform the cytotoxicity assays, including one cisplatin-resistant model, and the results showed lower EC50 for 1 over 2 in every case: B16F10 (4.1 mu M and 15.6 mu M), A431 (4.0 mu M and >50 mu M) and OVCAR3 (4.2 mu M and 24.5 mu M). However, a lower toxicity to fibroblast 3T3 cell line was observed for 2 (30.58 mu M) when compared to 1 (7.17 mu M), resulting in comparable therapeutic indexes. Both complexes presented strong affinity to HSA: they distorted the secondary structure of the protein, as verified by circular dichroism, but 1 additionally presented the apparent fluorescence quenching constant (Kapp) ten times greater than 2, which was probably due to the fact of 1 being able to denature HSA. The ethidium bromide displacement assay showed that neither 1 nor 2 are strong DNA intercalators, which is in agreement with what was observed through the UV-vis titration. In both cases, the 260 nm band presented hyperchromism, which can indicate ionic interactions or DNA damage. In fact, 1 was able to damage the pGEM plasmid, similarly to cisplatin, as verified by agarose gel electrophoresis and Atomic Force Microscopy. Biophysical studies in cancer cells model membranes were also performed in order to investigate the interaction of the gold complexes to lipid bilayers and revealed that the compounds interact with the membranes by exhibiting partition coefficients of 103 order of magnitude. Overall, both complexes were found to be promising candidates for the development of a future anticancer drug against low sensitive or cisplatin resistant tumors.
      原文链接:
    • NSTL
    • Elsevier

    Discovery of HIV entry inhibitors via a hybrid CXCR4 and CCR5 receptor pharmacophore-based virtual screening approach (vol 155, 105537, 2020)

    Saadabadi, AtefehVanmeert, MichielSalo-Ahen, Outi M. H.Abdullah, Iskandar...
    1页
      原文链接:
    • NSTL
    • Elsevier

    Formulation and design optimization of nano-transferosomes using pioglitazone and eprosartan mesylate for concomitant therapy against diabetes and hypertension

    Ramkanth, S.Anitha, P.Gayathri, R.Mohan, S....
    11页
    查看更多>>摘要：Hypertension, a form of cardiovascular diseases, is considered a major risk factor associated with deaths in type 2 diabetes patients. The current medication systems for treating such chronic coexisting diseases are limited and challenging due to the difficulties in overcoming the side effects from complex therapeutic and treatment regimen. The objective of the present study is to design and optimize pioglitazone (PIO) and eprosartan mesylate (EM)-loaded nano-transferosomes (NTs) using Design-Expert software, aiming its transdermal delivery as a novel combination therapy for concomitant treatment of hypertensive diabetic patients. The developed formulations were characterized for various parameters, including in-vitro skin permeation, skin irritation, in-vivo antidiabetic, and antihypertensive activities. NTs were prepared using PIO and EM as the two model drugs and optimized using Box-Behnken design by considering phospholipid (X1), surfactant (X2), ratio of solvents (X3), and sonication time (X4), as independent variables, each at three levels. Entrapment efficiency (Y1 and Y2) and flux (Y3 and Y4) of PIO and EM, respectively, were selected as dependent variables. Among all the prepared formulations, one optimized formulation was chosen by the point prediction method and evaluated for drug-polymer compatibility, particle size, and surface charge analysis, followed by skin permeation and pharmacodynamic studies. The optimized nano-transferosomal gel (ONTF) showed all responses which confirm with the values predicted by the design. Pharmacodynamic studies showed improved and prolonged management of diabetes and hypertension in Wistar rats after the ONTF was applied, compared to oral and drug-loaded NT formulations. Results of the current study suggest that the development of such combinational delivery system can result in a rational therapeutic regimen for effective treatment of concomitant disease conditions of diabetic hypertensive patients.
      原文链接:
    • NSTL
    • Elsevier

    Comparisons of basic target-mediated drug disposition (TMDD) and ligand facilitated target removal (LFTR)

    Jansson-Lofmark, RasmusGabrielsson, JohanPeletier, Lambertus A.
    11页
    查看更多>>摘要：In the well-known model for basic Target-Mediated Drug Disposition (TMDD), drug binds to the target and the resulting drug-target complex is removed by a first order process, leading to loss of both drug and target. In the present note we study what happens when, instead, drug is returned to the free drug pool so that it can a new target molecule. What results is a mechanism in which the drug, here referred to as the ligand, facilitates the removal of the target,and then returns to the free ligand pool. Accordingly the process will be referred to as Ligand-Facilitated Target Removal (LFTR). It is shown through simulations and mathematical analysis how the two models differ and how their signature profiles typically appear. We also derive a useful parameter of both models, the in vivo potency EC50 (L50) which contains both ligand-target binding properties (kon, koff), target turnover (kdeg) and ligand-target complex kinetics (ke(RL)). Thus, this parameter contains a conglomerate of properties and is therefore potentially more informative about relevant (clinical) exposure than the binding affinity (Kd) alone. The derived potency parameter EC50 may therefore be used as a more robust ranking parameter among small and large drug molecules in drug discovery. Subsequently the LFTR model is applied to experimentally obtained literature data and the relevant parameters are estimated.
      原文链接:
    • NSTL
    • Elsevier

    Activation of benzoate model prodrugs by mycobacteria. Comparison with mammalian plasma and liver hydrolysis

    Valente, EmiliaTesta, BernardConstantino, Luis
    8页
    查看更多>>摘要：Due to difficulties in drug penetration in M. tuberculosis, a prodrug approach based on mycobacterial activation appears as a promising strategy to increase the delivery of antitubercular drugs to the target microorganisms. Esters have been successful used by us and others to deliver drugs to mycobacteria, however because very little is known about the metabolic hydrolysis of esters by mycobacteria in connection with prodrug activation, we decided to study the process further. For that we selected a series of 13 benzoates with different chain lengths and ramifications in the alkoxy side as model prodrugs and examined their hydrolysis by a mycobacterial homogenate, comparing the results with those obtained parallelly in human plasma and in total rat liver homogenate. In all biological media, the benzoates with a linear alkyl group showed a parabolic dependence between log(k) and logP (or the number of carbons of the linear alkyl chain) that reached a maximal value for the n-butyl chain. Considering linear correlations for the total number of compounds between log(k) and chosen descriptors, for mycobacterial esterases, pKa of the leaving alcohol (pKa(LG)) seem to be the most important descriptor. Plasma esterases seem to be quite sensitive to the Taft polarity parameter sigma* and also to pKa(LG) and less sensitive to steric effects. Liver esterases seem to be more sensitive to the Taft steric descriptor E-S(c). Lipophilicity correlates weakly with log (k) in all the 3 media, however, is more important when one looks for mycobacterial activation selectivity in relation to plasma metabolism or in relation to liver homogenate metabolism. The importance of lipophilicity increases further when biparametric expressions are considered. We showed that it is easy to activate a wide variety of benzoate esters using a mycobacterial homogenate. The data also suggest that with careful design is possible to obtain tuberculostatic prodrug esters sensitive to mycobacterial hydrolases while reasonably resistant to plasma and liver hydrolysis. One important observation is that mycobacterial hydrolysis is less affected by bulky substituents than liver homogenate or plasma hydrolysis. tert-Butyl is probably the substituent in the alkoxy side that seems more adequate to resist simultaneously plasma and liver metabolism, while allowing activation by mycobacterial esterases. Hexyl is also a good option for the medicinal chemist if a linear alkoxy chain is needed.
      原文链接:
    • NSTL
    • Elsevier

    Development of polyoxyethylene (2) oleyl ether-gliadin nanoparticles: Characterization and in vitro cytotoxicity

    Voci, SilviaGagliardi, AgneseSalvatici, Maria CristinaFresta, Massimo...
    12页
    查看更多>>摘要：Natural polymers have been widely investigated as materials for the delivery of active compounds as a consequence of their biocompatibility, low-cost and the opportunity they furnish to obtain micro- and nanostructures. In this investigation, commercial wheat gliadin was used as raw material with the aim of obtaining a vegetal protein-based nanoformulation to be used for various applications. The influence of non-ionic and anionic surfactants on the physico-chemical properties of gliadin nanoparticles was evaluated in order to propose a suitable candidate able to stabilize the colloidal structure. The use of Super Refined polyoxyethylene (2) oleyl ether gave the best results, promoting the formation of spherical-shaped nanosystems with a narrow size distribution. The oleyl ether-based emulsifier prevented the destabilization of the colloidal systems when pH- and temperaturedependent stress was applied. A freeze-dried formulation was obtained when mannose was used as a cryoprotectant. Polyoxyethylene (2) oleyl ether-stabilized nanosystems were shown to retain and release both hydrophilic and lipophilic model compounds in a controlled manner. The cytotoxicity of the surfactant-free and polyoxyethylene (2) oleyl ether-stabilized gliadin based nanosystems was assessed on human cells, both normal and tumoural, in order to investigate the concentrations of particles that can be used during in vitro experiments. Polyoxyethylene (2) oleyl ether-stabilized gliadin-based nanosystems are promising carriers for the delivery of several active compounds.
      原文链接:
    • NSTL
    • Elsevier

    Role of organic anion transporter 3 in the renal excretion of biapenem and potential drug-drug interactions

    Li, WenyanJiao, ZhengLiu, YanhuiYao, Jiacheng...
    9页
    查看更多>>摘要：Biapenem is a carbapenem antibiotic. It is excreted predominantly through the kidney as unchanged forms. However, the molecular mechanism of renal excretion of biapenem and potential drug-drug interactions (DDIs) were still unknown. In the present study, the role of organic anion transporters (OAT) 1/3 and organic cation transporters (OCT) 2 in the renal excretion of biapenem, and the potential DDIs between biapenem and six clinical commonly prescribed antibiotics and antiviral drugs that acted as substrates or inhibitors of OAT3 were evaluated in vitro. Further, the effect of probenecid on the pharmacokinetics of biapenem was explored in the rats. We observed that biapenem could not inhibit the transport activities of OAT1 or OCT2, while mildly inhibited OAT3 (IC50 >500 mu M). Among the tested antibiotics and antiviral drugs, the relatively high DDI index values (maximal unbound plasma concentration over IC50, Imax,u/IC50) were found for piperacillin, linezolid and benzylpenicillin, which were 2.84, 1.7 and 0.62, respectively. Although probenecid had the highest DDI index (27.1) in vitro, no significant impact of it on the pharmacokinetics of biapenem was observed in the rats. Our results indicated that biapenem was primarily eliminated by the glomerular filtration, while OAT3-mediated renal tubular secretion was a minor route. Biapenem is not a clinically relevant substrate or inhibitor because of its low affinity to OAT3. According to current results, it would be safe to use biapenem with other antibiotics and antiviral drugs that acted as substrates or inhibitors of OAT3.
      原文链接:
    • NSTL
    • Elsevier

    An automated cocktail method for in vitro assessment of direct and time-dependent inhibition of nine major cytochrome P450 enzymes-application to establishing CYP2C8 inhibitor selectivity

    Backman, Janne T.Kahma, HelinaAurinsalo, LauraNeuvonen, Mikko...
    14页
    查看更多>>摘要：We developed an in vitro high-throughput cocktail assay with nine major drug-metabolizing CYP enzymes, optimized for screening of time-dependent inhibition. The method was applied to determine the selectivity of the time-dependent CYP2C8 inhibitors gemfibrozil 1-O-beta-glucuronide and clopidogrel acyl-beta-D-glucuronide. In vitro incubations with CYP selective probe substrates and pooled human liver microsomes were conducted in 96-well plates with automated liquid handler techniques and metabolite concentrations were measured with quantitative UHPLC-MS/MS analysis. After determination of inter-substrate interactions and Km values for each reaction, probe substrates were divided into cocktails I (tacrine/CYP1A2, bupropion/CYP2B6, amodiaquine/CYP2C8, tolbutamide/CYP2C9 and midazolam/CYP3A4/5) and II (coumarin/CYP2A6, S-mephenytoin/CYP2C19, dextromethorphan/CYP2D6 and astemizole/CYP2J2). Time-dependent inhibitors (furafylline/CYP1A2, selegiline/ CYP2A6, clopidogrel/CYP2B6, gemfibrozil 1-O-beta-glucuronide/CYP2C8, tienilic acid/CYP2C9, ticlopidine/ CYP2C19, paroxetine/CYP2D6 and ritonavir/CYP3A) and direct inhibitor (terfenadine/CYP2J2) showed similar inhibition with single substrate and cocktail methods. Established time-dependent inhibitors caused IC50 fold shifts ranging from 2.2 to 30 with the cocktail method. Under time-dependent inhibition conditions, gemfibrozil 1-O-beta-glucuronide was a strong (90% inhibition) and selective (<< 20% inhibition of other CYPs) inhibitor of CYP2C8 at concentrations ranging from 60 to 300 mu M, while the selectivity of clopidogrel acyl-beta-D-glucuronide was limited at concentrations above its IC80 for CYP2C8. The time-dependent IC50 values of these glucuronides for CYP2C8 were 8.1 and 38 mu M, respectively. In conclusion, a reliable cocktail method including the nine most important drug-metabolizing CYP enzymes was developed, optimized and validated for detecting timedependent inhibition. Moreover, gemfibrozil 1-O-beta-glucuronide was established as a selective inhibitor of CYP2C8 for use as a diagnostic inhibitor in in vitro studies.
      原文链接:
    • NSTL
    • Elsevier

    Effect of surfactant on the in vitro dissolution and the oral bioavailability of a weakly basic drug from an amorphous solid dispersion

    Nguyen-Thach TungCao-Son TranTran-Linh NguyenThi-Minh-Hue Pham...
    9页
    查看更多>>摘要：This study aimed to investigate the effect of a surfactant on the liquid-liquid phase separation, dissolution, diffusion, and the oral bioavailability of a weakly basic drug (l-tetrahydropalmatine; l-THP) from an amorphous solid dispersion (ASD). The carrier used in the ASD was optimized by the application of casting film, solvent shift, and pH shift methods. The interaction between the optimized carrier (HPMCP) and l-THP was then evaluated by Fourier transform-infrared spectroscopy and powder X-ray diffraction. The impact of the surfactant on ASD prepared by the spray-drying method was evaluated by both in vitro and in vivo studies. The results of in vitro studies, including liquid-liquid phase separation, drug diffusion, and pH-shift dissolution, indicated that the addition of a surfactant at a certain concentration below critical micelle concentration to ASD caused the precipitation of and a reduction in the membrane diffusion of l-THP in pH 6.8. This observation was confirmed in an in vivo study in which the drug concentration of l-THP in rabbit plasma was determined by the LC-MS/MS analysis method. Then the absolute and relative bioavailability of l-THP was calculated from the obtained pharmacokinetic parameters. Specifically, the addition of 1.5% surfactant (Poloxamer 188) to the binary ASD decreased the relative bioavailability of l-THP by approximately 2.4 times compared with the original binary ASD. Besides, the study proved that l-THP had low absolute bioavailability (around 1.24%), and the application of binary ASD was meaningful in enhancing the oral bioavailability of l-THP by around 334.77% compared to the raw material. The study is expected to provide a better understanding of how different dosage forms influence the bioavailability of l-THP, thereby allowing the selection of the optimal approach for this weakly basic drug.
      原文链接:
    • NSTL
    • Elsevier